Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: DLD is a mitochondrial matrix protein; the phylogenetic (IBA) mitochondrion annotation is correct and consistent with the mitochondrial transit peptide (residues 1-35) and abundant experimental localization data. Reason: Well-supported by an N-terminal mitochondrial targeting sequence and multiple experimental localization studies. Broad but accurate; the more specific mitochondrial matrix term captures the same information at finer granularity.
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the core, defining molecular function of DLD/E3 (EC 1.8.1.4). The phylogenetic annotation matches abundant human experimental evidence and the UniProt catalytic-activity annotation (dihydrolipoyl-lysyl-protein + NAD+ = lipoyl-lysyl-protein + NADH + H+; RHEA:15045). Reason: DLD catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains of E2/H components with NAD+ as the ultimate electron acceptor. Directly supported by enzymatic assays and structural work; this is the most specific correct MF term.
GO:0006103 2-oxoglutarate metabolic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: As the shared E3 component of the 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase complex, DLD participates in 2-oxoglutarate metabolism within the TCA cycle. The phylogenetic annotation is biologically correct. Reason: Accurate but general; DLD's involvement is via its shared dehydrogenase activity in the OGDH complex rather than a 2-oxoglutarate-specific function. The more specific process term 2-oxoglutarate decarboxylation to succinyl-CoA (GO:0120551) better captures the pathway step.
GO:0045252 oxoglutarate dehydrogenase complex	IBA GO_REF:0000033	ACCEPT	Summary: DLD is the E3 subunit of the 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase complex, composed of OGDH (E1), DLST (E2) and DLD (E3). Membership is well established and independently supported by experimental (IDA) and NAS annotations. Reason: Genuine complex membership; DLD physically associates with OGDH and DLST as the shared E3 component.
GO:0050660 flavin adenine dinucleotide binding	IBA GO_REF:0000033	ACCEPT	Summary: DLD is a flavoprotein that binds one FAD per subunit; FAD is the redox cofactor that mediates electron transfer from the dihydrolipoyl group to NAD+. The phylogenetic annotation is correct and matches the UniProt COFACTOR annotation. Reason: FAD binding is an essential, experimentally established cofactor-binding function integral to the dehydrogenase mechanism. Supporting Evidence: PMID:8506365 These mutations appear to be significant in that they alter the active site and possibly the binding of FAD.
GO:0001669 acrosomal vesicle	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: Electronic annotation derived from a UniProt subcellular-location keyword. A secretory-vesicle/acrosome localization is reported in UniProt but only via a single study and by similarity; it reflects a sperm-specific pool, not the primary function. Reason: DLD is overwhelmingly a mitochondrial matrix enzyme. The acrosome localization is a specialized minor pool inferred electronically from a subcellular-location keyword and does not represent a core function of the gene product.
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (ARBA/InterPro, mapped to RHEA:15045 / EC 1.8.1.4) to the core dihydrolipoyl dehydrogenase activity. This matches the experimentally verified function. Reason: Correct core molecular function, redundantly captured across IBA, EXP, IDA, IMP and TAS evidence.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic annotation from a UniProt subcellular-location keyword. A minor nuclear pool of DLD is genuine - a small fraction of the 2-oxoglutarate dehydrogenase complex localizes to the nucleus (about 1-1.6% of total DLD) where it supplies succinyl-CoA for histone succinylation. Reason: The nuclear localization is experimentally supported (PMID:29211711) but represents a minor, specialized pool; the mitochondrial matrix is the primary site. Supporting Evidence: PMID:29211711 about 1–1.6% of total OGDH, DLST, and DLD was localized in the nucleus
GO:0005759 mitochondrial matrix	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to the mitochondrial matrix, the primary site of DLD. This is the correct and most specific localization, consistent with the UniProt subcellular location and its role in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system. Reason: DLD mainly localizes to the mitochondrial matrix; this term is accurate and appropriately specific.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO electronic annotation to the very general parent term oxidoreductase activity. DLD is indeed an oxidoreductase, but a far more specific and accurate term exists. Reason: Too general. The specific molecular function is dihydrolipoyl dehydrogenase (NADH) activity, which is already annotated with experimental evidence. Proposed replacements: dihydrolipoyl dehydrogenase (NADH) activity
GO:0016668 oxidoreductase activity, acting on a sulfur group of donors, NAD(P) as acceptor	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO electronic annotation to an intermediate parent term. DLD does act on a sulfur group of donors (the dithiol/disulfide of the lipoyl cofactor) with NAD+ as acceptor, so the term is accurate but less specific than the annotated dihydrolipoyl dehydrogenase (NADH) activity. Reason: Correct grouping term (direct parent of GO:0004148) but redundant with the more specific experimentally supported MF; retained as an accurate but general classification.
GO:0031514 motile cilium	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: Electronic annotation from a UniProt subcellular-location keyword; the cilium/flagellum localization is inferred by similarity to a rodent ortholog (Q811C4) and relates to a putative sperm-flagellum pool. Reason: Not a core localization for human DLD. Inferred electronically by similarity; the enzyme is overwhelmingly a mitochondrial matrix protein.
GO:0050660 flavin adenine dinucleotide binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic annotation of FAD binding, consistent with the experimentally established and IBA-supported flavin cofactor binding. Reason: Correct cofactor-binding function; DLD binds one FAD per subunit as an integral part of its catalytic mechanism.
GO:0005515 protein binding	IPI PMID:16263718 How dihydrolipoamide dehydrogenase-binding protein binds dih...	MARK AS OVER ANNOTATED	Summary: IPI interaction with PDHX (O00330), the E3-binding protein that tethers DLD to the E2 core of the pyruvate dehydrogenase complex. The interaction is real and functionally important, but the bare protein binding term is uninformative. Reason: Generic protein binding conveys no specific molecular function. The physiologically meaningful information (DLD-PDHX tethering within PDH) is captured by complex-membership annotations. Retained per policy for IPI evidence but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:16442803 Structural insight into interactions between dihydrolipoamid...	MARK AS OVER ANNOTATED	Summary: IPI interaction with PDHX (O00330), from the crystallographic study of the E3/E3-binding-protein interface. Functionally relevant but captured by the generic, uninformative protein binding term. Reason: Bare protein binding is uninformative; the DLD-PDHX interaction underlying PDH assembly is better represented by complex-membership annotations. Retained per policy.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: IPI to PDHX (O00330) from a large-scale interactome study (BioPlex-type). Generic protein binding without specific functional meaning. Reason: Uninformative bare protein binding derived from a high-throughput interactome screen; retained per policy but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ...	MARK AS OVER ANNOTATED	Summary: IPI interactions (PRDX6/P30041 and YWHAE/P62258) from a mitochondrial protein interaction map. Generic protein binding with no specific molecular function. Reason: Uninformative bare protein binding from a high-throughput interactome screen; retained per policy but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI interactions (PDHX/O00330 and ITGB1BP1/O14713) from the HuRI binary interactome map. Generic protein binding without specific functional meaning. Reason: Uninformative bare protein binding from a high-throughput binary interactome screen; retained per policy but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IPI interaction with HTT (P42858, huntingtin) from a neurodegenerative-disease interactome study. Generic protein binding with no specific molecular function. Reason: Uninformative bare protein binding from a high-throughput interactome screen; retained per policy but flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI interaction with PDHX (O00330) from the BioPlex 3.0 dual proteome-scale network. Generic protein binding without specific functional meaning. Reason: Uninformative bare protein binding from a high-throughput interactome screen; retained per policy but flagged as over-annotated.
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: Electronic (Ensembl Compara orthology) annotation to mitochondrion, the primary compartment for DLD. Correct but general; mitochondrial matrix is more specific. Reason: DLD is a mitochondrial matrix protein; this parent localization is accurate.
GO:0005929 cilium	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic (Ensembl Compara orthology) annotation to cilium, inferred by similarity to a rodent ortholog. Not a core localization for human DLD. Reason: DLD is overwhelmingly mitochondrial; the cilium/flagellum assignment is an electronic inference from orthology and reflects at most a specialized sperm pool.
GO:0006086 pyruvate decarboxylation to acetyl-CoA	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/orthology) annotation to pyruvate decarboxylation to acetyl-CoA, the pyruvate dehydrogenase complex reaction in which DLD acts as the E3 subunit. Also independently supported by IDA and IC evidence. Reason: Correct biological process; DLD is the shared E3 subunit of the PDH complex that links glycolysis to the TCA cycle.
GO:0006099 tricarboxylic acid cycle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronic (orthology) annotation to the TCA cycle, reflecting DLD's role as the E3 subunit of the 2-oxoglutarate dehydrogenase complex (which catalyzes a TCA-cycle step). Also supported by NAS evidence. Reason: Accurate but broad process. DLD's TCA involvement is via the OGDH complex; the more specific step term (2-oxoglutarate decarboxylation to succinyl-CoA, GO:0120551) is preferred as the informative process.
GO:0043159 acrosomal matrix	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic (orthology) annotation to the acrosomal matrix, reflecting a putative sperm-specific pool inferred by similarity to a rodent ortholog. Not a core localization. Reason: DLD is predominantly a mitochondrial matrix enzyme; the acrosomal-matrix assignment is an electronic orthology inference for a specialized minor pool.
GO:0045252 oxoglutarate dehydrogenase complex	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/orthology) annotation of membership in the 2-oxoglutarate dehydrogenase complex, redundant with experimental (IDA) and IBA/NAS annotations for the same complex. Reason: Genuine complex membership as the shared E3 subunit of OGDH.
GO:0045254 pyruvate dehydrogenase complex	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/orthology) annotation of membership in the pyruvate dehydrogenase complex, redundant with experimental (IDA/IPI) annotations for the same complex. Reason: Genuine complex membership as the shared E3 subunit of PDH.
GO:0019477 L-lysine catabolic process	IMP PMID:37701333 Biochemical characterization of patients with dihydrolipoami...	ACCEPT	Summary: DLD deficiency patients accumulate lysine-degradation intermediates (2-ketoadipic and 2-hydroxyadipic acids), reflecting DLD's role as the shared E3 subunit of the 2-oxoadipate dehydrogenase complex (OADH) in the lysine catabolic pathway. Reason: Experimentally supported via patient biochemistry; DLD contributes to lysine degradation through the OADH complex, which shares its E3 with the other 2-oxoacid dehydrogenases. Supporting Evidence: PMID:37701333 also highlight the under-recognized role of DLD in the lysine degradation PMID:37701333 2‐ketoadipic and 2‐hydroxyadipic acids were detected in the urine of two individuals during acute decompensation and represent relatively specific markers of DLDD
GO:0005739 mitochondrion	NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu...	ACCEPT	Summary: ComplexPortal NAS localization to mitochondrion, associated with the 2-oxoglutarate dehydrogenase complex. Consistent with the well-established mitochondrial localization. Reason: Correct; DLD is a mitochondrial protein. Mitochondrial matrix is the more specific term.
GO:0005759 mitochondrial matrix	NAS PMID:3593587 Purification and characterization of human liver branched-ch...	ACCEPT	Summary: ComplexPortal NAS localization to the mitochondrial matrix, associated with the BCKDH complex. This is the primary and correct localization of DLD. Reason: DLD is a mitochondrial matrix enzyme; the matrix is the most specific accurate compartment.
GO:0006099 tricarboxylic acid cycle	NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu...	KEEP AS NON CORE	Summary: ComplexPortal NAS annotation to the TCA cycle via the 2-oxoglutarate dehydrogenase complex. Accurate but broad. Reason: DLD contributes to a TCA-cycle step through the OGDH complex; the specific step term GO:0120551 is more informative. Retained as accurate context.
GO:0006103 2-oxoglutarate metabolic process	NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu...	KEEP AS NON CORE	Summary: ComplexPortal NAS annotation to 2-oxoglutarate metabolism via the OGDH complex. Accurate but general. Reason: DLD's role in 2-oxoglutarate metabolism is via the OGDH complex; the specific step term GO:0120551 (2-oxoglutarate decarboxylation to succinyl-CoA) is more informative.
GO:0009083 branched-chain amino acid catabolic process	IDA PMID:3593587 Purification and characterization of human liver branched-ch...	ACCEPT	Summary: Purified human liver BCKDH complex (containing the dissociable lipoamide oxidoreductase, i.e. DLD/E3) oxidized all three branched-chain 2-keto acids (KIV, KIC, KMV), demonstrating DLD's participation in branched-chain amino acid catabolism. Reason: Experimentally supported role as the E3 subunit of the BCKDH complex in BCAA degradation. Supporting Evidence: PMID:3593587 The BCKADH effectively oxidized all of KIV, KIC, and KMV PMID:3593587 The minor band corresponded in molecular weight to lipoamide oxidoreductase which was purified separately.
GO:0045252 oxoglutarate dehydrogenase complex	NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu...	ACCEPT	Summary: ComplexPortal NAS annotation of DLD as the E3 component of the 2-oxoglutarate dehydrogenase complex, consistent with the structural characterization of the human OGDH complex. Reason: Genuine complex membership; corroborated by experimental (IDA) and IBA annotations.
GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex	IPI PMID:3593587 Purification and characterization of human liver branched-ch...	ACCEPT	Summary: The purified human liver BCKDH complex included a dissociable lipoamide oxidoreductase (DLD/E3) band; the complex required exogenous lipoamide oxidoreductase for full activity, establishing DLD as the E3 component of BCKDH. Reason: Genuine complex membership as the shared E3 subunit of the BCKDH complex. Supporting Evidence: PMID:3593587 The purified BCKADH represented only approximately 20% of the maximum activity when assayed without addition of exogenous lipoamide oxidoreductase, indicating that lipoamide oxidoreductase component was readily dissociable from the complex.
GO:0005739 mitochondrion	NAS PMID:24534072 Component co-expression and purification of recombinant huma...	ACCEPT	Summary: ComplexPortal NAS localization to mitochondrion (in the context of the recombinant PDH complex). Consistent with the established mitochondrial localization. Reason: Correct; DLD is a mitochondrial protein.
GO:0006086 pyruvate decarboxylation to acetyl-CoA	IDA PMID:24534072 Component co-expression and purification of recombinant huma...	ACCEPT	Summary: A functional recombinant human pyruvate dehydrogenase complex (all five components, including DLD/E3) was reconstituted and shown to convert pyruvate to acetyl-CoA, directly demonstrating DLD's participation in this process. Reason: Directly supported; DLD is the E3 subunit of the PDH complex that decarboxylates pyruvate to acetyl-CoA. Supporting Evidence: PMID:24534072 The mammalian pyruvate dehydrogenase complex (PDC) is a multi-component mitochondrial enzyme that plays a key role in the conversion of pyruvate to acetyl-CoA connecting glycolysis to the citric acid cycle.
GO:0045254 pyruvate dehydrogenase complex	IPI PMID:19240034 Subunit and catalytic component stoichiometries of an in vit...	ACCEPT	Summary: Study of subunit and catalytic-component stoichiometries of an in vitro reconstituted human PDH complex, establishing DLD/E3 as a bona fide component of the complex. Reason: Genuine complex membership as the shared E3 subunit of PDH.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence detects DLD in the nucleoplasm. This is consistent with the documented minor nuclear pool of the 2-oxoglutarate dehydrogenase complex. Reason: A genuine but minor nuclear pool exists (about 1-1.6% of total DLD; PMID:29211711). The primary localization and function are mitochondrial, so this is non-core.
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	EXP PMID:16770810 Novel mutations in dihydrolipoamide dehydrogenase deficiency...	ACCEPT	Summary: DLD deficiency in two cousins was diagnosed by reduced DLD (E3) enzyme activity, with enzyme-kinetic measurements on patient fibroblasts, experimentally implicating the dihydrolipoyl dehydrogenase activity. Reason: Experimental evidence for the core dihydrolipoyl dehydrogenase activity of DLD. Supporting Evidence: PMID:16770810 We have diagnosed dihydrolipoamide dehydrogenase (DLD) deficiency in two male second cousins
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	EXP PMID:17404228 Cryptic proteolytic activity of dihydrolipoamide dehydrogena...	ACCEPT	Summary: This study of DLD's cryptic proteolytic activity characterizes the enzyme's primary dihydrolipoamide dehydrogenase activity in the native homodimer and shows that destabilizing the dimer causes loss of DLD activity and gain of protease activity. Reason: Experimental support for the core dehydrogenase activity (in the native dimer); the same paper documents the moonlighting protease as a distinct, non-core activity. Supporting Evidence: PMID:17404228 The mitochondrial enzyme, dihydrolipoamide dehydrogenase (DLD), is essential for energy metabolism across eukaryotes.
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	EXP PMID:20160912 Interaction of E1 and E3 components with the core proteins o...	ACCEPT	Summary: Characterization of E1 and E3 interactions with the PDH core proteins, experimentally supporting DLD's dihydrolipoyl dehydrogenase activity within the complex. Reason: Experimental support for the core molecular function of DLD.
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	EXP PMID:20385101 Characterization of interactions of dihydrolipoamide dehydro...	ACCEPT	Summary: Characterization of DLD interactions with its E3-binding protein in the human PDH complex, experimentally supporting DLD's dihydrolipoyl dehydrogenase activity. Reason: Experimental support for the core molecular function of DLD.
GO:0006086 pyruvate decarboxylation to acetyl-CoA	IDA PMID:16442803 Structural insight into interactions between dihydrolipoamid...	ACCEPT	Summary: Structural study of the E3/E3-binding-protein interface in the human PDH complex, supporting DLD's role in the pyruvate-to-acetyl-CoA reaction as the tethered E3 component. Reason: Consistent with DLD being the E3 subunit of the PDH complex. Supporting Evidence: PMID:16442803 utilizes the specific dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the essential E3 component to the 60-meric core of the complex
GO:0045254 pyruvate dehydrogenase complex	IDA PMID:14638692 Organization of the cores of the mammalian pyruvate dehydrog...	ACCEPT	Summary: Characterization of the mammalian PDH core (E2 and E2.E3BP) and its capacity to bind the E1 and E3 components; E3 (DLD) binds to the E2.E3BP core outside the central dodecahedron, establishing DLD as a component of the assembled complex. Reason: Genuine complex membership as the shared E3 subunit of PDH. Supporting Evidence: PMID:14638692 small angle x-ray scattering showed that E3 binds to E2.E3BP outside the central dodecahedron
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	IDA PMID:9242632 Dihydrolipoamide dehydrogenase-binding protein of the human ...	ACCEPT	Summary: Reconstitution of the human pyruvate dehydrogenase complex with E3BP and E3 (DLD) demonstrated DLD's dihydrolipoamide dehydrogenase activity within the functional complex. Reason: Experimental (IDA) support for the core molecular function; DLD is required to reconstitute a functional PDH complex. Supporting Evidence: PMID:9242632 is required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes
GO:0006086 pyruvate decarboxylation to acetyl-CoA	IC PMID:9242632 Dihydrolipoamide dehydrogenase-binding protein of the human ...	ACCEPT	Summary: Curator inference (IC) from DLD's dihydrolipoyl dehydrogenase activity (GO:0004148) that DLD acts within the pyruvate decarboxylation to acetyl-CoA process. Reason: Sound inference; as the E3 subunit of PDH, DLD is integral to converting pyruvate to acetyl-CoA.
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	IMP PMID:15712224 A novel mutation in the dihydrolipoamide dehydrogenase E3 su...	ACCEPT	Summary: A homozygous DLD mutation (R482G) reduced E3 subunit activity to ~20% of control, providing mutation-based evidence for the dihydrolipoyl dehydrogenase activity of DLD. Reason: Loss-of-function mutation reduces E3 activity, directly implicating DLD in this molecular function. Supporting Evidence: PMID:15712224 E3 subunit activity was shown to be deficient (20% of control values)
GO:0120551 2-oxoglutarate decarboxylation to succinyl-CoA	IMP PMID:15712224 A novel mutation in the dihydrolipoamide dehydrogenase E3 su...	ACCEPT	Summary: A DLD mutation produced an atypical alpha-ketoglutarate dehydrogenase deficiency (KGDC deficiency), directly implicating DLD in the 2-oxoglutarate decarboxylation to succinyl-CoA step of the TCA cycle via the OGDH complex. Reason: Mutation-based (IMP) evidence for DLD's involvement in the OGDH-catalyzed 2-oxoglutarate decarboxylation step; a specific and informative process term. Supporting Evidence: PMID:15712224 The alpha-ketoglutarate dehydrogenase complex (KGDC) catalyses the decarboxylation of alpha-ketoglutarate into succinyl-coenzyme A in the Krebs cycle.
GO:0120552 branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA	IDA PMID:3593587 Purification and characterization of human liver branched-ch...	ACCEPT	Summary: The purified human liver BCKDH complex (with dissociable DLD/E3) oxidized KIV, KIC and KMV to yield the corresponding branched-chain acyl products, requiring NAD and CoASH, directly demonstrating DLD's role in this decarboxylation process. Reason: Directly supported; DLD is the E3 subunit that enables the BCKDH-catalyzed decarboxylation of branched-chain 2-keto acids. Specific and informative process term. Supporting Evidence: PMID:3593587 NAD and CoASH were absolutely required for the reaction.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteomics detected DLD as a mitochondrial protein, consistent with its established localization. Reason: Correct mitochondrial localization corroborated by many independent lines of evidence.
GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex	IDA PMID:3593587 Purification and characterization of human liver branched-ch...	ACCEPT	Summary: The purified human liver BCKDH complex contained a dissociable lipoamide oxidoreductase band (DLD/E3), establishing DLD as the E3 component of the complex. Reason: Genuine, experimentally established complex membership as the shared E3 subunit of BCKDH. Supporting Evidence: PMID:3593587 The minor band corresponded in molecular weight to lipoamide oxidoreductase which was purified separately.
GO:0160167 oxoadipate dehydrogenase complex	IDA PMID:29191460 The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogen...	ACCEPT	Summary: The human 2-oxoadipate dehydrogenase E1 component (hE1a/DHTKD1) recruits the dihydrolipoyl succinyltransferase (E2o) and dihydrolipoyl dehydrogenase (E3/DLD) components, establishing DLD as the shared E3 of the 2-oxoadipate dehydrogenase complex. Reason: Experimentally established membership; DLD is shared with the OADH complex, which participates in lysine/tryptophan degradation. Supporting Evidence: PMID:29191460 The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	IDA PMID:16442803 Structural insight into interactions between dihydrolipoamid...	ACCEPT	Summary: Structural/biochemical characterization of human E3 (DLD) in complex with the E3-binding domain, supporting its dihydrolipoyl dehydrogenase activity within the PDH complex. Reason: Experimental (IDA) support for the core molecular function; DLD binds as an E3 homodimer and functions within PDH. Supporting Evidence: PMID:16442803 resulting in one E3BD binding site on the E3 homodimer
GO:0005634 nucleus	IDA PMID:29211711 KAT2A coupled with the α-KGDH complex acts as a histone H3 s...	KEEP AS NON CORE	Summary: Cell-fractionation and immunofluorescence showed that a small fraction (~1-1.6%) of DLD, as part of the 2-oxoglutarate dehydrogenase complex, localizes to the nucleus where it supplies succinyl-CoA to KAT2A for histone H3 succinylation. Reason: A genuine but minor, specialized nuclear pool. The core localization and function of DLD are mitochondrial, so the nuclear role is non-core. Supporting Evidence: PMID:29211711 about 1–1.6% of total OGDH, DLST, and DLD was localized in the nucleus
GO:0005739 mitochondrion	IDA PMID:29211711 KAT2A coupled with the α-KGDH complex acts as a histone H3 s...	ACCEPT	Summary: The same study confirmed that the bulk of DLD (as part of the 2-oxoglutarate dehydrogenase complex) resides in mitochondria, with only a small nuclear fraction. Reason: Correct primary localization; the mitochondrion holds the majority of DLD.
GO:0045252 oxoglutarate dehydrogenase complex	IDA PMID:29211711 KAT2A coupled with the α-KGDH complex acts as a histone H3 s...	ACCEPT	Summary: Co-immunoprecipitation with antibodies against OGDH, DLST and DLD demonstrated that these endogenous alpha-KGDH components associate with each other, confirming DLD as a component of the 2-oxoglutarate dehydrogenase complex. Reason: Directly demonstrated complex membership as the E3 subunit of OGDH. Supporting Evidence: PMID:29211711 dihydrolipoyl succinyltransferase (DLST), and dihydrolipoyl dehydrogenase (DLD)—revealed that these endogenous proteins were associated with each other
GO:0045254 pyruvate dehydrogenase complex	IDA PMID:9242632 Dihydrolipoamide dehydrogenase-binding protein of the human ...	ACCEPT	Summary: Reconstitution of the human PDH complex established DLD (E3) as a component anchored to the E2 core via the E3-binding protein (E3BP). Reason: Genuine complex membership as the shared E3 subunit of PDH; supported by reconstitution experiments. Supporting Evidence: PMID:9242632 is required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes
GO:0005739 mitochondrion	HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated...	ACCEPT	Summary: High-throughput phosphoproteomics of functional mitochondria detected DLD as a mitochondrial inner-compartment protein, consistent with its known localization (and its documented phosphorylation). Reason: Correct mitochondrial localization.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-203946	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-204169	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-5693148	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-5693153	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-5694018	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-71401	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838035	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838289	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9853499	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9853512	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9858321	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9858589	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9858590	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9859148	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9859163	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9859172	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9861616	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9861667	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9861734	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9865115	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9912480	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9912527	ACCEPT	Summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the established primary localization. Reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid dehydrogenase complexes and the glycine cleavage system.
GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity	TAS PMID:8506365 Identification of two missense mutations in a dihydrolipoami...	ACCEPT	Summary: Study of an E3-deficient patient (dihydrolipoamide:NAD+ oxidoreductase, EC 1.8.1.4) with two missense mutations; the assertion of DLD's dihydrolipoyl dehydrogenase activity is well supported. Reason: Author-stated (TAS) core molecular function, consistent with all other evidence. Supporting Evidence: PMID:8506365 dihydrolipoamide dehydrogenase (E3; dihydrolipoamide:NAD+ oxidoreductase, EC 1.8.1.4)
GO:0005739 mitochondrion	TAS PMID:3278312 Cloning and cDNA sequence of the dihydrolipoamide dehydrogen...	ACCEPT	Summary: Cloning of the human DLD cDNA identified an N-terminal 35-residue mitochondrial import leader sequence, supporting mitochondrial localization. Reason: Author-stated (TAS) mitochondrial localization; consistent with the transit peptide and all other localization evidence. Supporting Evidence: PMID:3278312 The first 35-amino acid residues of the open reading frame probably correspond to a typical mitochondrial import leader sequence.

