DLD encodes dihydrolipoyl dehydrogenase, a FAD-dependent homodimer that transfers electrons from reduced protein-bound lipoyl groups to NAD+. It regenerates lipoyl cofactors as the shared E3 component of pyruvate, 2-oxoglutarate, branched-chain ketoacid and 2-oxoadipate dehydrogenase systems, and as the L protein of the glycine cleavage system. These functions connect carbohydrate oxidation, the tricarboxylic acid cycle and amino-acid degradation. The canonical precursor is imported into the mitochondrial matrix; a smaller nuclear OGDH pool supplies succinyl-CoA for KAT2A-mediated histone succinylation. DLD can also display a distinct proteolytic activity under conditions that alter its dimer interface, with physiological deployment less clearly established than its metabolic role. Alternative splicing produces shorter protein forms. DLD deficiency disrupts several metabolic systems, causing variable combinations of lactic acidosis, encephalopathy and liver dysfunction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000530301 Β· PTN000530301 SUPPORTS TRANSFER The human target PTN002505536 descends from this asserted node in the official PTHR22912 tree. The protected PAINT IBD supports inheritance; target experimental sources in the donor list are valid grounding, not circular evidence. Supporting Evidence: file:interpro/panther/PTHR22912/PTHR22912-paint.tsv PTHR22912 PTN000530301 GO:0005739 C IBD false file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic assertion is supported. Reason: The defined reaction is oxidation of a protein-bound dihydrolipoyl group with NAD+ reduction. Direct human activity measurements independently support this conserved function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000530299 Β· PTN000530299 SUPPORTS TRANSFER The human target PTN002505536 descends from this asserted node in the official PTHR22912 tree. The protected PAINT IBD supports inheritance; target experimental sources in the donor list are valid grounding, not circular evidence. Supporting Evidence: file:interpro/panther/PTHR22912/PTHR22912-paint.tsv PTHR22912 PTN000530299 GO:0004148 F IBD false file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) file:human/DLD/DLD-deep-research-falcon.md Electrons are transferred from FADHβ to NADβΊ, producing NADH. |
| GO:0006103 2-oxoglutarate metabolic process | IBA GO_REF:0000033 | MODIFY | Summary: The inherited metabolic role is sound; the defined OGDH reaction sequence is more precise. Reason: GO:0120551 is a checked is_a/part_of descendant of GO:0006103. DLD performs the lipoyl-regeneration reaction within this three-step pathway; it does not itself decarboxylate 2-oxoglutarate. This refines scope without rejecting the PAINT node. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000530299 Β· PTN000530299 SUPPORTS TRANSFER The human target PTN002505536 descends from this asserted node in the official PTHR22912 tree. The protected PAINT IBD supports inheritance; target experimental sources in the donor list are valid grounding, not circular evidence. Proposed replacements: 2-oxoglutarate decarboxylation to succinyl-CoA Supporting Evidence: file:interpro/panther/PTHR22912/PTHR22912-paint.tsv PTHR22912 PTN000530299 GO:0006103 P IBD false file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0045252 oxoglutarate dehydrogenase complex | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic assertion is supported. Reason: DLD is the catalytic E3 component of OGDH. Its shared use in other enzyme systems does not weaken this complex-membership assertion. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000530301 Β· PTN000530301 SUPPORTS TRANSFER The human target PTN002505536 descends from this asserted node in the official PTHR22912 tree. The protected PAINT IBD supports inheritance; target experimental sources in the donor list are valid grounding, not circular evidence. Supporting Evidence: file:interpro/panther/PTHR22912/PTHR22912-paint.tsv PTHR22912 PTN000530301 GO:0045252 C IBD false file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic assertion is supported. Reason: FAD is the bound redox cofactor of the DLD homodimer and is required for the integrated catalytic unit; this is not a separate enzyme activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000530299 Β· PTN000530299 SUPPORTS TRANSFER The human target PTN002505536 descends from this asserted node in the official PTHR22912 tree. The protected PAINT IBD supports inheritance; target experimental sources in the donor list are valid grounding, not circular evidence. Supporting Evidence: file:interpro/panther/PTHR22912/PTHR22912-paint.tsv PTHR22912 PTN000530299 GO:0050660 F IBD false file:human/DLD/DLD-uniprot.txt Binds 1 FAD per subunit. |
| GO:0001669 acrosomal vesicle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain acrosomal localization from positive rodent homolog evidence. Reason: PMID:15888450 detects hamster DLD in the acrosome with anti-E3 staining and antigen-preabsorption controls (Fig. 2), and detects acrosomal E3 in mouse sperm (Fig. 3A/B). These positive homolog observations support the UniProt-derived acrosomal-vesicle inference as non-core. The human anti-E3 experiment did not detect a signal; positive anti-whole-PDH staining does not identify DLD specifically. Direct human acrosomal localization therefore remains unresolved, and no human isoform-specific result or reproductive process is inferred. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q811C4 Β· Rodent DLD localization SUPPORTS TRANSFER Positive hamster and mouse acrosomal staining supports transfer; the human antibody result does not provide subunit-specific confirmation. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000269|PubMed:15888450}. |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion agrees with established DLD biology. Reason: Combined automated evidence agrees with directly measured human dihydrolipoyl oxidation and the reviewed UniProt catalytic reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P09622 Β· DLD source evidence SUPPORTS TRANSFER The actual target domain/official record and source evidence were checked; no contrary biological propagation condition was found. Supporting Evidence: file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain the small nuclear pool. Reason: Human HEK293 and U251 fractionation and imaging detect a minor nuclear DLD pool with the OGDH complex. The complex supplies succinyl-CoA to KAT2A; DLD is not assigned histone succinyltransferase activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P09622 Β· Human DLD SUPPORTS TRANSFER UniProt localization is corroborated by target-specific nuclear experiments. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Nucleus {ECO:0000269|PubMed:29211711}. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion agrees with established DLD biology. Reason: The canonical precursor is imported into mitochondria, and the relevant E3-containing enzyme systems occupy the matrix. Alternative products are not individually localized by this inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P09622 Β· DLD source evidence SUPPORTS TRANSFER The actual target domain/official record and source evidence were checked; no contrary biological propagation condition was found. Supporting Evidence: file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: Replace the broad oxidoreductase category with the established DLD reaction. Reason: The target InterPro match and mapping are valid. GO:0004148 is a checked descendant of the source term and specifies the measured protein-bound dihydrolipoyl/NAD+ reaction. This is a scope refinement, not a wrong-family claim. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001100 Β· IPR001100 SUPPORTS TRANSFER Actual target match and interpro2go mapping verified; the reaction is more specific than the mapped category. Proposed replacements: dihydrolipoyl dehydrogenase (NADH) activity Supporting Evidence: file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0016668 oxidoreductase activity, acting on a sulfur group of donors, NAD(P) as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: Replace the broad oxidoreductase category with the established DLD reaction. Reason: The target InterPro match and mapping are valid. GO:0004148 is a checked descendant of the source term and specifies the measured protein-bound dihydrolipoyl/NAD+ reaction. This is a scope refinement, not a wrong-family claim. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR012999 Β· IPR012999 SUPPORTS TRANSFER Actual target match and interpro2go mapping verified; the reaction is more specific than the mapped category. Proposed replacements: dihydrolipoyl dehydrogenase (NADH) activity Supporting Evidence: file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0031514 motile cilium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain motile-cilium localization from positive hamster flagellar evidence. Reason: PMID:15888450 Fig. 2A/C identifies DLD in the principal piece of the hamster sperm flagellum, including loss of staining after antigen preabsorption. This positive homolog result supports the UniProt-derived motile-cilium inference as non-core. HPA additionally reports human principal-piece staining with uncertain reliability; it is corroborating context rather than a definitive human assay. The separate HPA primary-cilium observation does not support this motile-cilium term. No sperm process or localization of every human product is inferred. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q811C4 Β· Rodent DLD localization SUPPORTS TRANSFER Positive hamster principal-piece staining supports the motile flagellar inference. Human principal-piece reliability is uncertain; primary-cilium staining is a distinct observation. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Cell projection, cilium, flagellum {ECO:0000250|UniProtKB:Q811C4}. |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | ACCEPT | Summary: The electronic assertion agrees with established DLD biology. Reason: InterPro IPR006258 spans residues 42β502 of the canonical sequence and carries the FAD-binding mapping. The redox cofactor is independently established biochemically. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR006258 Β· DLD source evidence SUPPORTS TRANSFER The actual target domain/official record and source evidence were checked; no contrary biological propagation condition was found. |
| GO:0005515 protein binding | IPI PMID:16263718 How dihydrolipoamide dehydrogenase-binding protein binds dih... | REMOVE | Summary: Direct structural DLDβPDHX binding is retained. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: PMID:16263718 The dihydrolipoamide dehydrogenase-binding protein (E3BP) and the dihydrolipoamide acetyltransferase (E2) component enzyme form the structural core of the human pyruvate dehydrogenase complex by providing the binding sites for two other component proteins, dihydrolipoamide dehydrogenase (E3) and pyruvate dehydrogenase (E1), as well as pyruvate dehydrogenase kinases and phosphatases. file:human/DLD/DLD-uniprot.txt Interacts with PDHX (PubMed:16442803, PubMed:20160912, PubMed:20361979, PubMed:20385101). |
| GO:0005515 protein binding | IPI PMID:16442803 Structural insight into interactions between dihydrolipoamid... | REMOVE | Summary: Direct DLDβPDHX recruitment is retained. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: PMID:16442803 to tether the essential E3 component to the 60-meric core of the complex |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Retain the BioPlex DLDβPDHX association. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: PMID:28514442 Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome, and constitutes, to our knowledge, the largest such network so far. file:human/DLD/DLD-uniprot.txt Interacts with PDHX (PubMed:16442803, PubMed:20160912, PubMed:20361979, PubMed:20385101). |
| GO:0005515 protein binding | IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ... | REMOVE | Summary: Retain DLDβPRDX6 association at the measured scope. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: file:human/DLD/DLD-uniprot.txt P09622; P62258: YWHAE; NbExp=5; IntAct=EBI-353366, EBI-356498; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Retain the binary DLDβPDHX interaction. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Interacts with PDHX (PubMed:16442803, PubMed:20160912, PubMed:20361979, PubMed:20385101). file:human/DLD/DLD-uniprot.txt P09622; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-353366, EBI-2127319; |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Retain fragment-specific DLDβHTT binding. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: PMID:32814053 Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects βΌ5,000 human proteins via βΌ30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of βΌ500 ND-related proteins and integration of literature interactions. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Retain the BioPlex 3 DLDβPDHX association. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. file:human/DLD/DLD-uniprot.txt Interacts with PDHX (PubMed:16442803, PubMed:20160912, PubMed:20361979, PubMed:20385101). |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O08749 Β· DLD source evidence SUPPORTS TRANSFER The actual target domain/official record and source evidence were checked; no contrary biological propagation condition was found. Supporting Evidence: file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005929 cilium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain a broad cilium inference anchored to rodent sperm flagellar localization. Reason: The mouse O08749 source has a cilium IDA annotation to PMID:15888450. In that original, Fig. 2A/C provides direct DLD localization to the hamster sperm flagellar principal piece, whereas Fig. 3A/B establishes mouse acrosomal staining. The positive hamster motile-flagellum result supports contextual retention of the broad cilium claim through the homolog evidence; the narrower mouse assay resolution remains explicit. HPA reports human principal-piece and primary-cilium staining separately, both with uncertain reliability. The rodent motile flagellum is not evidence of a human primary-cilium pool, and primary-cilium staining is not used to substantiate motile-cilium localization. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O08749 Β· Rodent DLD localization SUPPORTS TRANSFER Mouse donor GOA was verified. Original direct flagellar localization is hamster; mouse staining is acrosomal. The broad cilium inference retains this source-resolution limit. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Cell projection, cilium, flagellum {ECO:0000250|UniProtKB:Q811C4}. |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion agrees with established DLD biology. Reason: DLD performs the final lipoyl-regeneration step of the pyruvate dehydrogenase reaction sequence, which is included in this process definition. Source lifecycle: this historical GO_REF:0000120 record is replaced in the genuine current GOA by the GO_REF:0000107 record retained at zero-based index 86. The retired flag records that provenance replacement, not withdrawal of the biological ACCEPT verdict. Original term, evidence, reference and qualifier are unchanged. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P09622 Β· DLD source evidence SUPPORTS TRANSFER The actual target domain/official record and source evidence were checked; no contrary biological propagation condition was found. Supporting Evidence: file:human/DLD/DLD-uniprot.txt The pyruvate dehydrogenase (PDH) complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). |
| GO:0006099 tricarboxylic acid cycle | IEA GO_REF:0000107 | MODIFY | Summary: Specify the OGDH reaction sequence within the broader metabolic process. Reason: DLD catalyzes lipoyl regeneration as part of conversion of 2-oxoglutarate to succinyl-CoA. GO:0120551 is a checked descendant of the original term and includes the full three-enzyme reaction sequence, rather than assigning E1 chemistry to DLD. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O08749 Β· Mouse Dld SUPPORTS TRANSFER The inherited TCA role is sound; human evidence supports the specific participating step. Proposed replacements: 2-oxoglutarate decarboxylation to succinyl-CoA Supporting Evidence: file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0043159 acrosomal matrix | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain acrosomal-matrix localization from positive hamster compartment-resolved evidence. Reason: PMID:15888450 Fig. 4 tests hamster sperm by detergent removal of membranes, mechanical dislodgement of matrix and induced acrosomal exocytosis. DLD remains with the detergent-resistant acrosomal matrix and is released during complete acrosome reaction, positively supporting this compartment. The mouse O08749 donor carries the finer acrosomal-matrix annotation, but the explicitly mouse experiment in Fig. 3A/B shows acrosomal staining without the hamster matrix dissection. This rodent homolog evidence supports a non-core human inference with the species-resolution limitation retained. DLD-specific human acrosomal localization is unresolved because anti-E3 staining failed and anti-whole-PDH staining is not subunit-specific. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O08749 Β· Rodent DLD localization SUPPORTS TRANSFER Original hamster detergent/shearing/exocytosis experiments resolve acrosomal matrix. Mouse staining is acrosomal without equivalent subcompartment resolution. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000269|PubMed:15888450}. |
| GO:0045252 oxoglutarate dehydrogenase complex | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion agrees with established DLD biology. Reason: The shared E3 subunit is a genuine component of the oxoglutarate dehydrogenase system. Source lifecycle: this historical GO_REF:0000120 record is replaced in the genuine current GOA by the GO_REF:0000107 record retained at zero-based index 87. The retired flag records that provenance replacement, not withdrawal of the biological ACCEPT verdict. Original term, evidence, reference and qualifier are unchanged. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P09622 Β· DLD source evidence SUPPORTS TRANSFER The actual target domain/official record and source evidence were checked; no contrary biological propagation condition was found. Supporting Evidence: file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0045254 pyruvate dehydrogenase complex | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion agrees with established DLD biology. Reason: Direct recruitment by PDHX and reconstituted human PDC establish this membership. Source lifecycle: this historical GO_REF:0000120 record is replaced in the genuine current GOA by the GO_REF:0000107 record retained at zero-based index 88. The retired flag records that provenance replacement, not withdrawal of the biological ACCEPT verdict. Original term, evidence, reference and qualifier are unchanged. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P09622 Β· DLD source evidence SUPPORTS TRANSFER The actual target domain/official record and source evidence were checked; no contrary biological propagation condition was found. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Part of the multimeric pyruvate dehydrogenase (PDH) complex that contains multiple copies of pyruvate dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). |
