BCKDHA encodes the alpha subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex. Two BCKDHA and two BCKDHB chains form its E1 enzyme, which decarboxylates the ketoacids derived from leucine, isoleucine and valine and reductively acylates the lipoyl group carried by DBT. BCKDHA contributes residues that bind thiamine diphosphate and associated metal ions at the shared active site. DBT subsequently transfers the acyl group to CoA, and DLD reoxidizes the reduced lipoyl group. This coupled reaction constitutes the committed oxidative step of branched-chain amino acid catabolism in the mitochondrial matrix, downstream of transamination. BCKDK and PPM1K regulate the complex through reversible phosphorylation of the E1 alpha subunit. Phosphorylation of precursor Ser337, corresponding to mature-chain Ser292, disrupts recognition of the DBT lipoyl domain and reductive acylation more strongly than the initial decarboxylation reaction. Biallelic damaging BCKDHA variants cause maple syrup urine disease type 1A.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009083 branched-chain amino acid catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: BCKDHA contributes the E1 step of branched-chain amino acid breakdown. Reason: The alpha-beta E1 enzyme performs oxidative decarboxylation after transamination, directly contributing to catabolism. Human biochemical and structural evidence agrees with the phylogenetic annotation. No PAINT placement is challenged, and the target in WITH/FROM is legitimate descendant evidence. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IBA GO_REF:0000033 | ACCEPT | Summary: BCKDHA is an integral subunit of the mitochondrial BCKDH complex. Reason: The human alpha2-beta2 E1 assembly contains two BCKDHA chains and is one component of the multienzyme complex. This agrees with the IBA; no inference from donor count or self-inclusion is made. |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: BCKDHA contributes to the specific branched-chain ketoacid E1 reaction. Reason: The EC/Rhea mapping matches GO:0003863, whose acceptor is the protein-bound lipoyl group. The shared E1 active site catalyzes decarboxylation and reductive acylation; this does not assign DBT acyl-CoA transfer or DLD oxidation to isolated BCKDHA. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: The mature BCKDHA enzyme acts in the mitochondrial matrix. Reason: The source location mapping agrees with the reviewed UniProt matrix assignment and cleaved mitochondrial transit sequence. A purified crystal structure alone is not treated as a direct localization assay. Supporting Evidence: file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0016624 oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: The electronic oxidoreductase annotation is valid but broader than the known E1 activity. Reason: GO:0003863 is the verified specific child of GO:0016624 and describes the ketoacid-to-lipoyl reaction of the alpha-beta E1 enzyme. Refine to that established function without changing the original source object. Proposed replacements: branched-chain 2-oxo acid dehydrogenase activity |
| GO:0005515 protein binding | IPI PMID:12902323 Roles of His291-alpha and His146-beta' in the reductive acyl... | MODIFY | Summary: Human E1 active-site experiments support BCKDHA contribution to the specific E1 reaction. Reason: The complete PMID:12902323 abstract reports that alteration of His291-alpha impairs both E1 reactions and thiamine-diphosphate binding, while assigning this alpha residue a structural/cofactor-positioning role. Together with the human alpha2-beta2 structure in PMID:10745006, this supports replacing generic binding with GO:0003863 using contributes_to. The specific function is supported by the biochemical and structural results, not inferred from the P21953 interaction alone. The proposed activity belongs to the assembled alpha-beta E1 enzyme; the source enables qualifier and IPI provenance remain unchanged as the original assertion. This refines an existing row to an already supported activity and adds no new annotation. Proposed replacements: branched-chain 2-oxo acid dehydrogenase activity |
| GO:0005515 protein binding | IPI PMID:15166214 Cross-talk between thiamin diphosphate binding and phosphory... | MODIFY | Summary: Human E1 structure and alpha-loop mutagenesis support contribution to E1 catalysis. Reason: The complete PMID:15166214 abstract describes the human heterotetrameric cofactor-binding enzyme, alpha-chain phosphorylation-loop substitutions, impaired recognition of the lipoylated E2 domain, and reduced reductive acylation. These experiments support the informative replacement GO:0003863 with contributes_to, rather than autonomous catalysis by BCKDHA. This assessment uses the explicit biochemical results; it does not claim a complete-paper or pair-assay reconstruction. The original P21953 partner, IPI evidence and enables qualifier are preserved as source data. The replacement duplicates an already supported functional assertion rather than creating new coverage. Proposed replacements: branched-chain 2-oxo acid dehydrogenase activity |