Core Functions

Dihydrolipoyl dehydrogenase (E3) activity - the shared, defining function of DLD. As a FAD-dependent, NAD+-linked flavoenzyme homodimer, DLD reoxidizes the dihydrolipoyl groups on the lipoyl-bearing E2/H components of mitochondrial 2-oxoacid dehydrogenase complexes and the glycine cleavage system, transferring electrons to NAD+ via FAD. This single activity is used by the pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain alpha-ketoacid dehydrogenase and 2-oxoadipate dehydrogenase complexes.

Molecular Function:

dihydrolipoyl dehydrogenase (NADH) activity

Directly Involved In:

pyruvate decarboxylation to acetyl-CoA 2-oxoglutarate decarboxylation to succinyl-CoA branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA

Cellular Locations:

mitochondrial matrix

Supporting Evidence:

PMID:16442803
utilizes the specific dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the essential E3 component to the 60-meric core of the complex
PMID:15712224
The E3 subunit is common to two other enzymatic complexes, namely pyruvate dehydrogenase complex (PDC) and branched-chain ketoacid dehydrogenase complex (BCKDC).

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:14638692

Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components.

PMID:15712224

A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency.

PMID:16263718

How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex.

PMID:16442803

Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex.

PMID:16770810

Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline-normal PDH complex activity.

PMID:17404228

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase.

PMID:19240034

Subunit and catalytic component stoichiometries of an in vitro reconstituted human pyruvate dehydrogenase complex.

PMID:20160912

Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex.

PMID:20385101

Characterization of interactions of dihydrolipoamide dehydrogenase with its binding protein in the human pyruvate dehydrogenase complex.

PMID:20833797

Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes.

PMID:24534072

Component co-expression and purification of recombinant human pyruvate dehydrogenase complex from baculovirus infected SF9 cells.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29128334

A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.

PMID:29191460

The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species.

PMID:29211711

KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:3278312

Cloning and cDNA sequence of the dihydrolipoamide dehydrogenase component human alpha-ketoacid dehydrogenase complexes.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

PMID:3593587

Purification and characterization of human liver branched-chain alpha-keto acid dehydrogenase complex.

PMID:36854377

MRPS36 provides a structural link in the eukaryotic 2-oxoglutarate dehydrogenase complex.

PMID:37701333

Biochemical characterization of patients with dihydrolipoamide dehydrogenase deficiency.

PMID:8506365

Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient.

PMID:9242632

Dihydrolipoamide dehydrogenase-binding protein of the human pyruvate dehydrogenase complex. DNA-derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex.

Reactome:R-HSA-203946

PDK isozymes phosphorylate PDHC subunit E1

Reactome:R-HSA-204169

PDP1,2 dephosphorylate p-lipo-PDH

Reactome:R-HSA-5693148

BCKDK phosphorylates BCKDH

Reactome:R-HSA-5693153

PPM1K dephosphorylates p-BCKDH

Reactome:R-HSA-5694018

DLD dimer:2xFAD oxidises GCSH:DHLL to GCSH:lipoate

Reactome:R-HSA-71401

OGDH dimer decarboxylates 2-OG

Reactome:R-HSA-9838035

CLPXP binds mitochondrial matrix proteins

Reactome:R-HSA-9838289

CLPXP degrades mitochondrial matrix proteins

Reactome:R-HSA-9853499

DLD dimer dehydrogenates dihydrolipoyl

Reactome:R-HSA-9853512

DLST transfers succinyl to CoA

Reactome:R-HSA-9858321

DHTKD1 dimer decarboxylates 2-OA

Reactome:R-HSA-9858589

DLD dimer dehydrogenates dihydrolipoyl

Reactome:R-HSA-9858590

DLST transfers glutaryl to CoA

Reactome:R-HSA-9859148

BCKDHA:BCKDHB tetramer decarboxylates KIC, KMVA, KIV

Reactome:R-HSA-9859163

DBT transfers BCAA to CoA

Reactome:R-HSA-9859172

DLD dimer dehydrogenates dihydrolipoyl

Reactome:R-HSA-9861616

DLD dimer dehydrogenates dihydrolipoyl

Reactome:R-HSA-9861667

DLAT trimer transfers acetyl to CoA

Reactome:R-HSA-9861734

PDH E1 decarboxylates PYR, transferring acetyl to DLAT

Reactome:R-HSA-9865115

DBT loss-of-function mutants don't synthesize BCAA-CoA

Reactome:R-HSA-9912480

BCKDK loss-of-function mutations do not phosphorylate BCKDH

Reactome:R-HSA-9912527

H139Hfs13* PPM1K does not dephosphorylate BCKDH

Deep Research

Falcon

(DLD-deep-research-falcon.md)

Comprehensive Research Report: Human DLD (Dihydrolipoamide Dehydrogenase, Mitochondrial) Falcon Edison Scientific Literature 55 citations 2 artifacts 2026-07-05T19:55:08.904246

Edison artifact artifact-00 (text/markdown)

Edison artifact artifact-01 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

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Comprehensive Research Report: Human DLD (Dihydrolipoamide Dehydrogenase, Mitochondrial)

Gene: DLD (synonyms: GCSL, LAD, PHE3) | UniProt: P09622 | EC: 1.8.1.4 | Organism: Homo sapiens

1. Gene Identity and Protein Overview

The human DLD gene encodes dihydrolipoamide dehydrogenase (also known as dihydrolipoyl dehydrogenase, lipoamide dehydrogenase [LADH], or the E3 subunit), a flavin adenine dinucleotide (FAD)-dependent disulfide oxidoreductase belonging to the class-I pyridine nucleotide-disulfide oxidoreductase family (yan2023rolesofdihydrolipoamide pages 1-3). The mature protein functions as an obligate homodimer, with each monomer being approximately 50–54 kDa and comprising 474 amino acid residues after cleavage of the mitochondrial targeting sequence (szabo2019underlyingmolecularalterations pages 3-4, duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6). DLD is synthesized as a precursor with an N-terminal mitochondrial targeting peptide that is proteolytically removed upon import into the mitochondrial matrix, where it carries out its primary functions (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-4).

2. Enzymatic Function and Catalytic Mechanism

2.1 Primary Reaction

DLD catalyzes the NAD⁺-dependent oxidation of dihydrolipoamide to lipoamide:

Dihydrolipoamide + NAD⁺ → Lipoamide + NADH + H⁺

This reaction regenerates the oxidized lipoyl cofactor covalently attached to the E2 subunits (or H-protein in the glycine cleavage system) of its partner multienzyme complexes, while simultaneously producing NADH for the mitochondrial electron transport chain (yan2023rolesofdihydrolipoamide pages 1-3, szabo2023structuralandbiochemical pages 1-3, duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6).

2.2 Catalytic Mechanism

DLD employs a ping-pong bi-bi mechanism in which two half-reactions are spatially separated by the non-covalently bound FAD prosthetic group (szabo2019underlyingmolecularalterations pages 3-4, szabo2023structuralandbiochemical pages 1-3). The electron transfer pathway proceeds as follows:

First half-reaction (si face of FAD): The dihydrolipoamide substrate enters the active site through an approximately 10-Å-long hydrophobic channel. Electrons are transferred from the dithiol of dihydrolipoamide to the redox-active disulfide bond formed by Cys45 and Cys50, reducing it. The electrons then flow to the FAD isoalloxazine ring, reducing it to FADH₂ (szabo2023structuralandbiochemical pages 1-3, yan2023rolesofdihydrolipoamide pages 5-7).
Second half-reaction (re face of FAD): Electrons are transferred from FADH₂ to NAD⁺, producing NADH. The catalytic base His452′ from the adjacent monomer in the homodimer is critical for this step (szabo2023structuralandbiochemical pages 1-3).

A solvent-accessible H⁺/H₂O channel facilitates catalysis by providing an outlet for water molecules during substrate binding and hydrogen ion release during NAD⁺ reduction (szabo2019underlyingmolecularalterations pages 3-4). Importantly, both monomers contribute catalytically important residues to each active site, making the homodimeric assembly essential for function (szabo2023structuralandbiochemical pages 1-3).

2.3 Structural Organization

Each DLD monomer contains four distinct structural domains: (1) the FAD-binding domain (residues 1–149), (2) the NAD⁺/NADH-binding domain (residues 150–282), (3) the central domain (residues 283–350), and (4) the C-terminal interface domain (residues 351–474) (szabo2019underlyingmolecularalterations pages 3-4, duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6). The active site is divided by the FAD prosthetic group into two compartments: the lipoamide-binding site containing the redox-active Cys45-Cys50 disulfide, and the NAD⁺/NADH-binding site (szabo2019underlyingmolecularalterations pages 3-4). High-resolution crystal structures of wild-type human E3 have been determined at 1.75 Å resolution (szabo2019underlyingmolecularalterations pages 3-4).

3. Participation in Mitochondrial Multienzyme Complexes

DLD is unique among metabolic enzymes in serving as the shared E3 component of five distinct mitochondrial multienzyme systems (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, szabo2024mitochondrialalphaketoacid pages 1-6, yan2023rolesofdihydrolipoamide pages 1-3). In all of these, DLD performs the same terminal catalytic step: reoxidation of the dihydrolipoyl moiety on the E2 subunit (or H-protein) with concomitant reduction of NAD⁺ to NADH (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, szabo2023structuralandbiochemical pages 1-3).

Complex Name	Abbreviation	Metabolic Pathway	Overall Reaction Catalyzed	E1 / E2 subunits (or analogous components)
Pyruvate dehydrogenase complex	PDHc	Carbohydrate metabolism; links glycolysis to the TCA cycle	Pyruvate + CoA + NAD+ → Acetyl-CoA + CO2 + NADH. DLD/E3 catalyzes the shared terminal step: oxidation of E2-bound dihydrolipoamide to lipoamide with reduction of NAD+ to NADH.	E1: pyruvate dehydrogenase (PDHA1/PDHB heterotetramer); E2: dihydrolipoamide S-acetyltransferase (DLAT). In human PDHc, E3 is tethered via E3-binding protein (PDHX/E3BP). (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, duarte2021dihydrolipoamidedehydrogenasepyruvate pages 2-4, brautigam2006structuralinsightinto pages 1-2, szabo2024mitochondrialalphaketoacid pages 16-19)
α-Ketoglutarate dehydrogenase complex	KGDHc	Tricarboxylic acid cycle	2-Oxoglutarate + CoA + NAD+ → Succinyl-CoA + CO2 + NADH. DLD/E3 reoxidizes the lipoyl cofactor on E2 and transfers electrons to NAD+.	E1: 2-oxoglutarate dehydrogenase (OGDH/OGDHL family context); E2: dihydrolipoyl succinyltransferase (DLST). (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, szabo2024mitochondrialalphaketoacid pages 1-6, hansen2022theαketoglutaratedehydrogenase pages 2-4)
Branched-chain α-keto acid dehydrogenase complex	BCKDHc	Branched-chain amino acid catabolism (leucine, isoleucine, valine)	Branched-chain α-keto acids + CoA + NAD+ → branched-chain acyl-CoAs + CO2 + NADH. DLD/E3 performs the common final reoxidation of dihydrolipoamide and reduction of NAD+ to NADH.	E1: branched-chain α-keto acid dehydrogenase E1 (BCKDHA/BCKDHB); E2: dihydrolipoamide branched-chain transacylase E2 (DBT). (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, szabo2024mitochondrialalphaketoacid pages 1-6, yan2023rolesofdihydrolipoamide pages 1-3)
α-Ketoadipate dehydrogenase complex	KADHc	Lysine, hydroxylysine, and tryptophan catabolism	2-Oxoadipate + CoA + NAD+ → glutaryl-CoA + CO2 + NADH. DLD/E3 again carries out the terminal lipoyl reoxidation/NADH-producing step.	E1: 2-oxoadipate dehydrogenase (DHTKD1); E2: shares the E2 component DLST with KGDHc in mammalian mitochondria. (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, szabo2024mitochondrialalphaketoacid pages 1-6)
Glycine cleavage system	GCS	Glycine degradation and mitochondrial one-carbon metabolism	Glycine + tetrahydrofolate + NAD+ → 5,10-methylene-THF + CO2 + NH3 + NADH. DLD functions as the L-protein, reoxidizing the reduced lipoyl moiety on H-protein while reducing NAD+ to NADH.	Analogous components rather than E1/E2: P-protein = glycine decarboxylase (GLDC), H-protein = GCSH, T-protein = aminomethyltransferase (AMT), L-protein = DLD. (yan2023rolesofdihydrolipoamide pages 1-3, kikuchi2008glycinecleavagesystem pages 2-5, leung2021glycinecleavagesystem pages 1-2)

Table: This table summarizes the mitochondrial enzyme systems that use human DLD as their shared E3/L-protein component. It highlights the pathway context, overall chemistry, and partner catalytic subunits/components needed to interpret DLD’s functional annotation.

3.1 Pyruvate Dehydrogenase Complex (PDHc)

The human PDHc is a ~9.5 MDa macromolecular assembly with icosahedral symmetry, comprising approximately 30 E1p subunits, 60 E2p subunits, and 12 E3 homodimers, along with 12 copies of E3-binding protein (E3BP/PDHX) (brautigam2006structuralinsightinto pages 1-2, duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-4). PDHc catalyzes the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA, linking glycolysis to the TCA cycle (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 2-4). In eukaryotic PDHc, DLD does not bind E2 directly; instead, it is tethered to the complex via E3BP, which contains a specific E3-binding domain (E3BD) that contacts the E3 homodimer across its 2-fold symmetry axis with extremely tight affinity (Kd ~7.8 × 10⁻²¹⁰ M) (brautigam2006structuralinsightinto pages 1-2, szabo2024mitochondrialalphaketoacid pages 16-19, brautigam2006structuralinsightinto pages 2-3). Recent in-situ cryo-electron tomography has revealed that up to 12 E3 homodimers localize primarily along the pentagonal openings of the PDHc core, and that the number of peripheral E1 and E3 components varies dynamically among individual PDHc particles, suggesting an activity regulation mechanism coordinating metabolic demands (wang2025dynamicsofthe pages 1-3).

