BCKDHB encodes the beta subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex. Two BCKDHB and two BCKDHA chains form its E1 enzyme (EC 1.2.4.4), whose shared active sites decarboxylate the ketoacids derived from leucine, isoleucine and valine and reductively acylate the lipoyl group of DBT. The beta chain contributes cofactor-binding and catalytic residues at the alpha-beta interface, as well as contacts for a structural potassium ion. E1 tetramers and DLD dimers associate with a 24-subunit cubic DBT core. DBT transfers the acyl group to CoA, and DLD reoxidizes the reduced lipoyl group. This coupled oxidation is the committed step of branched-chain amino acid catabolism in the mitochondrial matrix, downstream of transamination. Reversible phosphorylation of the alpha subunit regulates the assembled enzyme. Biallelic damaging BCKDHB variants cause maple syrup urine disease type 1B; loss of the beta subunit can also destabilize the alpha subunit.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009083 branched-chain amino acid catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: BCKDHB contributes catalysis within the E1 component of the branched-chain amino acid catabolic pathway. Reason: The PAINT assignment is consistent with human E1 structure, biochemical activity and the catalytic beta-subunit residue studied in PMID:12902323. This is participation in the reaction, not necessity alone. The target appearing among the descendant evidence is expected and does not make the inference circular. The PAINT node was not reconstructed in this consultation. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IBA GO_REF:0000033 | ACCEPT | Summary: BCKDHB is an E1 beta chain of the BCKDH multienzyme complex. Reason: The phylogenetic complex assignment agrees with human alpha2beta2 E1 structure and human liver complex purification. Human BCKDHB in the supporting-entity list is legitimate experimental grounding for the PAINT inference. |
| GO:0007584 response to nutrient | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: BCKDHB participates in the nutritionally regulated BCKDH metabolic system. Reason: Retain the physiological response as context rather than the defining molecular role. PMID:15576032 describes hormonal and dietary regulation of assembled BCKDH through E1-alpha phosphorylation. The IBA embodies a curator node-placement judgment; neither one rat descendant nor the annotation date is a basis for weakening it. No phylogeny-based challenge is made here. |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assignment identifies the E1 branched-chain 2-oxo acid dehydrogenase reaction. Reason: Human biochemical and structural evidence supports the mapped chemistry. BCKDHB contributes to the shared active site in assembled E1, including an experimentally studied beta histidine; the mapping is not interpreted as activity of an isolated beta chain. Preserve the machine-supplied qualifier. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: BCKDHB normally acts in the mitochondrial matrix. Reason: The localization transfer agrees with the reviewed UniProt matrix location, mitochondrial precursor and the assembled BCKDH system. This gene-level statement does not establish localization or catalytic competence of every alternative product. |
| GO:0005515 protein binding | IPI PMID:12902323 Roles of His291-alpha and His146-beta' in the reductive acyl... | KEEP AS NON CORE | Summary: Human E1 beta/alpha association accompanies experiments on His146-beta and His291-alpha. Reason: The abstract distinguishes the beta catalytic residue from the alpha loop residue. RCSB entry 1OLS cites PMID:12902323 and maps its two human protein entities to BCKDHB P21953 and BCKDHA P12694; IntAct EBI-1036952 records this pair with X-ray crystallography evidence. These source-specific records support the alpha/beta association without a new coordinate or interface analysis. Retain the supported generic association as non-core under the explicit ClinGen project instruction; the existing complex and shared-active-site annotations retain the mechanistic interpretation. |
| GO:0005515 protein binding | IPI PMID:15166214 Cross-talk between thiamin diphosphate binding and phosphory... | KEEP AS NON CORE | Summary: BCKDHB associates with BCKDHA in the ThDP-dependent E1 heterotetramer. Reason: The abstract examines ThDP binding and alpha-subunit phosphorylation-loop structure in assembled human E1. RCSB entry 1V1R cites PMID:15166214 and maps its two human protein entities to BCKDHB P21953 and BCKDHA P12694; IntAct EBI-1039093 links the same pair and source by X-ray crystallography. Retain the supported association as non-core under the explicit ClinGen project instruction. The metadata check does not establish a separate partner-specific binding activity or assign alpha-chain regulation to the beta chain. |
