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.
| 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 1β1.6% 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... | REMOVE | 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: Bare protein binding is uninformative. The E3-E3BP (PDHX) contact is a genuine subunit-assembly interaction within the pyruvate dehydrogenase complex, which is represented by the complex cellular-component annotations; the paper supports no more specific molecular function for DLD. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:16442803 Structural insight into interactions between dihydrolipoamid... | REMOVE | 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 E3-E3BP (PDHX) contact is a genuine subunit-assembly interaction within the pyruvate dehydrogenase complex, which is represented by the complex cellular-component annotations; the paper supports no more specific molecular function for DLD. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI to PDHX (O00330) from a large-scale interactome study (BioPlex-type). Generic protein binding without specific functional meaning. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for DLD. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ... | REMOVE | Summary: IPI interactions (PRDX6/P30041 and YWHAE/P62258) from a mitochondrial protein interaction map. Generic protein binding with no specific molecular function. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for DLD. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI interactions (PDHX/O00330 and ITGB1BP1/O14713) from the HuRI binary interactome map. Generic protein binding without specific functional meaning. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for DLD. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI interaction with HTT (P42858, huntingtin) from a neurodegenerative-disease interactome study. Generic protein binding with no specific molecular function. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for DLD. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI interaction with PDHX (O00330) from the BioPlex 3.0 dual proteome-scale network. Generic protein binding without specific functional meaning. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for DLD. Removal does not mean the reported interaction is false. |
| 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 2βketoadipic and 2βhydroxyadipic 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 Ξ±-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 1β1.6% of total OGDH, DLST, and DLD was localized in the nucleus |
| GO:0005739 mitochondrion | IDA PMID:29211711 KAT2A coupled with the Ξ±-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 Ξ±-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)βrevealed 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. |
| GO:0019464 glycine decarboxylation via glycine cleavage system | TAS Reactome:R-HSA-5694018 | NEW | Summary: DLD is the L protein of the mitochondrial glycine cleavage system. It catalyses the final step of the cycle, reoxidising the dihydrolipoyl group on the H protein (GCSH) and passing the electrons to NAD+, which regenerates the lipoylated H protein for the next round of glycine decarboxylation. Reason: DLD performs a catalytic step of this process (the L-protein reaction), so it meets the participation bar rather than merely being required. The process is absent from human and mouse DLD in GOA even though the review's own core function already describes the glycine cleavage role and Reactome curates the human reaction with DLD as catalyst. Orthologs carry the term: yeast LPD1 (P09624) is annotated to GO:0019464 (RCA) and part_of the glycine cleavage complex (IMP), and E. coli lpd (P0A9P0) to GO:0019464 (IMP). GOA already gives human DLD the sibling process terms for the other complexes in which it acts as the E3/L component (GO:0006086, GO:0120551, GO:0120552, GO:0019477), so glycine cleavage is the one missing member of that set. The repo's glycine cleavage system module (modules/glycine_cleavage_system.yaml) already models the L-protein reaction with GO:0019464 and uses human DLD (P09622) as the eukaryotic exemplar, grounded on the same Reactome reaction. Supporting Evidence: Reactome:R-HSA-5694018 The last step in the glycine cleavage system is the reoxidation of the reduced lipoate (dihydrolipoyl group) attached to the H protein (GCSH:DHLL) catalysed by the L protein (mitochondrial dihydrolipoyl dehydrogenase, DLD) file:human/DLD/DLD-deep-research-falcon.md 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) |
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