3.2 α-Ketoglutarate Dehydrogenase Complex (KGDHc)

KGDHc catalyzes the rate-limiting step of the TCA cycle, converting α-ketoglutarate to succinyl-CoA. DLD serves as the E3 subunit alongside OGDH (E1) and DLST (E2) (szabo2024mitochondrialalphaketoacid pages 1-6, hansen2022theαketoglutaratedehydrogenase pages 2-4). This complex is particularly significant as a signaling hub controlling post-translational modifications (succinylation), hypoxic responses, and ROS homeostasis in mitochondria (hansen2022theαketoglutaratedehydrogenase pages 2-4).

3.3 Branched-Chain α-Keto Acid Dehydrogenase Complex (BCKDHc)

BCKDHc catalyzes the oxidative decarboxylation of branched-chain α-keto acids derived from leucine, isoleucine, and valine catabolism (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, szabo2024mitochondrialalphaketoacid pages 1-6).

3.4 α-Ketoadipate Dehydrogenase Complex (KADHc)

KADHc participates in the catabolism of lysine, hydroxylysine, and tryptophan (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6, szabo2024mitochondrialalphaketoacid pages 1-6).

3.5 Glycine Cleavage System (GCS)

In the GCS, DLD functions as the L-protein, catalyzing the final step of glycine degradation by reoxidizing the reduced lipoyl moiety on H-protein (GCSH) while reducing NAD⁺ to NADH. The overall GCS reaction yields CO₂, NH₃, 5,10-methylene-tetrahydrofolate, and NADH from glycine (kikuchi2008glycinecleavagesystem pages 2-5, leung2021glycinecleavagesystem pages 1-2). Unlike the E1/E2 nomenclature used for the α-keto acid dehydrogenase complexes, the GCS uses the designations P-protein (GLDC), H-protein (GCSH), T-protein (AMT), and L-protein (DLD) (leung2021glycinecleavagesystem pages 1-2).

4. Subcellular Localization

DLD is synthesized as a precursor protein in the cytosol and imported into the mitochondrial matrix, where its targeting peptide is cleaved to produce the mature enzyme (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-4, duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6). The mitochondrial matrix is the site of action for all five multienzyme complexes in which DLD participates (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-4, babady2007crypticproteolyticactivity pages 1-2). DLD is ubiquitously expressed across tissues, with particularly high expression in metabolically active organs including heart, kidney, liver, and brain (duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6). Although DLD is predominantly a mitochondrial matrix enzyme, a non-mitochondrial isoform of DLDH has been reported in rat serum, representing a rare extra-mitochondrial occurrence (yan2023rolesofdihydrolipoamide pages 7-8).

5. Moonlighting (Non-Canonical) Functions

DLD is recognized as a moonlighting protein, possessing several non-canonical activities that emerge particularly under pathological conditions.

5.1 Diaphorase Activity

DLD exhibits NADH-specific diaphorase activity, catalyzing NADH oxidation using various electron acceptors including molecular oxygen (O₂), ferric iron, nitric oxide, and ubiquinone (yan2023rolesofdihydrolipoamide pages 1-3, babady2007crypticproteolyticactivity pages 1-2). This FAD- and NADH-dependent activity is believed to have a pro-oxidant role and increases when the mitochondrial matrix is acidified, such as during ischemia-reperfusion injury (babady2007crypticproteolyticactivity pages 4-5).

5.2 Proteolytic Activity

When the DLD homodimer is destabilized—by mutations, altered pH, or other conditions—the protein reveals a cryptic serine protease activity utilizing a catalytic dyad (Ser456–Glu431) located at the dimer interface (babady2007crypticproteolyticactivity pages 1-2, babady2007crypticproteolyticactivity pages 4-5). This proteolytic activity can cleave mitochondrial substrates such as frataxin, a protein involved in iron metabolism and antioxidant defense (babady2007crypticproteolyticactivity pages 5-6). Disease-causing mutations in the dimer interface domain (e.g., D444V, R447G) independently enhance this proteolytic activity (vaubel2011mutationsinthe pages 10-11).

5.3 Reactive Oxygen Species (ROS) Generation

DLD functions as a significant source of mitochondrial ROS. Its diaphorase activity reduces O₂ to superoxide radicals and Fe³⁺ to Fe²⁺, the latter catalyzing hydroxyl radical production through Fenton chemistry (babady2007crypticproteolyticactivity pages 1-2, vaubel2011mutationsinthe pages 1-2). DLD-dependent ROS generation is enhanced when NADH/NAD⁺ ratios are elevated and is a recognized contributor to oxidative damage in neurodegenerative conditions (vaubel2011mutationsinthe pages 1-2). However, DLD's ability to scavenge nitric oxide and reduce ubiquinone to ubiquinol suggests it may also exert antioxidant effects under certain conditions (babady2007crypticproteolyticactivity pages 1-2).

6. Role in Cuproptosis

A major recent discovery (2022–present) is DLD's involvement in cuproptosis, a copper-dependent form of regulated cell death. Genome-wide CRISPR screening identified DLD as one of seven genes (along with FDX1, LIAS, LIPT1, DLAT, PDHA1, and PDHB) whose knockout significantly mitigates copper-induced cytotoxicity (qi2023oncogenicroleof pages 1-2, chen2025roleandmechanisms pages 2-4). In the cuproptosis mechanism, excess intracellular copper binds to the thiol groups on lipoylated TCA cycle proteins, causing their aberrant oligomerization and triggering proteotoxic stress (zhao2024cuproptosisthenovel pages 3-4, chen2025mechanismsofcopper pages 2-3). DLD is essential for the lipoylation pathway that enables this copper-mediated protein aggregation (zhao2024cuproptosisthenovel pages 3-4).

Recent research has elucidated a more specific mechanism: activated DLD, induced by excess copper under alkaline mitochondrial pH conditions, drives NADH accumulation. Copper-mediated opening of the mitochondrial permeability transition pore (mPTP) facilitates NADH translocation to the cytosol, triggering NADH-reductive stress, which promotes aberrant purine biosynthesis, severe ATP depletion, and energy stress leading to cell death (zhang2026nadh‐reductivestressinduced pages 3-4, zhang2026nadh‐reductivestressinduced pages 7-8). Pharmacological inhibition of DLD with CPI-613 effectively blocks copper-induced NADH elevation and attenuates cuproptosis (zhang2026nadh‐reductivestressinduced pages 3-4).

7. Disease Associations

7.1 DLD Deficiency (OMIM #246900)

DLD deficiency is a rare autosomal recessive disorder caused by biallelic mutations in the DLD gene. Because DLD is shared among multiple metabolic complexes, its deficiency simultaneously impairs pyruvate oxidation, the TCA cycle, branched-chain amino acid catabolism, and glycine degradation (szabo2019underlyingmolecularalterations pages 4-5, szabo2024mitochondrialalphaketoacid pages 36-39).

Clinical presentations include:
- Early-onset (neonatal): Severe metabolic decompensation with lactic acidosis, hypoglycemia, hyperammonemia, encephalopathy, Leigh syndrome, hypertrophic cardiomyopathy, and often premature death (szabo2019underlyingmolecularalterations pages 4-5, szabo2024mitochondrialalphaketoacid pages 36-39, quinonez2013leighsyndromein pages 1-3).
- Hepatic form: Episodic liver failure with metabolic decompensation, generally longer survival (odievre2005anovelmutation pages 5-8, szabo2024mitochondrialalphaketoacid pages 36-39).
- Myopathic form: Riboflavin-responsive mitochondrial myopathy, recently recognized (staretzchacham2021theeffectsof pages 9-10, szabo2023structuralandbiochemical pages 21-22).

The most prevalent disease-causing variant, G194C (c.685G>T), is the Ashkenazi Jewish founder mutation with a carrier frequency of approximately 1:94 (szabo2019underlyingmolecularalterations pages 4-5, odievre2005anovelmutation pages 5-8). At least 14 disease-causing variants have been characterized, affecting various protein domains (szabo2019underlyingmolecularalterations pages 4-5). Structural studies have revealed that mutations in the dimer interface (e.g., D444V, R447G, R460G, E340K) are particularly severe because they not only reduce catalytic activity but also enhance ROS-generating and proteolytic moonlighting activities, thereby compounding pathology through oxidative damage to neighboring mitochondrial components including the lipoic acid cofactors of partner complexes (vaubel2011mutationsinthe pages 10-11, vaubel2011mutationsinthe pages 1-2).

DLD mutation	Nucleotide change / alias	Structural / biochemical effect	Reported clinical phenotype	Key notes / population context
G194C	c.685G>T; historically also reported as p.G229C in precursor numbering	Common pathogenic variant; relatively minor local structural changes near substitution site, with nearby cofactor-binding residues largely preserved compared with more disruptive variants	Often associated with comparatively milder disease and later presentation; recurrent hepatic failure/liver-predominant phenotype reported; DLD deficiency overall can include lactic acidosis and neurologic involvement	Ashkenazi Jewish founder mutation; carrier frequency reported as ~1:94 in Ashkenazi Jews; also reported in Arab Muslim patients (szabo2019underlyingmolecularalterations pages 4-5, odievre2005anovelmutation pages 5-8, staretzchacham2021theeffectsof pages 9-10, szabo2023structuralandbiochemical pages 21-22)
D444V	mature-protein numbering; interface-domain variant	Dimer-interface mutation; enhanced ROS-generating and proteolytic/diaphorase moonlighting activities; promotes oxidative damage to mitochondrial targets	Severe DLD deficiency presentations, including liver disease and metabolic decompensation; contributes to severe clinical course through oxidative injury mechanisms	Reported in Ashkenazi Jewish patients; widely studied as a pathogenic interface mutation (vaubel2011mutationsinthe pages 10-11, babady2007crypticproteolyticactivity pages 5-6, vaubel2011mutationsinthe pages 1-2, staretzchacham2021theeffectsof pages 9-10)
R460G	—	Dimer-interface mutation; enhances diaphorase activity and ROS production	Severe multisystem disorder of infancy	Included among severe interface mutations linked to oxidative damage and profound infantile disease (szabo2019underlyingmolecularalterations pages 4-5, vaubel2011mutationsinthe pages 10-11, vaubel2011mutationsinthe pages 1-2)
R447G	—	Dimer-interface mutation; perturbs solvent-accessible channel leading to active site; enhances ROS, and in some studies proteolytic activity	Severe multisystem disorder / severe infantile disease	Structural and functional evidence supports interface destabilization as pathogenic mechanism (szabo2019underlyingmolecularalterations pages 4-5, vaubel2011mutationsinthe pages 10-11, vaubel2011mutationsinthe pages 1-2)
E340K	—	Mutation associated with altered cryptic activities; enhanced diaphorase activity and ROS production	Severe multisystem disorder of infancy	Disease severity likely reflects both enzyme deficiency and oxidative-damage mechanisms (szabo2023structuralandbiochemical pages 21-22, vaubel2011mutationsinthe pages 10-11, vaubel2011mutationsinthe pages 1-2)
P453L	—	Most deleterious structural change among analyzed variants; active site extensively compromised	Severe phenotype expected/associated with markedly impaired enzyme function	Identified as especially disruptive in crystallographic analysis (szabo2019underlyingmolecularalterations pages 3-4, szabo2019underlyingmolecularalterations pages 4-5)
G426E	—	Dimer-interface variant; alters local charge distribution and introduces dynamics at substitution site; minor structural changes but functionally important	Pathogenic DLD deficiency; severity variable	Illustrates that even subtle structural changes at interface can impair multienzyme-complex function (szabo2019underlyingmolecularalterations pages 3-4, szabo2019underlyingmolecularalterations pages 4-5)
I445M	—	Dimer-interface variant; perturbs H+/H2O channel to active site	Pathogenic DLD deficiency; associated with impaired catalysis	Channel perturbation provides a structural explanation for dysfunction (szabo2019underlyingmolecularalterations pages 3-4, szabo2023structuralandbiochemical pages 1-3)
I12T	—	Unstable protein retaining dimeric form but with markedly compromised forward/reverse LADH activity and reduced FAD affinity	Pathogenic DLD deficiency	N-terminal variant showing severe biochemical impairment without the same structural class as interface mutants (szabo2023structuralandbiochemical pages 1-3, szabo2019underlyingmolecularalterations pages 4-5)
M326V	—	Protein instability, functional dimer disassembly, significant FAD loss, virtually undetectable catalytic activity	Pathogenic DLD deficiency	Demonstrates loss-of-stability mechanism (szabo2023structuralandbiochemical pages 1-3, szabo2019underlyingmolecularalterations pages 4-5)
G101del	—	Protein instability, dimer disassembly, significant FAD loss, virtually undetectable catalytic activity	Pathogenic DLD deficiency; reported in myopathic / Leigh-related clinical literature	Strong example of instability-driven deficiency (szabo2023structuralandbiochemical pages 1-3, staretzchacham2021theeffectsof pages 9-10, szabo2023structuralandbiochemical pages 21-22)
I318T	—	Minor conformational perturbations with residual enzymatic activity retained	Pathogenic DLD deficiency with residual function	Supports genotype–biochemistry gradient rather than uniform complete loss of function (szabo2023structuralandbiochemical pages 1-3, szabo2019underlyingmolecularalterations pages 4-5)
I358T / I353T	I358T in structural literature; I353T reported clinically in one case	Minor conformational perturbations / residual activity for I358T; I353T reported as disease-causing in Leigh syndrome case report	I353T associated with episodic encephalopathy, lactic acidosis, hypoglycemia, learning disability, and Leigh syndrome; I358T supports a residual-activity model	Numbering may differ between reports due to precursor vs mature protein conventions (szabo2023structuralandbiochemical pages 1-3, quinonez2013leighsyndromein pages 4-6, quinonez2013leighsyndromein pages 1-3)
R482G	c.1444A>G	Novel pathogenic variant in highly conserved region	Neurological deterioration beginning at birth/early infancy, hyperlactatemia, hypotonia/rigidity/choreoathetoid movements, early death	Reported in siblings with atypical α-ketoglutarate dehydrogenase deficiency / DLD deficiency phenotype (odievre2005anovelmutation pages 5-8, odievre2005anovelmutation pages 1-3)
G136del	—	Previously reported pathogenic deletion	Reported with DLD deficiency; in compound heterozygosity with I353T in a patient with episodic encephalopathy, lactic acidosis, hypoglycemia, and Leigh syndrome	Established disease-causing mutation in prior literature (quinonez2013leighsyndromein pages 4-6, quinonez2013leighsyndromein pages 1-3)

Table: This table summarizes disease-causing human DLD variants, linking structural/biochemical effects to reported clinical phenotypes. It is useful for functional annotation because it connects specific residues and mechanistic defects to recognizable metabolic and neurologic presentations.