| GO:0005515 protein binding | IPI PMID:15576032 Molecular mechanism for regulation of the human mitochondria... | MODIFY | Summary: Alpha-loop phosphorylation experiments identify the specific E1 function affected by BCKDHA. Reason: The complete PMID:15576032 abstract reports that phosphorylation of human E1 Ser292-alpha disrupts the lipoyl-domain interaction and reductive acylation, with a smaller effect on decarboxylation. This is direct functional evidence for BCKDHA contribution to GO:0003863 in the alpha-beta E1 assembly, beyond merely observing the BCKDHB interaction. Propose contributes_to for the replacement activity; retain the original enables qualifier, P21953 partner and IPI provenance in the source assertion. BCKDHA is the regulated E1 subunit, not the kinase performing phosphorylation. No new row or independent alpha-chain enzyme is proposed. Proposed replacements: branched-chain 2-oxo acid dehydrogenase activity |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | UNDECIDED | Summary: The BioPlex 2.0 BCKDHB co-association remains plausible, but its pair-specific evidence was not adjudicated. Reason: The exact P21953 partner is consistent with the established alpha-beta E1 assembly. However, the gene-pair supplementary data from this affinity-purification screen were not independently reconstructed. UNDECIDED records that source-specific evidence limit without disputing the curator or the known interaction. The screen alone does not establish a more specific molecular function or direct physical contact. The independently supported E1 function is represented elsewhere. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | UNDECIDED | Summary: The BioPlex 3.0 BCKDHB co-association remains plausible, but its pair and cell-context evidence was not adjudicated. Reason: The original P21953 partner agrees with the known E1 assembly, but the pair-level supplement and cell-line assignment were not independently checked. UNDECIDED therefore records the unadjudicated source-specific evidence, rather than asserting that the interaction is false. A co-association screen alone does not justify replacing this row with a catalytic function. The independently supported E1 function remains represented in the review. |
| GO:0005759 mitochondrial matrix | NAS PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: The curated complex record places BCKDHA in the mitochondrial matrix. Reason: The human liver complex purification supports BCKDH biochemistry; its abstract alone is not a matrix-fraction localization experiment. The NAS localization is retained with curator deference and the reviewed UniProt matrix assignment. |
| GO:0009083 branched-chain amino acid catabolic process | IDA PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: Human BCKDH oxidizes the ketoacid products of branched-chain amino acids. Reason: The purified human complex metabolizes the valine-, leucine- and isoleucine-derived ketoacids. BCKDHA supplies part of the E1 reaction machinery, satisfying participation in this catabolic process rather than merely being a consumed substrate. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IPI PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: BCKDHA belongs to the purified human BCKDH multienzyme assembly. Reason: The source characterizes the purified human liver complex, and the alpha subunit assignment is corroborated by later E1 structures. Do not assign the three major gel bands individually from the abstract: it does not identify each band there. Supporting Evidence: PMID:10745006 170 kDa alpha(2)beta(2) heterotetrameric E1b component |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: The rat-ortholog transfer agrees with human matrix localization. Reason: P11178 is preserved as the source donor. The reviewed human protein is a processed mitochondrial matrix enzyme, providing independent target-level corroboration. The donor experiment was not reconstructed, and the biological judgment does not depend on the relationship wording. Supporting Evidence: file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0120552 branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA | IMP PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | ACCEPT | Summary: BCKDHA contributes a catalytic step of the branched-chain acyl-CoA pathway. Reason: Human E1 structures and disease variants link the alpha chain to the cofactor and subunit architecture needed for E1 activity. GO:0120552 covers the complete three-reaction system, and BCKDHA performs part of that system through E1; it is not claimed to catalyze all three reactions. The PMID:15576032 excerpt describes phosphorylation switching E1 reductive acylation off; it is interpreted as perturbation evidence for the normal E1 step, not as a positive activity measurement in the phosphorylated state. Supporting Evidence: PMID:15576032 effectively shuts off the E1b-catalyzed reductive acylation reaction |
