BCKDHA encodes the E1 alpha (E1a) subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKDH/BCKD/BCKDC) complex. Together with the E1 beta subunit (BCKDHB) it assembles into an alpha2-beta2 heterotetrameric E1 component, the branched-chain 2-oxo acid decarboxylase. This E1 component associates with the dihydrolipoyl transacylase E2 core (DBT), which forms a 24-meric cubic scaffold, and with the dihydrolipoamide dehydrogenase E3 (DLD) to build the complete BCKDH multienzyme complex in the mitochondrial matrix. The complex catalyzes the first, committed, rate-limiting and irreversible step of branched-chain amino acid (BCAA; leucine, isoleucine, valine) catabolism, namely the oxidative decarboxylation of the branched-chain 2-oxo (alpha-keto) acids (4-methyl-2-oxopentanoate/KIC from leucine, (S)-3-methyl-2-oxopentanoate/KMV from isoleucine, and 3-methyl-2-oxobutanoate/KIV from valine) to their branched-chain acyl-CoA derivatives, releasing CO2 and generating NADH through the coupled E1/E2/E3 reaction sequence. E1a specifically carries out the thiamine-diphosphate (TPP)-dependent decarboxylation of the 2-oxo acid and then the reductive acylation that transfers the acyl group to the lipoyl-lysine of the E2 component (EC 1.2.4.4). Catalysis requires thiamine diphosphate and Mg2+ as cofactors, with structural K+ ions; the TPP/Mg2+ binding residues reside on the E1a subunit. BCKDH activity is controlled by reversible phosphorylation of E1a (Ser337 of the UniProt precursor, equivalent to Ser292 of the mature subunit and to the "Ser292-alpha" of the structural literature) by the kinase BCKDK (inactivating) and dephosphorylation by the phosphatase PPM1K/PP2Cm (activating). Biallelic loss-of-function variants in BCKDHA cause maple syrup urine disease type IA (MSUD1A), an autosomal recessive inborn error of metabolism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009083 branched-chain amino acid catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred involvement of the E1-alpha subunit in branched-chain amino acid catabolism. This is the core biological process for BCKDHA and is well supported by biochemistry across orthologs; the IBA is at an appropriate level of specificity. Reason: BCKDHA is the E1-alpha subunit of the BCKDH complex, which performs the committed rate-limiting step of BCAA (leucine/isoleucine/valine) catabolism. Directly supported by biochemistry of the purified human complex and by MSUD disease biology. Supporting Evidence: PMID:3593587 The BCKADH effectively oxidized all of KIV, KIC, and KMV, yielding apparent Km values in the range of 14-17 microM for those alpha-keto acids. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred membership of E1-alpha in the branched-chain alpha-ketoacid dehydrogenase complex. Correct and well supported; E1-alpha (with E1-beta) forms the E1 heterotetramer that is part of the complete BCKDH complex assembled on the E2/DBT core. Reason: The alpha2-beta2 E1 heterotetramer is an integral part of the BCKDH complex, demonstrated structurally and biochemically for the human enzyme. Supporting Evidence: PMID:10745006 the 170 kDa alpha(2)beta(2) heterotetrameric E1b component of the branched-chain alpha-ketoacid dehydrogenase multienzyme complex |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of the E1 branched-chain 2-oxo acid dehydrogenase activity (EC 1.2.4.4; RHEA:13457, RHEA:84639, RHEA:84643), corresponding to the specific molecular function of the BCKDH E1 component and matching the UniProt catalytic activity reactions. This is the correct core molecular function. Reason: The IEA (EC/RHEA-mapped) term precisely matches the reaction catalyzed by the E1 component to which E1-alpha contributes; it is corroborated by experimental IDA annotations to the same term. Supporting Evidence: PMID:3593587 The BCKADH effectively oxidized all of KIV, KIC, and KMV, yielding apparent Km values in the range of 14-17 microM for those alpha-keto acids. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping from the UniProt subcellular location keyword (mitochondrion matrix). Correct; the mature protein is imported into the mitochondrial matrix after cleavage of its N-terminal transit peptide, where the BCKDH complex functions. Reason: Mitochondrial matrix localization is directly established by the crystal structure/UniProt subcellular location and consistent with the presence of a cleavable mitochondrial transit peptide (residues 1-45). Supporting Evidence: PMID:10745006 the branched-chain alpha-ketoacid dehydrogenase multienzyme complex |
| GO:0016624 oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IPR001017, DH_E1) electronic mapping to the parent oxidoreductase term. GO:0016624 is the direct is_a parent of the specific BCKDH E1 activity GO:0003863, so it is not wrong, but it is unnecessarily general for E1-alpha given that the specific decarboxylase function is already annotated. Reason: The annotation is a legitimate but overly broad electronic parent term. The specific molecular function GO:0003863 (branched-chain 2-oxo acid dehydrogenase activity), which is_a GO:0016624, is already supported by experimental (IDA) and EC/RHEA (IEA) evidence and should be used instead. 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... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI with WITH/FROM = UniProtKB:P21953 (BCKDHB), i.e. the physiological E1-alpha/E1-beta interaction underlying the alpha2-beta2 heterotetramer. The interaction itself is real and central, but the GO term protein binding is uninformative and does not convey the functional relationship. Reason: Per curation guidelines, bare protein binding is uninformative. The biologically meaningful content (E1-alpha/E1-beta heterotetramer) is captured by the complex-membership annotation GO:0160157 and by core_functions; this IPI adds no functional specificity. |