7.2 Neurodegenerative Disease

DLD is implicated in neurodegeneration, particularly through the KGDHc axis. Reduced KGDHc activity is a consistent finding in Alzheimer's disease, and DLD heterozygous knockout animals show decreased ROS production from both forward and reverse electron flow (hansen2022theαketoglutaratedehydrogenase pages 2-4, OpenTargets Search: -DLD). Recent work has linked dysregulation of mitochondrial KGDHc, including DLD, to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models (OpenTargets Search: -DLD).

7.3 Cancer

Pan-cancer analysis has demonstrated that DLD is differentially expressed across multiple tumor types, with high expression in colon, liver, lung, stomach, renal, and ovarian cancers. In ovarian cancer, high DLD expression correlates with poorer prognosis. DLD regulates metabolic pathways by modulating the intracellular NAD⁺/NADH ratio, thereby influencing tumor cell proliferation (qi2023oncogenicroleof pages 1-2).

7.4 OpenTargets Disease Associations

Database analysis reveals strong DLD–disease associations for pyruvate dehydrogenase deficiency (association score 0.85), pyruvate dehydrogenase E3 deficiency (0.84), Leigh syndrome (0.64), neurodegenerative disease (0.53), and inflammatory bowel disease (0.52) (OpenTargets Search: -DLD).

8. Recent Developments (2023–2025)

Several recent advances have expanded our understanding of DLD:

Structural pathomechanisms (2023): Szabo et al. reported crystal structures of additional pathogenic hE3 variants (I318T at 2.89 Å, I358T at 2.44 Å), demonstrating a genotype-to-structure-to-phenotype continuum. Variants G101del and M326V cause dimer disassembly and FAD loss, while I318T and I358T show minor perturbations correlating with retained residual activity (szabo2023structuralandbiochemical pages 1-3).
Comprehensive LADH deficiency review (2023): Szabó and Ambrus provided an updated overview emphasizing that clinical severity often does not parallel enzymatic activity loss, implicating auxiliary pathomechanisms including stimulated ROS production and dissociation from multienzyme complexes (szabo2023structuralandbiochemical pages 1-3).
α-Keto acid dehydrogenase complex review (2024): A comprehensive review by Szabó et al. covered metabolic significance, enzymatic operation, moonlighting activities, and pathological relevance of all mitochondrial α-keto acid dehydrogenase complexes, consolidating current understanding of DLD's role across these systems (szabo2024mitochondrialalphaketoacid pages 1-6, szabo2024mitochondrialalphaketoacid pages 51-53, szabo2024mitochondrialalphaketoacid pages 16-19, szabo2024mitochondrialalphaketoacid pages 9-13).
In-situ PDHc architecture (2025): Wang et al. reported the first in-situ cryo-electron tomography structure of intact mammalian PDHc, revealing dynamic peripheral organization with an average of 21 E1 and up to 12 E3 components per complex, suggesting a novel activity-regulation mechanism through coordinated peripheral subunit numbers (wang2025dynamicsofthe pages 1-3).
DLD in cuproptosis mechanism (2022–present): The discovery that DLD is a key mediator of copper-dependent cell death has opened new research avenues, with recent work establishing that DLD activation drives NADH-reductive stress as a central mechanism of cuproptosis (zhang2026nadh‐reductivestressinduced pages 3-4).

9. Summary

Human DLD encodes a mitochondrial matrix-localized FAD-dependent disulfide oxidoreductase that serves as the shared E3 component of five major mitochondrial multienzyme complexes: PDHc, KGDHc, BCKDHc, KADHc, and the glycine cleavage system. Its primary enzymatic function is the NAD⁺-dependent oxidation of dihydrolipoamide to lipoamide via a ping-pong mechanism involving a redox-active Cys45-Cys50 disulfide and FAD cofactor. This reaction is essential for regenerating the lipoyl cofactor in each partner complex and for producing NADH for oxidative phosphorylation. DLD additionally possesses moonlighting activities including diaphorase, protease, and ROS-generating functions that become pathologically significant when the enzyme's homodimeric structure is destabilized. Mutations in DLD cause a rare but severe metabolic disorder affecting multiple central metabolic pathways, and DLD has recently emerged as a critical mediator of cuproptosis—a copper-dependent form of cell death with implications for neurodegeneration and cancer therapeutics.

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(szabo2023structuralandbiochemical pages 21-22): Eszter Szabo, Eva Nemes-Nikodem, Krisztina Rubina Vass, Zsofia Zambo, Eszter Zrupko, Beata Torocsik, Oliver Ozohanics, Balint Nagy, and Attila Ambrus. Structural and biochemical investigation of selected pathogenic mutants of the human dihydrolipoamide dehydrogenase. International Journal of Molecular Sciences, 24:10826, Jun 2023. URL: https://doi.org/10.3390/ijms241310826, doi:10.3390/ijms241310826. This article has 2 citations.
(quinonez2013leighsyndromein pages 4-6): Shane C. Quinonez, Steven M. Leber, Donna M. Martin, Jess G. Thoene, and Jirair K. Bedoyan. Leigh syndrome in a girl with a novel dld mutation causing e3 deficiency. Pediatric neurology, 48 1:67-72, Jan 2013. URL: https://doi.org/10.1016/j.pediatrneurol.2012.09.013, doi:10.1016/j.pediatrneurol.2012.09.013. This article has 67 citations and is from a peer-reviewed journal.
(odievre2005anovelmutation pages 1-3): Marie-Hélène Odièvre, Dominique Chretien, Arnold Munnich, Brian H. Robinson, Renée Dumoulin, Sahben Masmoudi, Noman Kadhom, Agnès Rötig, Pierre Rustin, and Jean-Paul Bonnefont. A novel mutation in the dihydrolipoamide dehydrogenase e3 subunit gene (dld) resulting in an atypical form of α‐ketoglutarate dehydrogenase deficiency. Human Mutation, 25:323-324, Mar 2005. URL: https://doi.org/10.1002/humu.9319, doi:10.1002/humu.9319. This article has 112 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: -DLD): Open Targets Query (-DLD, 11 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(szabo2024mitochondrialalphaketoacid pages 51-53): Eszter Szabó, Bálint Nagy, András Czajlik, T. Komlódi, Olivér Ozohanics, László Tretter, and A. Ambrus. Mitochondrial alpha-keto acid dehydrogenase complexes: recent developments on structure and function in health and disease. Sub-cellular biochemistry, 104:295-381, 2024. URL: https://doi.org/10.1007/978-3-031-58843-3_13, doi:10.1007/978-3-031-58843-3_13. This article has 16 citations.
(szabo2024mitochondrialalphaketoacid pages 9-13): Eszter Szabó, Bálint Nagy, András Czajlik, T. Komlódi, Olivér Ozohanics, László Tretter, and A. Ambrus. Mitochondrial alpha-keto acid dehydrogenase complexes: recent developments on structure and function in health and disease. Sub-cellular biochemistry, 104:295-381, 2024. URL: https://doi.org/10.1007/978-3-031-58843-3_13, doi:10.1007/978-3-031-58843-3_13. This article has 16 citations.

Artifacts

Citations

yan2023rolesofdihydrolipoamide pages 1-3
szabo2023structuralandbiochemical pages 1-3
szabo2019underlyingmolecularalterations pages 3-4
duarte2021dihydrolipoamidedehydrogenasepyruvate pages 2-4
wang2025dynamicsofthe pages 1-3
leung2021glycinecleavagesystem pages 1-2
duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-6
yan2023rolesofdihydrolipoamide pages 7-8
babady2007crypticproteolyticactivity pages 4-5
babady2007crypticproteolyticactivity pages 5-6
vaubel2011mutationsinthe pages 10-11
vaubel2011mutationsinthe pages 1-2
babady2007crypticproteolyticactivity pages 1-2
zhao2024cuproptosisthenovel pages 3-4
szabo2019underlyingmolecularalterations pages 4-5
qi2023oncogenicroleof pages 1-2
duarte2021dihydrolipoamidedehydrogenasepyruvate pages 4-4
yan2023rolesofdihydrolipoamide pages 5-7
szabo2024mitochondrialalphaketoacid pages 1-6
brautigam2006structuralinsightinto pages 1-2
szabo2024mitochondrialalphaketoacid pages 16-19
kikuchi2008glycinecleavagesystem pages 2-5
brautigam2006structuralinsightinto pages 2-3
chen2025roleandmechanisms pages 2-4
chen2025mechanismsofcopper pages 2-3
szabo2024mitochondrialalphaketoacid pages 36-39
quinonez2013leighsyndromein pages 1-3
odievre2005anovelmutation pages 5-8
staretzchacham2021theeffectsof pages 9-10
szabo2023structuralandbiochemical pages 21-22
quinonez2013leighsyndromein pages 4-6
odievre2005anovelmutation pages 1-3
szabo2024mitochondrialalphaketoacid pages 51-53
szabo2024mitochondrialalphaketoacid pages 9-13
LADH
https://doi.org/10.1089/ars.2022.0181,
https://doi.org/10.1093/hmg/ddz177,
https://doi.org/10.1007/s00018-021-03996-3,
https://doi.org/10.3390/ijms241310826,
https://doi.org/10.1007/978-3-031-58843-3_13,
https://doi.org/10.1016/j.str.2006.01.001,
https://doi.org/10.3390/ijms232012403,
https://doi.org/10.2183/pjab.84.246,
https://doi.org/10.3389/fgene.2021.625120,
https://doi.org/10.1038/s41467-025-56171-8,
https://doi.org/10.1073/pnas.0610618104,
https://doi.org/10.1074/jbc.m111.274415,
https://doi.org/10.3892/ol.2023.13800,
https://doi.org/10.3892/ijmm.2025.5558,
https://doi.org/10.1186/s12964-024-01743-2,
https://doi.org/10.3389/fimmu.2025.1633711,
https://doi.org/10.1002/advs.202520444,
https://doi.org/10.1016/j.pediatrneurol.2012.09.013,
https://doi.org/10.1002/humu.9319,
https://doi.org/10.3390/nu13103523,

📚 Additional Documentation

Notes

(DLD-notes.md)

DLD (P09622) review notes

Human dihydrolipoyl dehydrogenase (DLD), the E3 component. Shared, pleiotropic subunit.

Verified core biology

DLD is a FAD-dependent, NAD+-linked flavoenzyme (EC 1.8.1.4) that reoxidizes the
dihydrolipoyl group on the lipoyl-bearing E2/H components, transferring electrons to
NAD+ via its FAD. GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity. Functions as a
homodimer, one FAD per subunit; active site is a redox-active disulfide (Cys80-Cys85).
[UniProt P09622 CATALYTIC ACTIVITY / COFACTOR / MISCELLANEOUS blocks]
Shared E3 of FOUR complexes:
pyruvate dehydrogenase complex (PDH) — GO:0045254
2-oxoglutarate (alpha-ketoglutarate) dehydrogenase complex (OGDH) — GO:0045252
branched-chain alpha-ketoacid dehydrogenase complex (BCKDH) — GO:0160157
glycine cleavage system as the L protein (GCSL / GcvL)
Also the 2-oxoadipate dehydrogenase complex (OADH, DHTKD1-E1) — GO:0160167
[PMID:37701333 "including pyruvate dehydrogenase (PDH), alpha-ketoglutarate dehydrogenase
(KGDH), branched-chain alpha-keto acid dehydrogenase (BCKDH), and 2-oxoadipate
dehydrogenase (OADH)"; PMID:29191460 hE1a recruits hE2o and hE3 of OGDHc]
Localization: mitochondrial matrix (main). Small nuclear fraction (~1-1.6%) as part of
the nuclear α-KGDH complex that supplies succinyl-CoA to KAT2A for histone H3 succinylation
PMID:29211711.

Moonlighting / secondary

Cryptic serine protease activity when the homodimer is destabilized (S456-E431 dyad at
interface); induced by disruption of the native dimer, which also inhibits the primary
dehydrogenase activity PMID:17404228. Treat as non-core.
Reported cilium/flagellum/acrosome localization by similarity (Q811C4, rodent), sperm
capacitation/acrosome reaction — non-core, By similarity/IEA only.