| GO:0005515 protein binding | IPI PMID:15576032 Molecular mechanism for regulation of the human mitochondria... | KEEP AS NON CORE | Summary: BCKDHB and BCKDHA associate in the E1 component regulated through E1-alpha phosphorylation. Reason: The source addresses phosphorylation-dependent regulation of assembled E1 through the alpha chain. RCSB entry 1X7W cites PMID:15576032 and maps its human protein entities to BCKDHB P21953 and BCKDHA P12694; IntAct EBI-1041254 records the corresponding X-ray association. Retain the supported association as non-core under the explicit ClinGen project instruction. This check does not make BCKDHB the phosphorylated regulatory subunit or imply an autonomous kinase or phosphatase activity. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: BioPlex 2.0 records BCKDHB bait with BCKDHA prey in HEK293T cells. Reason: The official BioPlex 2.0 directed HEK293T network contains BCKDHB (GeneID 594) as bait and BCKDHA (GeneID 593) as prey, resolving the source-specific pair missing from the earlier abstract-only assessment. Retain this affinity-purification mass-spectrometry association as non-core under the explicit ClinGen project instruction. The dataset supports recovery in a complex, not an isolated binary interface or a separate molecular activity. Its presence in the later BioPlex release is not counted as independent replication. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex 3.0 records BCKDHB bait with BCKDHA prey in its HEK293T network. Reason: The official BioPlex 3.0 directed HEK293T network contains BCKDHB (GeneID 594) as bait and BCKDHA (GeneID 593) as prey. This resolves the pair and cell-line assignment for the cited network. Retain the affinity-purification mass-spectrometry association as non-core under the explicit ClinGen project instruction, without inferring a new molecular activity or independent replication of the edge already present in BioPlex 2.0. No matching edge was found in the inspected HCT116 directed file; that absence does not establish biological absence of the interaction. |
| GO:0006550 L-isoleucine catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: BCKDHB contributes to the catabolism of isoleucine through its corresponding branched-chain 2-oxo acid. Reason: The purified human liver BCKDH complex oxidizes KMV as well as the other two physiological branched-chain substrates. This substrate-specific process belongs to the normal E1 catalytic role. Preserve the ortholog-transfer evidence and supporting entities; the experiment measures assembled complex activity. |
| GO:0006552 L-leucine catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: BCKDHB contributes to the catabolism of leucine through its corresponding branched-chain 2-oxo acid. Reason: The purified human liver BCKDH complex oxidizes KIC as well as the other two physiological branched-chain substrates. This substrate-specific process belongs to the normal E1 catalytic role. Preserve the ortholog-transfer evidence and supporting entities; the experiment measures assembled complex activity. |
| GO:0006574 L-valine catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: BCKDHB contributes to the catabolism of valine through its corresponding branched-chain 2-oxo acid. Reason: The purified human liver BCKDH complex oxidizes KIV as well as the other two physiological branched-chain substrates. This substrate-specific process belongs to the normal E1 catalytic role. Preserve the ortholog-transfer evidence and supporting entities; the experiment measures assembled complex activity. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MODIFY | Summary: The protein-complex assignment can be made specific to the BCKDH complex. Reason: Human E1 structural and assembly studies identify BCKDHB as an alpha2beta2 E1 constituent of the branched-chain alpha-ketoacid dehydrogenase system. That evidence supports the more specific complex term while preserving the original broad source assertion. Proposed replacements: branched-chain alpha-ketoacid dehydrogenase complex |
| GO:0005759 mitochondrial matrix | NAS PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: The curated author statement places the human BCKDH system in the mitochondrial matrix. Reason: Retain the NAS localization with support from the normal UniProt matrix annotation. The cached purification abstract establishes human liver complex activity but does not itself detail the organelle-fractionation evidence; a paper title is not a localization assay. |
| GO:0009083 branched-chain amino acid catabolic process | IDA PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: Human BCKDH complex oxidizes the three branched-chain 2-oxo acid substrates. Reason: The human liver purification and kinetic abstract supports the complex contribution to branched-chain amino acid catabolism. BCKDHB forms the E1 beta chain; its participation is catalytic within E1, not inferred solely from disease. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IPI PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: BCKDHB is a constituent of the purified human BCKDH system. Reason: Retain the curator complex assignment based on purification and subunit composition. The cached abstract reports the purified multienzyme composition; independent human E1 structures identify its alpha and beta chains. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: The existing immunofluorescence annotation places BCKDHB in mitochondria. Reason: Retain this directly curated localization, which agrees with the independently supported matrix role. The original HPA image and individual experimental record were not inspected here; no sub-mitochondrial resolution is inferred from this broad annotation. |