| GO:0019477 L-lysine catabolic process | IMP PMID:37701333 Biochemical characterization of patients with dihydrolipoami... | ACCEPT | Summary: DLD participates in lysine degradation through the OADH system. Reason: The human patient study reports lysine-pathway metabolite changes; recombinant human OADH reconstitution independently establishes DLD as its E3 component. DLD performs the lipoyl-regeneration step, not direct lysine cleavage. The patient authors also consider excess 2-oxoglutarate as an explanation for low lysine. Supporting Evidence: PMID:37701333 Restoring the oxidized state allows lipoic acid to act as a necessary electron sink for the four mitochondrial keto-acid dehydrogenases: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, branched-chain Ξ±-keto-acid dehydrogenase, and 2-oxoadipate dehydrogenase. |
| GO:0005739 mitochondrion | NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu... | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. Supporting Evidence: PMID:36854377 One of the pivotal enzymes in this cycle is 2-oxoglutarate dehydrogenase complex (OGDHC), which generates NADH by oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | NAS PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: Retain the established mitochondrial-matrix compartment. Reason: The cited human-liver BCKDH abstract establishes the E3-containing complex, but is not itself a matrix imaging assay. The NAS compartment assertion agrees with the canonical precursor and independent localization/Reactome evidence; no unseen subfractionation procedure is claimed. Supporting Evidence: PMID:3593587 Human liver BCKADH complex was purified. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0006099 tricarboxylic acid cycle | NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu... | MODIFY | Summary: Specify the OGDH reaction sequence within the broader metabolic process. Reason: DLD catalyzes lipoyl regeneration as part of conversion of 2-oxoglutarate to succinyl-CoA. GO:0120551 is a checked descendant of the original term and includes the full three-enzyme reaction sequence, rather than assigning E1 chemistry to DLD. Proposed replacements: 2-oxoglutarate decarboxylation to succinyl-CoA Supporting Evidence: PMID:36854377 One of the pivotal enzymes in this cycle is 2-oxoglutarate dehydrogenase complex (OGDHC), which generates NADH by oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0006103 2-oxoglutarate metabolic process | NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu... | MODIFY | Summary: Specify the OGDH reaction sequence within the broader metabolic process. Reason: DLD catalyzes lipoyl regeneration as part of conversion of 2-oxoglutarate to succinyl-CoA. GO:0120551 is a checked descendant of the original term and includes the full three-enzyme reaction sequence, rather than assigning E1 chemistry to DLD. Proposed replacements: 2-oxoglutarate decarboxylation to succinyl-CoA Supporting Evidence: PMID:36854377 One of the pivotal enzymes in this cycle is 2-oxoglutarate dehydrogenase complex (OGDHC), which generates NADH by oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0009083 branched-chain amino acid catabolic process | IDA PMID:3593587 Purification and characterization of human liver branched-ch... | MODIFY | Summary: Specify the BCKDH reaction sequence within amino-acid catabolism. Reason: Purified human-liver BCKDH oxidizes branched-chain ketoacids, with dissociable E3 required to restore full activity. GO:0120552, a checked descendant of GO:0009083, captures the three-step reaction sequence to which DLD contributes lipoyl regeneration. This does not assign ketoacid decarboxylase activity to isolated DLD. Proposed replacements: branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA |
| GO:0045252 oxoglutarate dehydrogenase complex | NAS PMID:36854377 MRPS36 provides a structural link in the eukaryotic 2-oxoglu... | ACCEPT | Summary: Retain OGDH complex membership. Reason: The original crosslink/complexome study supports E3 integration through MRPS36-mediated contacts in the mammalian OGDH system. Distinguish the mouse/bovine experimental preparations and modeled human context from a newly solved endogenous human complex. Supporting Evidence: PMID:36854377 One of the pivotal enzymes in this cycle is 2-oxoglutarate dehydrogenase complex (OGDHC), which generates NADH by oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IPI PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: Retain participation in the human BCKDH enzyme system. Reason: The complete abstract reports purification of human-liver BCKDH, a readily dissociable E3 component, and restoration of overall activity by added lipoamide oxidoreductase. This supports the existing curator-backed assertion; the inaccessible full original is not replaced by invented assay details or target-product assignments. |
| GO:0005739 mitochondrion | NAS PMID:24534072 Component co-expression and purification of recombinant huma... | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. 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. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IDA PMID:24534072 Component co-expression and purification of recombinant huma... | ACCEPT | Summary: Retain the mitochondrial PDC role. Reason: The abstract explicitly describes recombinant human PDC components expressed in insect cells after removal of targeting signals, followed by lipoylation and functional reconstitution. It supports pathway participation; the engineered cytoplasmic expression system is not evidence against native mitochondrial localization and is not direct imaging of the human precursor. 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. file:human/DLD/DLD-uniprot.txt The pyruvate dehydrogenase (PDH) complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). |