Disease

DLD deficiency (DLDD, MIM 246900): combined deficiency of PDH + OGDH + BCKDH (and OADH).
MSUD variant + lactic acidosis + alpha-ketoglutaric aciduria. [UniProt DISEASE; dismech
Maple_Syrup_Urine_Disease.yaml "deficiency in the shared E3 subunit (DLD) produces..."]

Annotation strategy

Core MF: GO:0004148 (many EXP/IDA/IMP/IBA/TAS lines — ACCEPT).
FAD binding GO:0050660 — ACCEPT (cofactor, direct).
Complex membership (PDH GO:0045254, OGDH GO:0045252, BCKDH GO:0160157, OADH GO:0160167):
all genuine, ACCEPT (or KEEP for OADH as it is a shared but less-central role).
Processes: pyruvate decarboxylation to acetyl-CoA GO:0006086, 2-oxoglutarate
decarboxylation to succinyl-CoA GO:0120551, branched-chain keto acid decarboxylation
GO:0120552, TCA GO:0006099, 2-oxoglutarate metabolic GO:0006103, BCAA catabolic GO:0009083,
L-lysine catabolic GO:0019477 — all genuine given shared E3 role. ACCEPT the specific ones;
broad/parent ones KEEP_AS_NON_CORE.
protein binding IPIs (GO:0005515) x9 from IntAct/interactome screens (PDHX O00330 is the
physiological E3-binding-protein partner; HTT, ITGB1BP1, PRDX6, YWHAE, others are
screen hits) — MARK_AS_OVER_ANNOTATED (uninformative; do NOT remove per policy).
Localization: mitochondrion / mitochondrial matrix — ACCEPT. Nucleus/nucleoplasm — genuine
minor pool (KEEP_AS_NON_CORE). Cilium/motile cilium/flagellum/acrosome/acrosomal
vesicle/acrosomal matrix — By-similarity/IEA electronic; MARK_AS_OVER_ANNOTATED for human.
oxidoreductase activity GO:0016491 (too general) — MODIFY -> GO:0004148.
GO:0016668 (acting on sulfur group of donors, NAD(P) acceptor) — parent of GO:0004148,
keep as accurate-but-general -> KEEP_AS_NON_CORE.

DR: falcon deep-research file did not land within the 8-minute poll window; grounded in
UniProt, cached publications, and dismech.