| GO:0005759 mitochondrial matrix | NAS PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | ACCEPT | Summary: The human E1 structure-associated author statement supports mitochondrial matrix localization. Reason: The NAS annotation is consistent with the reviewed UniProt location and mitochondrial E1 biology. The structural abstract establishes human E1 architecture rather than a new matrix-localization experiment. |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: The ortholog-based annotation places BCKDHB function in the mitochondrial matrix. Reason: Retain the curator transfer from the existing rat source P21839; the target human UniProt matrix annotation and mitochondrial E1 biology agree. Preserve the exact source qualifier and supporting entity without claiming the donor experiment was reread. |
| 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: BCKDHB contributes E1 chemistry to the multistep production of branched-chain acyl-CoA. Reason: The structural study supports human E1 and mutation-associated disruption. GO:0120552 describes the complete three-reaction complex pathway, not only decarboxylation: E1 decarboxylates and reductively acylates E2 lipoamide, DBT transfers the acyl group to CoA, and DLD reoxidizes the lipoyl group. BCKDHB performs part of that pathway through the E1 active site. |
| 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 BCKDH complex executes the branched-chain acyl-CoA-forming pathway. Reason: The source measures overall oxidation of KIV, KIC and KMV with CoASH and NAD required. Retain the process assignment to its E1 beta subunit, while distinguishing the combined pathway output from the E1 reaction alone. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9865121 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. This is an E1 assembly-defect disease event; genotype-specific loss or residual activity does not invalidate normal beta-subunit matrix localization. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The high-throughput mitochondrial-proteome annotation agrees with BCKDHB mitochondrial localization. Reason: The complete study abstract establishes the MitoCoP proteomic approach, while the original GOA record supplies the BCKDHB-specific attribution. Its individual supplementary entry was not reread. Independent UniProt and human E1 evidence supports retaining mitochondrion as a valid broad location. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IMP PMID:2022752 Maple syrup urine disease. Complete defect of the E1 beta su... | ACCEPT | Summary: Loss of E1-beta destabilizes E1-alpha and impairs human BCKDH complex function. Reason: The patient-cell study reports absent beta protein, reduced alpha protein and residual complex activity near six percent of control. Retain the curator complex-membership assignment, corroborated independently by the human E1 structure. This phenotype does not establish that every mutant complex is completely absent. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: Recombinant human E1-alpha and E1-beta assemble into the E1 heterotetramer. Reason: The source expresses human chains in Escherichia coli with GroEL/GroES and examines assembly. Wild-type E1 is alpha2beta2, whereas tested alpha-chain variants impair assembly. BCKDHB is directly part of the assayed human heterotetramer, despite the disease focus on E1-alpha. Supporting Evidence: |
| 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 crystal structure directly includes the beta chain. Reason: The 2.7-angstrom structure establishes the human alpha2beta2 E1 component. Retain complex membership; the study is of E1 and does not resolve an entire four-megadalton BCKDH particle. Supporting Evidence: |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | ACCEPT | Summary: BCKDHB contributes to the shared human E1 dehydrogenase active site. Reason: Retain the contributes_to assignment supported by E1 structure and the experimentally studied beta-subunit catalytic residue. The beta chain is not merely a passive scaffold, but isolated beta-chain activity is not asserted. |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: BCKDHB contributes to the activity of the assembled E1 heterotetramer. Reason: Retain the curator contributes_to assignment. The source studies human alpha variants and wild-type beta in assembled E1; the focus on the alpha mutations does not exclude the beta chain from the assayed enzyme. Human beta-site mutagenesis supplies additional mechanistic grounding. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693148 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. This event concerns BCKDK regulation of the same matrix enzyme; it does not assign kinase activity to E1 beta. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693153 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. The event summary misnames E1 beta as the PPM1K dephosphorylation target; the alpha phosphorylation-loop evidence supports the existing DISPUTED reference assessment. That subunit-description error does not refute the matrix compartment. Supporting Evidence: Reactome:R-HSA-5693153 UniProtKB:P21953 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912527 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. This is a PPM1K disease-variant event affecting matrix-complex regulation, not beta-chain phosphatase activity. |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IMP PMID:2022752 Maple syrup urine disease. Complete defect of the E1 beta su... | ACCEPT | Summary: An E1-beta frameshift impairs assembled human BCKDH activity. Reason: The cached patient-cell abstract reports loss of beta protein, alpha destabilization and approximately six percent residual activity. Retain contributes_to for the E1 reaction; independent beta-site mutagenesis establishes that the beta subunit does catalytic work rather than serving only as a necessary substrate. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859148 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. The event describes assembled E1 catalysis in the matrix BCKDH system; it does not establish isolated beta-chain activity. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859163 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. The E2 acyl-transfer event concerns the shared matrix complex, with chemistry performed by DBT. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859172 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. The E3 reoxidation event concerns the shared matrix complex, with chemistry performed by DLD. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9865115 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. This is a DBT disease-variant event, not a claim that normal E1 beta loses matrix localization. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9907572 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. This is a DLD disease-variant event in the matrix multienzyme system, not a distinct localization measurement of BCKDHB. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912480 | ACCEPT | Summary: The mitochondrial matrix localization is retained for the human E1 beta subunit. Reason: Retain the source-attributed mitochondrial matrix compartment, independently corroborated by the reviewed human P21953 SUBCELLULAR LOCATION record. The fetched Reactome summary does not expose a compartment field, so it is not treated as an independent localization experiment. This is a BCKDK loss-of-function disease event affecting control of the matrix complex, not beta-chain kinase activity. |
| GO:0005739 mitochondrion | IMP PMID:2022752 Maple syrup urine disease. Complete defect of the E1 beta su... | ACCEPT | Summary: The BCKDHB defect concerns a precursor normally targeted to mitochondria. Reason: The 11-base-pair deletion lies in the targeting-leader coding region and causes a frameshift with defective mature beta protein. Retain the existing IMP localization with independent UniProt support; the experiment does not isolate an import-only defect or prove that loss of localization alone caused the phenotype. |
| GO:0009083 branched-chain amino acid catabolic process | IMP PMID:2022752 Maple syrup urine disease. Complete defect of the E1 beta su... | ACCEPT | Summary: Loss of E1-beta impairs the human BCKDH contribution to branched-chain amino acid catabolism. Reason: The patient-cell study establishes a beta-subunit defect and reduced complex activity. In conjunction with the defined beta catalytic contribution and human substrate kinetics, the process is directly relevant to BCKDHB; it is not assigned solely from a clinical association. |
| GO:0030976 thiamine pyrophosphate binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: Retain the previously authored ThDP-binding annotation with direct subunit-level support. Reason: The reviewed UniProt P21953 feature identifies precursor Tyr152 as a ThDP contact shared with the alpha chain, supported by PMID:10745006 and PDB:1DTW. That specific contact supports beta-chain cofactor binding within E1, without claiming that isolated BCKDHB binds the complete cofactor autonomously. The earlier statement assigning only thiazolium-ring contacts to beta is unnecessary and unsupported here. The potassium-loop quote and provider prose are not used as substitutes for the direct feature. Supporting Evidence: UniProtKB:P21953 file:human/BCKDHB/BCKDHB-uniprot.txt FT BINDING 152 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with alpha subunit" |
| GO:0030955 potassium ion binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: Retain the previously authored structural potassium-binding annotation. Reason: PMID:10745006 explicitly locates a structural potassium ion in the beta subunit, and UniProt annotates six coordinating residues in precursor numbering. Six residue-level features are not six separate ion-binding sites. The RCSB entry and UniProt support structural potassium coordination; coordinate geometry and density were not independently analyzed. This is not an ion-transport, regulatory or separate core catalytic function. Supporting Evidence: PMID:10745006 The second is located in the beta subunit near the interface UniProtKB:P21953 |
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Download this section (compressed HTML)Q: Does the P21953-2 product, whose sequence changes after residue 211 and lacks canonical residues 219–392, undergo mitochondrial import or assemble into a functional E1 enzyme?
Q: How do substitutions at the beta-chain potassium-coordinating residues affect local ion coordination, folding and the two E1 reaction steps separately?
Experiment: Compare sequence-verified canonical and P21953-2 products for mitochondrial import, alpha2-beta2 assembly, ThDP occupancy, ketoacid decarboxylation and DBT-lipoyl-domain reductive acylation. Test selected potassium-coordinating residue substitutions with folding controls.
Hypothesis: The large alternative-product truncation and changes near the potassium site may affect assembly and catalytic steps differently; equivalent activity is not established by the sources inspected.
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