| GO:0045254 pyruvate dehydrogenase complex | IPI PMID:19240034 Subunit and catalytic component stoichiometries of an in vit... | ACCEPT | Summary: Retain human PDC membership. Reason: The original reconstitutes human PDC from independently purified components and measures E3 recruitment by sedimentation, calorimetry and native gels. The experimentally saturated assembly stoichiometry is not imposed as an invariant copy number in living cells. Supporting Evidence: PMID:19240034 using an in vitro reconstituted PDC |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Retain nucleoplasmic localization as a secondary pool. Reason: The current official HPA page reports supported nucleoplasm staining, including HPA044849 in U2OS, alongside the principal mitochondrial localization. Independent human nuclear OGDH experiments corroborate a small nuclear DLD pool. No isoform-specific distribution is established. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Nucleus {ECO:0000269|PubMed:29211711}. |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | EXP PMID:16770810 Novel mutations in dihydrolipoamide dehydrogenase deficiency... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: Patient fibroblasts have DLD deficiency despite relatively spared PDH activity; the complete abstract reports enzyme kinetic measurements. Preserve the experimental enzyme-function assertion without inventing unavailable full-text assay details. Supporting Evidence: PMID:16770810 the DLD subunit deficiency had little effect on pyruvate dehydrogenase complex activity, but caused a severe reduction in the activities of other enzymes that utilize this subunit. file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | EXP PMID:17404228 Cryptic proteolytic activity of dihydrolipoamide dehydrogena... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: The human WT and mutant enzyme study distinguishes dehydrogenase from conditional proteolysis: the reported S456A variant loses proteolysis while retaining dehydrogenase activity. This existing redox assertion is not a protease annotation. Supporting Evidence: PMID:17404228 The mitochondrial enzyme, dihydrolipoamide dehydrogenase (DLD), is essential for energy metabolism across eukaryotes. file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | EXP PMID:20160912 Interaction of E1 and E3 components with the core proteins o... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: Original Methods measure free human E3 activity by NADH formation with dihydrolipoamide, separately from reconstituted overall PDC activity and E1 DCPIP assays. Supporting Evidence: PMID:20160912 Activities of free wild-type E3 and its mutants (not reconstituted in PDC) |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | EXP PMID:20385101 Characterization of interactions of dihydrolipoamide dehydro... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: Original Methods express and purify human WT/mutant E3, measure forward/reverse activity and reconstituted PDC NAD+ reduction. PDHX-binding defects are distinguished from isolated E3 catalysis. Supporting Evidence: PMID:20385101 hE3 specific activities in the forward and reverse directions were measured |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IDA PMID:16442803 Structural insight into interactions between dihydrolipoamid... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: Original human E3/E3BP structure and reconstituted PDC context support DLD participation through lipoyl regeneration; the E1 component performs pyruvate decarboxylation. Supporting Evidence: PMID:16442803 The 9.5 MDa human pyruvate dehydrogenase complex (PDC) utilizes the specific dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the essential E3 component to the 60-meric core of the complex. file:human/DLD/DLD-uniprot.txt The pyruvate dehydrogenase (PDH) complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). |
| GO:0045254 pyruvate dehydrogenase complex | IDA PMID:14638692 Organization of the cores of the mammalian pyruvate dehydrog... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: The complete abstract explicitly uses homogeneous human components and measures E3 binding outside the E2/E3BP core. This supports complex membership without treating proposed stoichiometry as universal. Supporting Evidence: PMID:14638692 We have prepared homogenous human components. |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | IDA PMID:9242632 Dihydrolipoamide dehydrogenase-binding protein of the human ... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: The complete abstract describes reconstitution with native E3 plus recombinant E1 and E2/E3BP. The long-established DLD activity is retained with curator deference; no unavailable detailed assay is claimed. Supporting Evidence: PMID:9242632 Protein X, recently renamed dihydrolipoamide dehydrogenase-binding protein (E3BP), is required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IC PMID:9242632 Dihydrolipoamide dehydrogenase-binding protein of the human ... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: E3 regeneration of the reduced lipoyl cofactor is a performed step in the reconstituted PDC reaction sequence. This is pathway participation, not attribution of the E1 decarboxylation chemistry to DLD. Supporting Evidence: PMID:9242632 Protein X, recently renamed dihydrolipoamide dehydrogenase-binding protein (E3BP), is required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. file:human/DLD/DLD-uniprot.txt The pyruvate dehydrogenase (PDH) complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | IMP PMID:15712224 A novel mutation in the dihydrolipoamide dehydrogenase E3 su... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: The abstract reports human fibroblast E3 activity at about 20% of controls and a DLD variant with a prominent OGDH phenotype. The activity assertion is supported without requiring every complex to be equally impaired. 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: Retain the established source-supported DLD assertion. Reason: The human patient fibroblast evidence links DLD deficiency to reduced OGDH function. The process definition includes the three coupled reactions, including DLD lipoyl regeneration, rather than only E1 chemistry. Supporting Evidence: PMID:15712224 The E3 subunit is common to two other enzymatic complexes, namely pyruvate dehydrogenase complex (PDC) and branched-chain ketoacid dehydrogenase complex (BCKDC). file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| 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: Retain participation in the human BCKDH enzyme system. Reason: The complete abstract reports purification of human-liver BCKDH, a readily dissociable E3 component, and restoration of overall activity by added lipoamide oxidoreductase. This supports the existing curator-backed assertion; the inaccessible full original is not replaced by invented assay details or target-product assignments. Supporting Evidence: PMID:3593587 lipoamide oxidoreductase component was readily dissociable from the complex |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: Retain participation in the human BCKDH enzyme system. Reason: The complete abstract reports purification of human-liver BCKDH, a readily dissociable E3 component, and restoration of overall activity by added lipoamide oxidoreductase. This supports the existing curator-backed assertion; the inaccessible full original is not replaced by invented assay details or target-product assignments. |