📄 View Raw YAML

id: P09622
gene_symbol: DLD
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DLD encodes dihydrolipoyl dehydrogenase (E3; dihydrolipoamide dehydrogenase, EC 1.8.1.4),
  a mitochondrial FAD-dependent, NAD+-linked flavoenzyme that functions as a homodimer with
  one FAD per subunit and a redox-active active-site disulfide. Its enzymatic role is to
  reoxidize the reduced (dihydro)lipoyl groups carried on the lipoyl-bearing domains of the
  E2/H components of several 2-oxoacid dehydrogenase systems, passing the electrons to NAD+
  via FAD (regenerating the oxidized lipoyl cofactor for another catalytic cycle). DLD is a
  shared subunit: it serves as the common E3 component of the pyruvate dehydrogenase complex
  (PDH), the 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase complex (OGDH), the
  branched-chain alpha-ketoacid dehydrogenase complex (BCKDH), and the 2-oxoadipate
  dehydrogenase complex (OADH), and it is also the L protein of the mitochondrial glycine
  cleavage system. Through these complexes DLD contributes to pyruvate decarboxylation to
  acetyl-CoA, the tricarboxylic acid cycle, branched-chain amino acid catabolism, and lysine
  degradation. It resides mainly in the mitochondrial matrix, with a small nuclear pool of the
  2-oxoglutarate dehydrogenase complex that supplies succinyl-CoA for KAT2A-mediated histone
  succinylation. Because the enzyme is shared across multiple complexes, loss-of-function
  variants cause dihydrolipoamide dehydrogenase (E3) deficiency, a combined disorder with
  features of maple syrup urine disease together with lactic acidosis and
  alpha-ketoglutaric aciduria.
alternative_products:
- name: '1'
  id: P09622-1
- name: '2'
  id: P09622-2
  sequence_note: VSP_055855
- name: '3'
  id: P09622-3
  sequence_note: VSP_055856
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: DLD is a mitochondrial matrix protein; the phylogenetic (IBA) mitochondrion
      annotation is correct and consistent with the mitochondrial transit peptide (residues
      1-35) and abundant experimental localization data.
    action: ACCEPT
    reason: Well-supported by an N-terminal mitochondrial targeting sequence and multiple
      experimental localization studies. Broad but accurate; the more specific mitochondrial
      matrix term captures the same information at finer granularity.
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This is the core, defining molecular function of DLD/E3 (EC 1.8.1.4). The
      phylogenetic annotation matches abundant human experimental evidence and the UniProt
      catalytic-activity annotation (dihydrolipoyl-lysyl-protein + NAD+ = lipoyl-lysyl-protein
      + NADH + H+; RHEA:15045).
    action: ACCEPT
    reason: DLD catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains of
      E2/H components with NAD+ as the ultimate electron acceptor. Directly supported by
      enzymatic assays and structural work; this is the most specific correct MF term.
- term:
    id: GO:0006103
    label: 2-oxoglutarate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As the shared E3 component of the 2-oxoglutarate (alpha-ketoglutarate)
      dehydrogenase complex, DLD participates in 2-oxoglutarate metabolism within the TCA
      cycle. The phylogenetic annotation is biologically correct.
    action: KEEP_AS_NON_CORE
    reason: Accurate but general; DLD's involvement is via its shared dehydrogenase activity in
      the OGDH complex rather than a 2-oxoglutarate-specific function. The more specific
      process term 2-oxoglutarate decarboxylation to succinyl-CoA (GO:0120551) better
      captures the pathway step.
- term:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: DLD is the E3 subunit of the 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase
      complex, composed of OGDH (E1), DLST (E2) and DLD (E3). Membership is well established
      and independently supported by experimental (IDA) and NAS annotations.
    action: ACCEPT
    reason: Genuine complex membership; DLD physically associates with OGDH and DLST as the
      shared E3 component.
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DLD is a flavoprotein that binds one FAD per subunit; FAD is the redox cofactor
      that mediates electron transfer from the dihydrolipoyl group to NAD+. The phylogenetic
      annotation is correct and matches the UniProt COFACTOR annotation.
    action: ACCEPT
    reason: FAD binding is an essential, experimentally established cofactor-binding function
      integral to the dehydrogenase mechanism.
    supported_by:
    - reference_id: PMID:8506365
      supporting_text: These mutations appear to be significant in that they alter the active
        site and possibly the binding of FAD.
- term:
    id: GO:0001669
    label: acrosomal vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation derived from a UniProt subcellular-location keyword. A
      secretory-vesicle/acrosome localization is reported in UniProt but only via a single
      study and by similarity; it reflects a sperm-specific pool, not the primary function.
    action: MARK_AS_OVER_ANNOTATED
    reason: DLD is overwhelmingly a mitochondrial matrix enzyme. The acrosome localization is
      a specialized minor pool inferred electronically from a subcellular-location keyword and
      does not represent a core function of the gene product.
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (ARBA/InterPro, mapped to RHEA:15045 / EC 1.8.1.4) to the
      core dihydrolipoyl dehydrogenase activity. This matches the experimentally verified
      function.
    action: ACCEPT
    reason: Correct core molecular function, redundantly captured across IBA, EXP, IDA, IMP and
      TAS evidence.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation from a UniProt subcellular-location keyword. A minor nuclear
      pool of DLD is genuine - a small fraction of the 2-oxoglutarate dehydrogenase complex
      localizes to the nucleus (about 1-1.6% of total DLD) where it supplies succinyl-CoA for
      histone succinylation.
    action: KEEP_AS_NON_CORE
    reason: The nuclear localization is experimentally supported (PMID:29211711) but represents
      a minor, specialized pool; the mitochondrial matrix is the primary site.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: about 1–1.6% of total OGDH, DLST, and DLD was localized in the nucleus
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation to the mitochondrial matrix, the primary site of DLD. This
      is the correct and most specific localization, consistent with the UniProt subcellular
      location and its role in matrix 2-oxoacid dehydrogenase complexes and the glycine
      cleavage system.
    action: ACCEPT
    reason: DLD mainly localizes to the mitochondrial matrix; this term is accurate and
      appropriately specific.
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation to the very general parent term oxidoreductase
      activity. DLD is indeed an oxidoreductase, but a far more specific and accurate term
      exists.
    action: MODIFY
    reason: Too general. The specific molecular function is dihydrolipoyl dehydrogenase (NADH)
      activity, which is already annotated with experimental evidence.
    proposed_replacement_terms:
    - id: GO:0004148
      label: dihydrolipoyl dehydrogenase (NADH) activity
- term:
    id: GO:0016668
    label: oxidoreductase activity, acting on a sulfur group of donors, NAD(P) as
      acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation to an intermediate parent term. DLD does act on
      a sulfur group of donors (the dithiol/disulfide of the lipoyl cofactor) with NAD+ as
      acceptor, so the term is accurate but less specific than the annotated
      dihydrolipoyl dehydrogenase (NADH) activity.
    action: KEEP_AS_NON_CORE
    reason: Correct grouping term (direct parent of GO:0004148) but redundant with the more
      specific experimentally supported MF; retained as an accurate but general classification.
- term:
    id: GO:0031514
    label: motile cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation from a UniProt subcellular-location keyword; the
      cilium/flagellum localization is inferred by similarity to a rodent ortholog (Q811C4)
      and relates to a putative sperm-flagellum pool.
    action: MARK_AS_OVER_ANNOTATED
    reason: Not a core localization for human DLD. Inferred electronically by similarity; the
      enzyme is overwhelmingly a mitochondrial matrix protein.
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation of FAD binding, consistent with the
      experimentally established and IBA-supported flavin cofactor binding.
    action: ACCEPT
    reason: Correct cofactor-binding function; DLD binds one FAD per subunit as an integral
      part of its catalytic mechanism.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16263718
  qualifier: enables
  review:
    summary: IPI interaction with PDHX (O00330), the E3-binding protein that tethers DLD to the
      E2 core of the pyruvate dehydrogenase complex. The interaction is real and functionally
      important, but the bare protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no specific molecular function. The physiologically
      meaningful information (DLD-PDHX tethering within PDH) is captured by complex-membership
      annotations. Retained per policy for IPI evidence but flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16442803
  qualifier: enables
  review:
    summary: IPI interaction with PDHX (O00330), from the crystallographic study of the
      E3/E3-binding-protein interface. Functionally relevant but captured by the generic,
      uninformative protein binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; the DLD-PDHX interaction underlying PDH
      assembly is better represented by complex-membership annotations. Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IPI to PDHX (O00330) from a large-scale interactome study (BioPlex-type). Generic
      protein binding without specific functional meaning.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare protein binding derived from a high-throughput interactome
      screen; retained per policy but flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29128334
  qualifier: enables
  review:
    summary: IPI interactions (PRDX6/P30041 and YWHAE/P62258) from a mitochondrial protein
      interaction map. Generic protein binding with no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare protein binding from a high-throughput interactome screen;
      retained per policy but flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IPI interactions (PDHX/O00330 and ITGB1BP1/O14713) from the HuRI binary
      interactome map. Generic protein binding without specific functional meaning.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare protein binding from a high-throughput binary interactome
      screen; retained per policy but flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: IPI interaction with HTT (P42858, huntingtin) from a neurodegenerative-disease
      interactome study. Generic protein binding with no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare protein binding from a high-throughput interactome screen;
      retained per policy but flagged as over-annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IPI interaction with PDHX (O00330) from the BioPlex 3.0 dual proteome-scale
      network. Generic protein binding without specific functional meaning.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare protein binding from a high-throughput interactome screen;
      retained per policy but flagged as over-annotated.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Electronic (Ensembl Compara orthology) annotation to mitochondrion, the primary
      compartment for DLD. Correct but general; mitochondrial matrix is more specific.
    action: ACCEPT
    reason: DLD is a mitochondrial matrix protein; this parent localization is accurate.
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Electronic (Ensembl Compara orthology) annotation to cilium, inferred by
      similarity to a rodent ortholog. Not a core localization for human DLD.
    action: MARK_AS_OVER_ANNOTATED
    reason: DLD is overwhelmingly mitochondrial; the cilium/flagellum assignment is an
      electronic inference from orthology and reflects at most a specialized sperm pool.
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic (ARBA/orthology) annotation to pyruvate decarboxylation to acetyl-CoA,
      the pyruvate dehydrogenase complex reaction in which DLD acts as the E3 subunit. Also
      independently supported by IDA and IC evidence.
    action: ACCEPT
    reason: Correct biological process; DLD is the shared E3 subunit of the PDH complex that
      links glycolysis to the TCA cycle.
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic (orthology) annotation to the TCA cycle, reflecting DLD's role as the
      E3 subunit of the 2-oxoglutarate dehydrogenase complex (which catalyzes a TCA-cycle
      step). Also supported by NAS evidence.
    action: KEEP_AS_NON_CORE
    reason: Accurate but broad process. DLD's TCA involvement is via the OGDH complex; the more
      specific step term (2-oxoglutarate decarboxylation to succinyl-CoA, GO:0120551) is
      preferred as the informative process.
- term:
    id: GO:0043159
    label: acrosomal matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Electronic (orthology) annotation to the acrosomal matrix, reflecting a putative
      sperm-specific pool inferred by similarity to a rodent ortholog. Not a core localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: DLD is predominantly a mitochondrial matrix enzyme; the acrosomal-matrix assignment
      is an electronic orthology inference for a specialized minor pool.
- term:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Electronic (ARBA/orthology) annotation of membership in the 2-oxoglutarate
      dehydrogenase complex, redundant with experimental (IDA) and IBA/NAS annotations for the
      same complex.
    action: ACCEPT
    reason: Genuine complex membership as the shared E3 subunit of OGDH.
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Electronic (ARBA/orthology) annotation of membership in the pyruvate dehydrogenase
      complex, redundant with experimental (IDA/IPI) annotations for the same complex.
    action: ACCEPT
    reason: Genuine complex membership as the shared E3 subunit of PDH.
- term:
    id: GO:0019477
    label: L-lysine catabolic process
  evidence_type: IMP
  original_reference_id: PMID:37701333
  qualifier: involved_in
  review:
    summary: DLD deficiency patients accumulate lysine-degradation intermediates (2-ketoadipic
      and 2-hydroxyadipic acids), reflecting DLD's role as the shared E3 subunit of the
      2-oxoadipate dehydrogenase complex (OADH) in the lysine catabolic pathway.
    action: ACCEPT
    reason: Experimentally supported via patient biochemistry; DLD contributes to lysine
      degradation through the OADH complex, which shares its E3 with the other 2-oxoacid
      dehydrogenases.
    supported_by:
    - reference_id: PMID:37701333
      supporting_text: also highlight the under-recognized role of DLD in the lysine
        degradation
    - reference_id: PMID:37701333
      supporting_text: 2‐ketoadipic and 2‐hydroxyadipic acids were detected in the urine of two
        individuals during acute decompensation and represent relatively specific markers of
        DLDD
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: located_in
  review:
    summary: ComplexPortal NAS localization to mitochondrion, associated with the 2-oxoglutarate
      dehydrogenase complex. Consistent with the well-established mitochondrial localization.
    action: ACCEPT
    reason: Correct; DLD is a mitochondrial protein. Mitochondrial matrix is the more specific
      term.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: NAS
  original_reference_id: PMID:3593587
  qualifier: located_in
  review:
    summary: ComplexPortal NAS localization to the mitochondrial matrix, associated with the
      BCKDH complex. This is the primary and correct localization of DLD.
    action: ACCEPT
    reason: DLD is a mitochondrial matrix enzyme; the matrix is the most specific accurate
      compartment.
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS annotation to the TCA cycle via the 2-oxoglutarate dehydrogenase
      complex. Accurate but broad.
    action: KEEP_AS_NON_CORE
    reason: DLD contributes to a TCA-cycle step through the OGDH complex; the specific step
      term GO:0120551 is more informative. Retained as accurate context.
- term:
    id: GO:0006103
    label: 2-oxoglutarate metabolic process
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS annotation to 2-oxoglutarate metabolism via the OGDH complex.
      Accurate but general.
    action: KEEP_AS_NON_CORE
    reason: DLD's role in 2-oxoglutarate metabolism is via the OGDH complex; the specific step
      term GO:0120551 (2-oxoglutarate decarboxylation to succinyl-CoA) is more informative.
- term:
    id: GO:0009083
    label: branched-chain amino acid catabolic process
  evidence_type: IDA
  original_reference_id: PMID:3593587
  qualifier: involved_in
  review:
    summary: Purified human liver BCKDH complex (containing the dissociable lipoamide
      oxidoreductase, i.e. DLD/E3) oxidized all three branched-chain 2-keto acids (KIV, KIC,
      KMV), demonstrating DLD's participation in branched-chain amino acid catabolism.
    action: ACCEPT
    reason: Experimentally supported role as the E3 subunit of the BCKDH complex in BCAA
      degradation.
    supported_by:
    - reference_id: PMID:3593587
      supporting_text: The BCKADH effectively oxidized all of KIV, KIC, and KMV
    - reference_id: PMID:3593587
      supporting_text: The minor band corresponded in molecular weight to
        lipoamide oxidoreductase which was purified separately.
- term:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: part_of
  review:
    summary: ComplexPortal NAS annotation of DLD as the E3 component of the 2-oxoglutarate
      dehydrogenase complex, consistent with the structural characterization of the human
      OGDH complex.
    action: ACCEPT
    reason: Genuine complex membership; corroborated by experimental (IDA) and IBA annotations.
- term:
    id: GO:0160157
    label: branched-chain alpha-ketoacid dehydrogenase complex
  evidence_type: IPI
  original_reference_id: PMID:3593587
  qualifier: part_of
  review:
    summary: The purified human liver BCKDH complex included a dissociable lipoamide
      oxidoreductase (DLD/E3) band; the complex required exogenous lipoamide oxidoreductase for
      full activity, establishing DLD as the E3 component of BCKDH.
    action: ACCEPT
    reason: Genuine complex membership as the shared E3 subunit of the BCKDH complex.
    supported_by:
    - reference_id: PMID:3593587
      supporting_text: The purified BCKADH
        represented only approximately 20% of the maximum activity when assayed without
        addition of exogenous lipoamide oxidoreductase, indicating that lipoamide
        oxidoreductase component was readily dissociable from the complex.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:24534072
  qualifier: located_in
  review:
    summary: ComplexPortal NAS localization to mitochondrion (in the context of the recombinant
      PDH complex). Consistent with the established mitochondrial localization.
    action: ACCEPT
    reason: Correct; DLD is a mitochondrial protein.
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IDA
  original_reference_id: PMID:24534072
  qualifier: involved_in
  review:
    summary: A functional recombinant human pyruvate dehydrogenase complex (all five
      components, including DLD/E3) was reconstituted and shown to convert pyruvate to
      acetyl-CoA, directly demonstrating DLD's participation in this process.
    action: ACCEPT
    reason: Directly supported; DLD is the E3 subunit of the PDH complex that decarboxylates
      pyruvate to acetyl-CoA.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: The mammalian pyruvate
        dehydrogenase complex (PDC) is a multi-component
        mitochondrial enzyme that plays a key role in the conversion of pyruvate to
        acetyl-CoA connecting glycolysis to the citric acid cycle.
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IPI
  original_reference_id: PMID:19240034
  qualifier: part_of
  review:
    summary: Study of subunit and catalytic-component stoichiometries of an in vitro
      reconstituted human PDH complex, establishing DLD/E3 as a bona fide component of the
      complex.
    action: ACCEPT
    reason: Genuine complex membership as the shared E3 subunit of PDH.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence detects DLD in the nucleoplasm. This is consistent with the
      documented minor nuclear pool of the 2-oxoglutarate dehydrogenase complex.
    action: KEEP_AS_NON_CORE
    reason: A genuine but minor nuclear pool exists (about 1-1.6% of total DLD; PMID:29211711).
      The primary localization and function are mitochondrial, so this is non-core.
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: EXP
  original_reference_id: PMID:16770810
  qualifier: enables
  review:
    summary: DLD deficiency in two cousins was diagnosed by reduced DLD (E3) enzyme activity,
      with enzyme-kinetic measurements on patient fibroblasts, experimentally implicating the