| 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 complex carries out the coupled oxidative pathway. Reason: The source measures ketoacid oxidation by the multienzyme system with CoA and NAD. BCKDHA contributes E1, while DBT and DLD execute the later transfer and redox steps. Their requirements do not establish separate NAD-binding or CoA-transfer functions on BCKDHA. Supporting Evidence: PMID:3593587 NAD and CoASH were absolutely required for the reaction. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9865121 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9865121 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: The mitochondrial proteome assignment is a valid broader location. Reason: The MitoCoP study supports human mitochondrial proteome mapping, consistent with established BCKDHA matrix localization. The BCKDHA-specific supplementary entry was not independently reconstructed; retain the curator-attributed broader compartment as non-core. Supporting Evidence: PMID:34800366 mitochondrial preparations of human cells file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:7883996 Molecular and biochemical basis of intermediate maple syrup ... | ACCEPT | Summary: BCKDHA mutations impair alpha-beta E1 assembly. Reason: The human-cell reconstitution and recombinant assembly results show that G245R and F364C alpha-chain variants disrupt E1 assembly and function. This directly supports complex membership rather than an autonomous alpha-chain enzyme. Supporting Evidence: PMID:7883996 mutations in the E1 alpha subunit disrupt both the E1 heterotetrameric assembly |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: Human E1 consists of two alpha and two beta subunits. Reason: The source reports recombinant human subunit assembly and physical characterization of alpha2-beta2 E1, with mutation-dependent assembly defects. BCKDHA membership in the BCKDH complex is well supported. Supporting Evidence: PMID:9582350 two E1alpha (45.5 kDa) and two E1beta |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | ACCEPT | Summary: The human E1 structure directly establishes BCKDHA complex membership. Reason: The resolved alpha2-beta2 assembly contains BCKDHA and BCKDHB. It is the E1 component of the larger BCKDH system; no independent whole-complex catalysis is assigned to BCKDHA alone. Supporting Evidence: PMID:10745006 alpha(2)beta(2) heterotetrameric E1b component |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | ACCEPT | Summary: BCKDHA contributes cofactor and structural residues to E1 catalysis. Reason: The source structure and variant evidence support the alpha-chain contribution to GO:0003863. Preserve the source contributes_to qualifier; the complementary beta chain is part of the active enzyme. |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: Correct alpha-subunit assembly is required for active human E1. Reason: The assembly study connects alpha-chain defects to loss of E1 and overall BCKDH activities. Retain the experimentally attributed contribution to the specific E1 molecular function in the heterotetrameric context. The short excerpt identifies the affected alpha subunit; the same source sentence states the resulting loss of E1 and BCKDH catalytic activities. Supporting Evidence: PMID:9582350 E1alpha subunit is affected |
| GO:0009083 branched-chain amino acid catabolic process | IMP PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: BCKDHA performs the E1 step in branched-chain amino acid catabolism. Reason: Human alpha-chain mutations impair assembly and enzyme activity in the branched-chain catabolic system. This is direct participation through a catalytic complex, not a downstream phenotype-only process assignment. Supporting Evidence: PMID:9582350 branched-chain ketoacid dehydrogenase catalytic activities. |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | KEEP AS NON CORE | Summary: The phosphoproteomic source supports a broad mitochondrial location. Reason: The paper analyzes functional mitochondria isolated from human muscle. Its abstract supports the assay context, while BCKDHA-specific phosphopeptides were not reconstructed here. Retain the curator-attributed location as non-core, consistent with independently established matrix residence. Supporting Evidence: PMID:20833797 functional mitochondria isolated from human muscle biopsies file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693148 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-5693148 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693153 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-5693153 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859148 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9859148 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859163 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9859163 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859172 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9859172 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9865115 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9865115 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9907572 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9907572 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912480 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9912480 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912527 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 alpha subunit. Reason: Accept mitochondrial matrix localization because the reviewed human UniProt SUBCELLULAR LOCATION explicitly places BCKDHA in that compartment. The original Reactome attribution is retained with this independent localization support. Supporting Evidence: Reactome:R-HSA-9912527 file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:7883996 Molecular and biochemical basis of intermediate maple syrup ... | ACCEPT | Summary: BCKDHA is required as an E1 subunit for the specific ketoacid reaction. Reason: Human-cell reconstitution and recombinant enzyme assays link alpha-chain variants to impaired E1 and BCKDH activity. Retain the source assertion, with the reaction attributed to the alpha-beta enzyme rather than an isolated alpha polypeptide. |