| GO:0160167 oxoadipate dehydrogenase complex | IDA PMID:29191460 The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogen... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: The complete abstract reports functional recombinant human DHTKD1 recruiting DLST and DLD. Retain OADH complex membership; the full original remains unavailable, and E1 substrate ratios/oxidant chemistry are not assigned to DLD. Supporting Evidence: PMID:29191460 The hE1a has recruited the dihydrolipoyl succinyltransferase (hE2o) and the dihydrolipoyl dehydrogenase |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | IDA PMID:16442803 Structural insight into interactions between dihydrolipoamid... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: Human E3 structural and biochemical evidence establishes the lipoyl/NAD+ oxidoreductase role in the complex. The E3BP carrier domain used for expression is not the enzyme substrate or an independent catalytic activity. Supporting Evidence: PMID:16442803 The 9.5 MDa human pyruvate dehydrogenase complex (PDC) utilizes the specific dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the essential E3 component to the 60-meric core of the complex. file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0005634 nucleus | IDA PMID:29211711 KAT2A coupled with the Ξ±-KGDH complex acts as a histone H3 s... | KEEP AS NON CORE | Summary: Retain the measured DLD compartment or OGDH membership. Reason: Human HEK293/U251 fractionation and microscopy detect a small nuclear DLD pool alongside the mitochondrial pool. DLD and DLST associate with KAT2A through OGDH; OGDH depletion disrupts the association. The complex supplies succinyl-CoA, whereas KAT2A performs histone succinyl transfer. This does not make DLD a histone-modifying enzyme. Supporting Evidence: PMID:29211711 Here we show that the Ξ±-ketoglutarate dehydrogenase (Ξ±-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. file:human/DLD/DLD-uniprot.txt Nucleus {ECO:0000269|PubMed:29211711}. |
| GO:0005739 mitochondrion | IDA PMID:29211711 KAT2A coupled with the Ξ±-KGDH complex acts as a histone H3 s... | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. Supporting Evidence: PMID:29211711 Here we show that the Ξ±-ketoglutarate dehydrogenase (Ξ±-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0045252 oxoglutarate dehydrogenase complex | IDA PMID:29211711 KAT2A coupled with the Ξ±-KGDH complex acts as a histone H3 s... | ACCEPT | Summary: Retain the measured DLD compartment or OGDH membership. Reason: Human HEK293/U251 fractionation and microscopy detect a small nuclear DLD pool alongside the mitochondrial pool. DLD and DLST associate with KAT2A through OGDH; OGDH depletion disrupts the association. The complex supplies succinyl-CoA, whereas KAT2A performs histone succinyl transfer. This does not make DLD a histone-modifying enzyme. Supporting Evidence: PMID:29211711 Here we show that the Ξ±-ketoglutarate dehydrogenase (Ξ±-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0045254 pyruvate dehydrogenase complex | IDA PMID:9242632 Dihydrolipoamide dehydrogenase-binding protein of the human ... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: The human E2/E3BP subcomplex reconstitutes PDC with native E3 and recombinant E1. This is positive complex membership evidence, not merely a name-based transfer from PDHX. Supporting Evidence: PMID:9242632 Protein X, recently renamed dihydrolipoamide dehydrogenase-binding protein (E3BP), is required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. file:human/DLD/DLD-uniprot.txt Part of the multimeric pyruvate dehydrogenase (PDH) complex that contains multiple copies of pyruvate dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. Supporting Evidence: PMID:20833797 We performed a phosphoproteomics study of functional mitochondria isolated from human muscle biopsies with the aim to obtain a comprehensive overview of mitochondrial phosphoproteins. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-203946 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-203946 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-204169 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-204169 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693148 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-5693148 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693153 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-5693153 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5694018 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: The event models DLD-mediated regeneration of a reduced lipoyl cofactor in the matrix. The same redox chemistry is reused across enzyme systems. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-5694018 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) (Harris et al. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-71401 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-71401 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD is represented among matrix proteins bound or degraded by CLPXP. Being its substrate supports compartment context, not DLD participation as the CLPXP protease. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9838035 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD is represented among matrix proteins bound or degraded by CLPXP. Being its substrate supports compartment context, not DLD participation as the CLPXP protease. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9838289 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9853499 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: The event models DLD-mediated regeneration of a reduced lipoyl cofactor in the matrix. The same redox chemistry is reused across enzyme systems. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9853499 Reactome:R-HSA-9853499 Dihydrolipoyl dehydrogenase (DLD), the E3 component of the 2-oxoglutarate dehydrogenase metabolon, forms a homodimer that catalyzes the dehydrogenation of dihydrolipoyllysine residues by producing NADH from NAD+, with the help of the FAD cofactor (Brautigam et al. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9853512 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9853512 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9858321 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9858321 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9858589 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: The event models DLD-mediated regeneration of a reduced lipoyl cofactor in the matrix. The same redox chemistry is reused across enzyme systems. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9858589 Reactome:R-HSA-9858589 Dihydrolipoyl dehydrogenase (DLD), the E3 component of the 2-oxoadipate dehydrogenase metabolon, forms a homodimer that catalyzes the dehydrogenation of dihydrolipoyllysine residues by producing NADH from NAD+, with the help of the FAD cofactor (Brautigam et al. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9858590 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9858590 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859148 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9859148 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859163 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9859163 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859172 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: The event models DLD-mediated regeneration of a reduced lipoyl cofactor in the matrix. The same redox chemistry is reused across enzyme systems. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9859172 Reactome:R-HSA-9859172 Dihydrolipoyl dehydrogenase (DLD), the E3 component of the branched-chain alpha-keto acid dehydrogenase complex (BCKDH), forms a homodimer that catalyzes the dehydrogenation of dihydrolipoyllysine residues by producing NADH from NAD+, with the help of the FAD cofactor (Brautigam et al. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9861616 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: The event models DLD-mediated regeneration of a reduced lipoyl cofactor in the matrix. The same redox chemistry is reused across enzyme systems. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9861616 Reactome:R-HSA-9861616 Dihydrolipoyl dehydrogenase (DLD), the E3 component of the 2-oxoglutarate dehydrogenase metabolon, forms a homodimer that catalyzes the dehydrogenation of dihydrolipoyllysine residues by producing NADH from NAD+, with the help of the FAD cofactor (Brautigam et al. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9861667 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9861667 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9861734 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD occurs as a matrix enzyme-system component. The event name does not imply that DLD performs another subunitβs decarboxylation, acyl transfer, phosphorylation or dephosphorylation. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9861734 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9865115 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD remains a matrix component in the modeled mutant enzyme-system context. The mutation and loss of function belong to the named DBT, BCKDK or PPM1K component, not to DLD. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9865115 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912480 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD remains a matrix component in the modeled mutant enzyme-system context. The mutation and loss of function belong to the named DBT, BCKDK or PPM1K component, not to DLD. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9912480 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912527 | ACCEPT | Summary: Retain the mitochondrial-matrix compartment. Reason: DLD remains a matrix component in the modeled mutant enzyme-system context. The mutation and loss of function belong to the named DBT, BCKDK or PPM1K component, not to DLD. This TAS localization agrees with independent human enzyme/localization evidence; it is not a separate molecular-function assertion for every reaction participant. Supporting Evidence: Reactome:R-HSA-9912527 file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity | TAS PMID:8506365 Identification of two missense mutations in a dihydrolipoami... | ACCEPT | Summary: Retain the established source-supported DLD assertion. Reason: The complete abstract reports markedly reduced E3 activity and protein in patient fibroblasts with DLD coding variants. It supports the known enzyme activity; the full original was not recovered for additional assay-specific claims. Supporting Evidence: PMID:8506365 Fibroblasts cultured from the patient contained only approximately 6% of the E3 activity of cells from a normal subject. file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). file:human/DLD/DLD-uniprot.txt Reaction=N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + NAD(+) = N(6)- [(R)-lipoyl]-L-lysyl-[protein] + NADH + H(+) |
| GO:0005739 mitochondrion | TAS PMID:3278312 Cloning and cDNA sequence of the dihydrolipoamide dehydrogen... | ACCEPT | Summary: The mitochondrion term is informative and is kept beside the annotated matrix rows. Reason: Root organelle policy: the mitochondrion term is informative and is kept beside the separately annotated mitochondrial matrix rows rather than modified to the sub-compartment. DLD is a matrix enzyme of the PDH, OGDH, BCKDH, 2-oxoadipate dehydrogenase and glycine cleavage systems, with a cleavable mitochondrial presequence; the organelle-level claim holds for this row's source. Supporting Evidence: PMID:3278312 The first 35-amino acid residues of the open reading frame probably correspond to a typical mitochondrial import leader sequence. file:human/DLD/DLD-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. |
| GO:0019464 glycine decarboxylation via glycine cleavage system | TAS Reactome:R-HSA-5694018 | NEW | Summary: Retain the historical glycine-cleavage L-protein proposal. Reason: DLD performs the final regeneration step by oxidizing the reduced lipoyl group on GCSH, so it is an active participant rather than a substrate of the process. Reactome identifies the DLD dimer/FAD active unit and human P09622 residues 36β509 in matrix. Same-role yeast LPD1 and bacterial LpdA annotations support the convention; the checked ancestry does not duplicate another current source process. This remains the prior TAS-level proposal, not a newly imported GOA assertion. Supporting Evidence: Reactome:R-HSA-5694018 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) (Harris et al. file:human/DLD/DLD-uniprot.txt Lipoamide dehydrogenase is a component of the glycine cleavage system |