      dihydrolipoyl dehydrogenase activity.
    action: ACCEPT
    reason: Experimental evidence for the core dihydrolipoyl dehydrogenase activity of DLD.
    supported_by:
    - reference_id: PMID:16770810
      supporting_text: We have diagnosed dihydrolipoamide dehydrogenase (DLD)
        deficiency in two male
        second cousins
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: EXP
  original_reference_id: PMID:17404228
  qualifier: enables
  review:
    summary: This study of DLD's cryptic proteolytic activity characterizes the enzyme's
      primary dihydrolipoamide dehydrogenase activity in the native homodimer and shows that
      destabilizing the dimer causes loss of DLD activity and gain of protease activity.
    action: ACCEPT
    reason: Experimental support for the core dehydrogenase activity (in the native dimer);
      the same paper documents the moonlighting protease as a distinct, non-core activity.
    supported_by:
    - reference_id: PMID:17404228
      supporting_text: The mitochondrial enzyme, dihydrolipoamide dehydrogenase (DLD), is
        essential for
        energy metabolism across eukaryotes.
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: EXP
  original_reference_id: PMID:20160912
  qualifier: enables
  review:
    summary: Characterization of E1 and E3 interactions with the PDH core proteins,
      experimentally supporting DLD's dihydrolipoyl dehydrogenase activity within the complex.
    action: ACCEPT
    reason: Experimental support for the core molecular function of DLD.
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: EXP
  original_reference_id: PMID:20385101
  qualifier: enables
  review:
    summary: Characterization of DLD interactions with its E3-binding protein in the human PDH
      complex, experimentally supporting DLD's dihydrolipoyl dehydrogenase activity.
    action: ACCEPT
    reason: Experimental support for the core molecular function of DLD.
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IDA
  original_reference_id: PMID:16442803
  qualifier: involved_in
  review:
    summary: Structural study of the E3/E3-binding-protein interface in the human PDH complex,
      supporting DLD's role in the pyruvate-to-acetyl-CoA reaction as the tethered E3
      component.
    action: ACCEPT
    reason: Consistent with DLD being the E3 subunit of the PDH complex.
    supported_by:
    - reference_id: PMID:16442803
      supporting_text: utilizes the specific
        dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the
        essential E3 component to the 60-meric core of the complex
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:14638692
  qualifier: part_of
  review:
    summary: Characterization of the mammalian PDH core (E2 and E2.E3BP) and its capacity to
      bind the E1 and E3 components; E3 (DLD) binds to the E2.E3BP core outside the central
      dodecahedron, establishing DLD as a component of the assembled complex.
    action: ACCEPT
    reason: Genuine complex membership as the shared E3 subunit of PDH.
    supported_by:
    - reference_id: PMID:14638692
      supporting_text: small angle
        x-ray scattering showed that E3 binds to E2.E3BP outside the central
        dodecahedron
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: IDA
  original_reference_id: PMID:9242632
  qualifier: enables
  review:
    summary: Reconstitution of the human pyruvate dehydrogenase complex with E3BP and E3 (DLD)
      demonstrated DLD's dihydrolipoamide dehydrogenase activity within the functional complex.
    action: ACCEPT
    reason: Experimental (IDA) support for the core molecular function; DLD is required to
      reconstitute a functional PDH complex.
    supported_by:
    - reference_id: PMID:9242632
      supporting_text: is required for anchoring dihydrolipoamide dehydrogenase (E3) to the
        dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase
        complexes of eukaryotes
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IC
  original_reference_id: PMID:9242632
  qualifier: acts_upstream_of_or_within
  review:
    summary: Curator inference (IC) from DLD's dihydrolipoyl dehydrogenase activity (GO:0004148)
      that DLD acts within the pyruvate decarboxylation to acetyl-CoA process.
    action: ACCEPT
    reason: Sound inference; as the E3 subunit of PDH, DLD is integral to converting pyruvate
      to acetyl-CoA.
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: IMP
  original_reference_id: PMID:15712224
  qualifier: enables
  review:
    summary: A homozygous DLD mutation (R482G) reduced E3 subunit activity to ~20% of control,
      providing mutation-based evidence for the dihydrolipoyl dehydrogenase activity of DLD.
    action: ACCEPT
    reason: Loss-of-function mutation reduces E3 activity, directly implicating DLD in this
      molecular function.
    supported_by:
    - reference_id: PMID:15712224
      supporting_text: E3 subunit
        activity was shown to be deficient (20% of control values)
- term:
    id: GO:0120551
    label: 2-oxoglutarate decarboxylation to succinyl-CoA
  evidence_type: IMP
  original_reference_id: PMID:15712224
  qualifier: involved_in
  review:
    summary: A DLD mutation produced an atypical alpha-ketoglutarate dehydrogenase deficiency
      (KGDC deficiency), directly implicating DLD in the 2-oxoglutarate decarboxylation to
      succinyl-CoA step of the TCA cycle via the OGDH complex.
    action: ACCEPT
    reason: Mutation-based (IMP) evidence for DLD's involvement in the OGDH-catalyzed
      2-oxoglutarate decarboxylation step; a specific and informative process term.
    supported_by:
    - reference_id: PMID:15712224
      supporting_text: The alpha-ketoglutarate dehydrogenase complex (KGDC)
        catalyses the
        decarboxylation of alpha-ketoglutarate into succinyl-coenzyme A in the Krebs
        cycle.
- term:
    id: GO:0120552
    label: branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA
  evidence_type: IDA
  original_reference_id: PMID:3593587
  qualifier: involved_in
  review:
    summary: The purified human liver BCKDH complex (with dissociable DLD/E3) oxidized KIV, KIC
      and KMV to yield the corresponding branched-chain acyl products, requiring NAD and CoASH,
      directly demonstrating DLD's role in this decarboxylation process.
    action: ACCEPT
    reason: Directly supported; DLD is the E3 subunit that enables the BCKDH-catalyzed
      decarboxylation of branched-chain 2-keto acids. Specific and informative process term.
    supported_by:
    - reference_id: PMID:3593587
      supporting_text: NAD and CoASH were
        absolutely required for the reaction.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteomics detected DLD as a mitochondrial protein,
      consistent with its established localization.
    action: ACCEPT
    reason: Correct mitochondrial localization corroborated by many independent lines of
      evidence.
- term:
    id: GO:0160157
    label: branched-chain alpha-ketoacid dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:3593587
  qualifier: part_of
  review:
    summary: The purified human liver BCKDH complex contained a dissociable lipoamide
      oxidoreductase band (DLD/E3), establishing DLD as the E3 component of the complex.
    action: ACCEPT
    reason: Genuine, experimentally established complex membership as the shared E3 subunit of
      BCKDH.
    supported_by:
    - reference_id: PMID:3593587
      supporting_text: The minor band corresponded in molecular weight to
        lipoamide oxidoreductase which was purified separately.
- term:
    id: GO:0160167
    label: oxoadipate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:29191460
  qualifier: part_of
  review:
    summary: The human 2-oxoadipate dehydrogenase E1 component (hE1a/DHTKD1) recruits the
      dihydrolipoyl succinyltransferase (E2o) and dihydrolipoyl dehydrogenase (E3/DLD)
      components, establishing DLD as the shared E3 of the 2-oxoadipate dehydrogenase complex.
    action: ACCEPT
    reason: Experimentally established membership; DLD is shared with the OADH complex, which
      participates in lysine/tryptophan degradation.
    supported_by:
    - reference_id: PMID:29191460
      supporting_text: The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase
        complexes share
        their E2 and E3 components for their function
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: IDA
  original_reference_id: PMID:16442803
  qualifier: enables
  review:
    summary: Structural/biochemical characterization of human E3 (DLD) in complex with the
      E3-binding domain, supporting its dihydrolipoyl dehydrogenase activity within the PDH
      complex.
    action: ACCEPT
    reason: Experimental (IDA) support for the core molecular function; DLD binds as an E3
      homodimer and functions within PDH.
    supported_by:
    - reference_id: PMID:16442803
      supporting_text: resulting in one E3BD binding site on the E3 homodimer
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:29211711
  qualifier: located_in
  review:
    summary: Cell-fractionation and immunofluorescence showed that a small fraction (~1-1.6%)
      of DLD, as part of the 2-oxoglutarate dehydrogenase complex, localizes to the nucleus
      where it supplies succinyl-CoA to KAT2A for histone H3 succinylation.
    action: KEEP_AS_NON_CORE
    reason: A genuine but minor, specialized nuclear pool. The core localization and function
      of DLD are mitochondrial, so the nuclear role is non-core.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: about 1–1.6% of total OGDH, DLST, and DLD was localized in the nucleus
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:29211711
  qualifier: located_in
  review:
    summary: The same study confirmed that the bulk of DLD (as part of the 2-oxoglutarate
      dehydrogenase complex) resides in mitochondria, with only a small nuclear fraction.
    action: ACCEPT
    reason: Correct primary localization; the mitochondrion holds the majority of DLD.
- term:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:29211711
  qualifier: part_of
  review:
    summary: Co-immunoprecipitation with antibodies against OGDH, DLST and DLD demonstrated
      that these endogenous alpha-KGDH components associate with each other, confirming DLD as
      a component of the 2-oxoglutarate dehydrogenase complex.
    action: ACCEPT
    reason: Directly demonstrated complex membership as the E3 subunit of OGDH.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: dihydrolipoyl succinyltransferase (DLST), and dihydrolipoyl
        dehydrogenase (DLD)—revealed that these endogenous proteins were associated with each
        other
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:9242632
  qualifier: part_of
  review:
    summary: Reconstitution of the human PDH complex established DLD (E3) as a component
      anchored to the E2 core via the E3-binding protein (E3BP).
    action: ACCEPT
    reason: Genuine complex membership as the shared E3 subunit of PDH; supported by
      reconstitution experiments.
    supported_by:
    - reference_id: PMID:9242632
      supporting_text: is required for anchoring dihydrolipoamide dehydrogenase (E3) to the
        dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase
        complexes of eukaryotes
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:20833797
  qualifier: located_in
  review:
    summary: High-throughput phosphoproteomics of functional mitochondria detected DLD as a
      mitochondrial inner-compartment protein, consistent with its known localization (and its
      documented phosphorylation).
    action: ACCEPT
    reason: Correct mitochondrial localization.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-203946
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-204169
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693148
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693153
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694018
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71401
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838035
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838289
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9853499
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9853512
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858321
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858589
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858590
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9859148
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9859163
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9859172
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861616
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861667
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861734
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865115
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9912480
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9912527
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing DLD (E3 dimer) in the mitochondrial matrix within
      curated 2-oxoacid dehydrogenase / glycine-cleavage reactions. Consistent with the
      established primary localization.
    action: ACCEPT
    reason: Correct mitochondrial matrix localization; DLD acts in matrix 2-oxoacid
      dehydrogenase complexes and the glycine cleavage system.
- term:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  evidence_type: TAS
  original_reference_id: PMID:8506365
  qualifier: enables
  review:
    summary: Study of an E3-deficient patient (dihydrolipoamide:NAD+ oxidoreductase, EC
      1.8.1.4) with two missense mutations; the assertion of DLD's dihydrolipoyl dehydrogenase
      activity is well supported.
    action: ACCEPT
    reason: Author-stated (TAS) core molecular function, consistent with all other evidence.
    supported_by:
    - reference_id: PMID:8506365
      supporting_text: dihydrolipoamide dehydrogenase (E3; dihydrolipoamide:NAD+
        oxidoreductase, EC 1.8.1.4)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:3278312
  qualifier: located_in
  review:
    summary: Cloning of the human DLD cDNA identified an N-terminal 35-residue mitochondrial
      import leader sequence, supporting mitochondrial localization.
    action: ACCEPT
    reason: Author-stated (TAS) mitochondrial localization; consistent with the transit peptide
      and all other localization evidence.
    supported_by:
    - reference_id: PMID:3278312
      supporting_text: The
        first 35-amino acid residues of the open reading frame probably correspond
        to a typical mitochondrial import leader sequence.
core_functions:
- description: Dihydrolipoyl dehydrogenase (E3) activity - the shared, defining function of
    DLD. As a FAD-dependent, NAD+-linked flavoenzyme homodimer, DLD reoxidizes the dihydrolipoyl
    groups on the lipoyl-bearing E2/H components of mitochondrial 2-oxoacid dehydrogenase
    complexes and the glycine cleavage system, transferring electrons to NAD+ via FAD. This
    single activity is used by the pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase,
    branched-chain alpha-ketoacid dehydrogenase and 2-oxoadipate dehydrogenase complexes.
  molecular_function:
    id: GO:0004148
    label: dihydrolipoyl dehydrogenase (NADH) activity
  directly_involved_in:
  - id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  - id: GO:0120551
    label: 2-oxoglutarate decarboxylation to succinyl-CoA
  - id: GO:0120552
    label: branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:16442803
    supporting_text: utilizes the specific
      dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the
      essential E3 component to the 60-meric core of the complex
  - reference_id: PMID:15712224
    supporting_text: The E3 subunit is common to
      two other enzymatic complexes, namely pyruvate dehydrogenase complex (PDC) and
      branched-chain ketoacid dehydrogenase complex (BCKDC).
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:14638692
  title: Organization of the cores of the mammalian pyruvate dehydrogenase complex
    formed by E2 and E2 plus the E3-binding protein and their capacities to bind the
    E1 and E3 components.
  findings: []
- id: PMID:15712224
  title: A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD)
    resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency.
  findings: []
- id: PMID:16263718
  title: How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide
    dehydrogenase in the human pyruvate dehydrogenase complex.
  findings: []
- id: PMID:16442803
  title: Structural insight into interactions between dihydrolipoamide dehydrogenase
    (E3) and E3 binding protein of human pyruvate dehydrogenase complex.
  findings: []
- id: PMID:16770810
  title: Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins
    with borderline-normal PDH complex activity.
  findings: []
- id: PMID:17404228
  title: Cryptic proteolytic activity of dihydrolipoamide dehydrogenase.
  findings: []
- id: PMID:19240034
  title: Subunit and catalytic component stoichiometries of an in vitro reconstituted
    human pyruvate dehydrogenase complex.
  findings: []
- id: PMID:20160912
  title: Interaction of E1 and E3 components with the core proteins of the human pyruvate
    dehydrogenase complex.
  findings: []
- id: PMID:20385101
  title: Characterization of interactions of dihydrolipoamide dehydrogenase with its
    binding protein in the human pyruvate dehydrogenase complex.
  findings: []
- id: PMID:20833797
  title: Phosphoproteome analysis of functional mitochondria isolated from resting
    human muscle reveals extensive phosphorylation of inner membrane protein complexes
    and enzymes.
  findings: []
- id: PMID:24534072
  title: Component co-expression and purification of recombinant human pyruvate dehydrogenase
    complex from baculovirus infected SF9 cells.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:29128334
  title: A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration
    Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.
  findings: []
- id: PMID:29191460
  title: The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes
    share their E2 and E3 components for their function and both generate reactive
    oxygen species.
  findings: []
- id: PMID:29211711
  title: KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:3278312
  title: Cloning and cDNA sequence of the dihydrolipoamide dehydrogenase component
    human alpha-ketoacid dehydrogenase complexes.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:3593587
  title: Purification and characterization of human liver branched-chain alpha-keto
    acid dehydrogenase complex.
  findings: []
- id: PMID:36854377
  title: MRPS36 provides a structural link in the eukaryotic 2-oxoglutarate dehydrogenase
    complex.
  findings: []
- id: PMID:37701333
  title: Biochemical characterization of patients with dihydrolipoamide dehydrogenase
    deficiency.
  findings: []
- id: PMID:8506365
  title: Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient
    patient.
  findings: []
- id: PMID:9242632
  title: Dihydrolipoamide dehydrogenase-binding protein of the human pyruvate dehydrogenase
    complex. DNA-derived amino acid sequence, expression, and reconstitution of the
    pyruvate dehydrogenase complex.
  findings: []
- id: Reactome:R-HSA-203946
  title: "PDK isozymes phosphorylate PDHC subunit E1"
  findings: []
- id: Reactome:R-HSA-204169
  title: "PDP1,2 dephosphorylate p-lipo-PDH"
  findings: []
- id: Reactome:R-HSA-5693148
  title: "BCKDK phosphorylates BCKDH"
  findings: []
- id: Reactome:R-HSA-5693153
  title: "PPM1K dephosphorylates p-BCKDH"
  findings: []
- id: Reactome:R-HSA-5694018
  title: "DLD dimer:2xFAD oxidises GCSH:DHLL to GCSH:lipoate"
  findings: []
- id: Reactome:R-HSA-71401
  title: "OGDH dimer decarboxylates 2-OG"
  findings: []
- id: Reactome:R-HSA-9838035
  title: "CLPXP binds mitochondrial matrix proteins"
  findings: []
- id: Reactome:R-HSA-9838289
  title: "CLPXP degrades mitochondrial matrix proteins"
  findings: []
- id: Reactome:R-HSA-9853499
  title: "DLD dimer dehydrogenates dihydrolipoyl"
  findings: []
- id: Reactome:R-HSA-9853512
  title: "DLST transfers succinyl to CoA"
  findings: []
- id: Reactome:R-HSA-9858321
  title: "DHTKD1 dimer decarboxylates 2-OA"
  findings: []
- id: Reactome:R-HSA-9858589
  title: "DLD dimer dehydrogenates dihydrolipoyl"
  findings: []
- id: Reactome:R-HSA-9858590
  title: "DLST transfers glutaryl to CoA"
  findings: []
- id: Reactome:R-HSA-9859148
  title: "BCKDHA:BCKDHB tetramer decarboxylates KIC, KMVA, KIV"
  findings: []
- id: Reactome:R-HSA-9859163
  title: "DBT transfers BCAA to CoA"
  findings: []
- id: Reactome:R-HSA-9859172
  title: "DLD dimer dehydrogenates dihydrolipoyl"
  findings: []
- id: Reactome:R-HSA-9861616
  title: "DLD dimer dehydrogenates dihydrolipoyl"
  findings: []
- id: Reactome:R-HSA-9861667
  title: "DLAT trimer transfers acetyl to CoA"
  findings: []
- id: Reactome:R-HSA-9861734
  title: "PDH E1 decarboxylates PYR, transferring acetyl to DLAT"
  findings: []
- id: Reactome:R-HSA-9865115
  title: "DBT loss-of-function mutants don't synthesize BCAA-CoA"
  findings: []
- id: Reactome:R-HSA-9912480
  title: "BCKDK loss-of-function mutations do not phosphorylate BCKDH"
  findings: []
- id: Reactome:R-HSA-9912527
  title: "H139Hfs13* PPM1K does not dephosphorylate BCKDH"
  findings: []