| GO:0009083 branched-chain amino acid catabolic process | IDA PMID:7883996 Molecular and biochemical basis of intermediate maple syrup ... | ACCEPT | Summary: BCKDHA contributes the E1 catalytic step of branched-chain amino acid degradation. Reason: The source links human alpha-chain assembly/function defects to impaired BCKDH activity. The gene product performs part of the pathway through the E1 complex, so this is a direct catabolic role. Supporting Evidence: PMID:7883996 function of the BCKAD complex |
| GO:0005739 mitochondrion | TAS PMID:11839747 Solution structure and dynamics of the lipoic acid-bearing d... | KEEP AS NON CORE | Summary: The cited complex study is compatible with mitochondrial localization. Reason: The accessible abstract studies the human DBT lipoyl domain within a mitochondrial multienzyme system. It does not independently establish every BCKDHA localization observation. Retain the valid broader mitochondrial annotation with curator deference and reviewed matrix corroboration. Supporting Evidence: PMID:11839747 substrate channeling in this mitochondrial multienzyme complex. file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0016831 carboxy-lyase activity | TAS PMID:11839747 Solution structure and dynamics of the lipoic acid-bearing d... | MODIFY | Summary: The broad decarboxylase description can be replaced by the complete specific E1 activity. Reason: The original TAS source discusses the human E2 lipoyl domain; its accessible abstract does not reconstruct the BCKDHA assay behind the curator statement. Independent E1 biochemistry establishes GO:0003863, encompassing decarboxylation coupled to lipoyl reductive acylation. This is a functional refinement, not a claim that GO:0003863 is a descendant of the lyase term. Proposed replacements: branched-chain 2-oxo acid dehydrogenase activity |
| GO:0030976 thiamine pyrophosphate binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: BCKDHA directly contacts thiamine diphosphate at the shared E1 active site. Reason: Retain the inherited proposal: reviewed UniProt maps alpha precursor residues 158, 159, 207, 239, 240, 265 and 336 to the shared ThDP ligand, citing the human 1DTW structure. PMID:12902323 directly describes alpha His291/mature coordination and a structural cofactor-positioning role. This is a distinct binding function absent from the 38 source rows, not a new independent enzyme core. Supporting Evidence: PMID:12902323 coordinates to the terminal phosphate oxygen atoms of bound ThDP. file:human/BCKDHA/BCKDHA-uniprot.txt |
| GO:0000287 magnesium ion binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: BCKDHA coordinates magnesium at the cofactor-binding site. Reason: Retain the inherited proposal: reviewed UniProt assigns Mg contacts to alpha precursor residues 238, 267 and 269 with experimental PMID:10745006/PDB:1DTW evidence. The official 1DTW record includes magnesium on the alpha-associated author chain. Do not treat ligand inventory alone as a physiological metal-specificity experiment or create a separate metal-binding core. |
| GO:0030955 potassium ion binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: BCKDHA contains a structural potassium-binding site near the cofactor loop. Reason: Retain the inherited proposal with chain precision: reviewed UniProt assigns four alpha-chain coordinating residues 206, 208, 211 and 212 to a structural K site. These are four residue contacts, not four distinct alpha-chain sites. The abstract distinguishes a second potassium site in beta; neither all potassium sites nor potassium transport is assigned to BCKDHA. |
Loading supporting content…
Download this section (compressed HTML)Q: Does the alternative P12694-2 product retain mitochondrial import, E1 assembly and regulated catalysis after its annotated transit-region deletion and insertion near the phosphorylation loop?
Suggested experts: Researchers studying BCKDH assembly and mitochondrial protein import
Experiment: Compare sequence-verified P12694-1 and P12694-2 constructs for mitochondrial import and alpha2-beta2 assembly, then measure ketoacid decarboxylation and DBT-lipoyl-domain reductive acylation separately before and after BCKDK treatment.
Hypothesis: The annotated splice differences may alter targeting or regulation without affecting all E1 reaction steps equally; this remains untested in the sources read.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)