| GO:0005515 protein binding | IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ... | REMOVE | Summary: Retain DLDβYWHAE physical association. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: file:human/DLD/DLD-uniprot.txt P09622; P62258: YWHAE; NbExp=5; IntAct=EBI-353366, EBI-356498; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Retain the verified DLDβITGB1BP1 binary interaction as non-core. Reason: Bare protein binding is uninformative under the protein-binding policy, so the row is removed; the reported interaction is not disputed. The physiologically meaningful DLD-PDHX (E3BP) interaction is captured by the accepted pyruvate dehydrogenase complex membership, and no more specific binding MF term applies. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Interacts with PDHX (PubMed:16442803, PubMed:20160912, PubMed:20361979, PubMed:20385101). file:human/DLD/DLD-uniprot.txt P09622; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-353366, EBI-2127319; |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IEA GO_REF:0000107 | ACCEPT | Summary: Retain the newly fetched orthology assertion. Reason: The source maps mouse Dld O08749/ENSMUSP00000106481 to the human ortholog. Its experimental enzyme-system annotations and independent human reconstitution establish the same DLD role. This is a genuine additional current GOA row, not a fabricated NEW annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O08749 Β· Mouse Dld SUPPORTS TRANSFER The exact current donor record and target annotation were checked; experimental pathway/complex grounding is present. Supporting Evidence: file:human/DLD/DLD-uniprot.txt The pyruvate dehydrogenase (PDH) complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). file:human/DLD/DLD-uniprot.txt The E3 subunit catalyzes reoxidation of the dihydrolipoyl moiety on lipoyl-bearing domains (LBDs) of E2 with NAD+ as the ultimate electron acceptor (PubMed:16442803, PubMed:16770810, PubMed:20160912, PubMed:20385101). |
| GO:0045252 oxoglutarate dehydrogenase complex | IEA GO_REF:0000107 | ACCEPT | Summary: Retain the newly fetched orthology assertion. Reason: The source maps mouse Dld O08749/ENSMUSP00000106481 to the human ortholog. Its experimental enzyme-system annotations and independent human reconstitution establish the same DLD role. This is a genuine additional current GOA row, not a fabricated NEW annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O08749 Β· Mouse Dld SUPPORTS TRANSFER The exact current donor record and target annotation were checked; experimental pathway/complex grounding is present. Supporting Evidence: file:human/DLD/DLD-uniprot.txt The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2), DLD (dihydrolipoamide dehydrogenase; E3) and the assembly factor KGD4 (By similarity). |
| GO:0045254 pyruvate dehydrogenase complex | IEA GO_REF:0000107 | ACCEPT | Summary: Retain the newly fetched orthology assertion. Reason: The source maps mouse Dld O08749/ENSMUSP00000106481 to the human ortholog. Its experimental enzyme-system annotations and independent human reconstitution establish the same DLD role. This is a genuine additional current GOA row, not a fabricated NEW annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O08749 Β· Mouse Dld SUPPORTS TRANSFER The exact current donor record and target annotation were checked; experimental pathway/complex grounding is present. Supporting Evidence: file:human/DLD/DLD-uniprot.txt Part of the multimeric pyruvate dehydrogenase (PDH) complex that contains multiple copies of pyruvate dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). |
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Download this section (compressed HTML)Q: What controls exposure of the DLD proteolytic interface in human cells, and which endogenous substrates are cleaved under physiological versus pathological conditions?
Q: Do the 410- and 461-residue natural DLD products retain lipoyl redox activity, proteolysis or mitochondrial import, and in which tissues are they translated?
Q: Should the serine-type peptidase definitions accommodate the experimentally proposed DLD serine/glutamate dyad, without requiring a catalytic triad?
Experiment: Compare unstressed and defined mitochondrial-stress conditions in human cells with endogenous DLD, matched DLD depletion and rescue by wild type or a sequence-verified proteolysis-deficient variant. Quantify DLD abundance, localization, oligomeric state and lipoyl-redox activity; map IΞΊBΞ΅ and other candidate cleavage products by targeted mass spectrometry. Test purified preparations under matched native and dimer-destabilizing conditions, with no-enzyme, substrate-only and contamination controls, and distinguish direct cleavage from proteasomal degradation. Sequence-verify the cleavage-deficient variants: mature-chain S456A/E431A correspond to precursor S491A/E466A after accounting for the 35-residue mitochondrial transit peptide.
Hypothesis: A defined change in wild-type DLD oligomeric state can expose conditional proteolysis in human cells without requiring a disease-associated interface mutation.
Type: Endogenous perturbation/rescue, cleavage-site proteomics and matched biochemical reconstitution
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The physiological or pathological conditions that expose proteolytic activity of endogenous wild-type human DLD, and its directly cleaved substrates in native human cells, remain incompletely established.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Purified human wild-type and mutant DLD cleave frataxin-derived substrates, with mutagenesis separating cleavage from lipoyl redox catalysis. Independent human protein preparations cleave IΞΊBΞ΅, and mouse N9/brain experiments link DLD to stress-associated IΞΊBΞ΅ loss. These findings establish conditional activity and a candidate cellular substrate mechanism, but do not yet define a general evolved proteolytic role in native human cells.
Significance: Distinguishing regulated native proteolysis from cleavage favored by preparation, dimer destabilization or pathology is necessary before treating it as a core DLD function.
What would resolve it: Demonstrate substrate cleavage by endogenous wild-type DLD in defined human cell conditions, measure the associated oligomeric state, and separate proteolysis from secondary redox or proteasome effects.
Provenance (the field's own admissions):
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