DLD

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Comprehensive Research Report: Human DLD (Dihydrolipoamide Dehydrogenase, Mitochondrial)

1. Gene Identity and Protein Overview

2. Enzymatic Function and Catalytic Mechanism

2.1 Primary Reaction

2.2 Catalytic Mechanism

2.3 Structural Organization

3. Participation in Mitochondrial Multienzyme Complexes

3.1 Pyruvate Dehydrogenase Complex (PDHc)

3.2 α-Ketoglutarate Dehydrogenase Complex (KGDHc)

3.3 Branched-Chain α-Keto Acid Dehydrogenase Complex (BCKDHc)

3.4 α-Ketoadipate Dehydrogenase Complex (KADHc)

3.5 Glycine Cleavage System (GCS)

4. Subcellular Localization

5. Moonlighting (Non-Canonical) Functions

5.1 Diaphorase Activity

5.2 Proteolytic Activity

5.3 Reactive Oxygen Species (ROS) Generation

6. Role in Cuproptosis

7. Disease Associations

7.1 DLD Deficiency (OMIM #246900)

7.2 Neurodegenerative Disease

7.3 Cancer

7.4 OpenTargets Disease Associations

8. Recent Developments (2023–2025)

9. Summary

Artifacts

Citations

📚 Additional Documentation

Notes

DLD (P09622) review notes

Verified core biology

Moonlighting / secondary

Disease

Annotation strategy

📄 View Raw YAML