| GO:0005515 protein binding | IPI PMID:15166214 Cross-talk between thiamin diphosphate binding and phosphory... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI with WITH/FROM = UniProtKB:P21953 (BCKDHB) from a mechanistic study of the human E1b decarboxylase (thiamine diphosphate binding / phosphorylation-loop conformation), i.e. again the E1-alpha/E1-beta interaction. Reason: The underlying E1-alpha/E1-beta interaction is genuine but the protein binding term is uninformative; the heterotetramer is already represented by GO:0160157 complex membership and core_functions. |
| GO:0005515 protein binding | IPI PMID:15576032 Molecular mechanism for regulation of the human mitochondria... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI with WITH/FROM = UniProtKB:P21953 (BCKDHB) from a study of phosphorylation-based regulation of the human BCKDH complex; the recorded interaction is the E1-alpha/E1-beta pairing within E1. Reason: Uninformative MF term. The functionally meaningful E1-alpha/E1-beta association is captured by the complex membership annotation (GO:0160157) and core_functions. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI (BioPlex 2.0 large-scale AP-MS interactome) with WITH/FROM = UniProtKB:P21953 (BCKDHB). High-throughput guilt-by-association evidence recapitulating the E1-alpha/E1-beta interaction. Reason: Uninformative protein binding term derived from a high-throughput screen; the E1-alpha/E1-beta relationship is already represented more informatively by GO:0160157. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI (BioPlex 3.0 large-scale AP-MS interactome) with WITH/FROM = UniProtKB:P21953 (BCKDHB). High-throughput evidence again capturing the E1-alpha/E1-beta interaction. Reason: Uninformative MF term from a high-throughput interactome; the E1-alpha/E1-beta association is already represented by GO:0160157 and core_functions. |
| GO:0005759 mitochondrial matrix | NAS PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: ComplexPortal (CPX-2216) NAS annotation to mitochondrial matrix, consistent with the localization of the purified human liver BCKDH complex and with the crystallographic/UniProt subcellular location. Correct localization. Reason: Mitochondrial matrix localization is well established for the BCKDH complex that contains E1-alpha; this NAS is corroborated by IEA (SubCell), ISS, and TAS annotations to the same term. |
| GO:0009083 branched-chain amino acid catabolic process | IDA PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: Direct experimental evidence (ComplexPortal, IDA) that the purified human liver BCKDH complex oxidizes the three branched-chain 2-oxo acids (KIV, KIC, KMV), placing E1-alpha in the BCAA catabolic process. This is the core biological process. Reason: The purified complex biochemically catabolizes all three branched-chain 2-oxo acids, directly demonstrating involvement in BCAA catabolism. Supporting Evidence: PMID:3593587 The BCKADH effectively oxidized all of KIV, KIC, and KMV, yielding apparent Km values in the range of 14-17 microM for those alpha-keto acids. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IPI PMID:3593587 Purification and characterization of human liver branched-ch... | ACCEPT | Summary: ComplexPortal (CPX-2216) evidence that E1-alpha is a subunit of the branched-chain alpha-ketoacid dehydrogenase complex, based on purification/characterization of the human liver complex showing the constituent subunits. Correct. Reason: The purified human liver complex resolves into its component subunits (including the ~46-51 kDa E1-alpha/E1-beta bands), establishing E1-alpha as part of the BCKDH complex. Supporting Evidence: PMID:3593587 the purified enzyme complex gave three major bands having molecular weights of 51,000, 46,000, and 36,000 |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer from rat ortholog (UniProtKB:P11178) asserting that E1-alpha is active in the mitochondrial matrix. Consistent with all other localization evidence; the is_active_in qualifier appropriately reflects where the enzyme carries out its function. Reason: Mitochondrial matrix is the established site of BCKDH function; the ISS is consistent with the direct human localization data. |
| 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: IMP from the crystal structure/mutational analysis of human E1b, in which MSUD-causing E1-alpha variants disrupt cofactor/K+ sites and subunit interfaces and abolish function, demonstrating the role of E1-alpha in the branched-chain 2-oxo acid decarboxylation-to-acyl-CoA process. This BP term precisely captures the pathway role of the complex. Reason: MSUD mutations in E1-alpha interfere with the cofactor and K+ sites and subunit interfaces, impairing the decarboxylation process, providing mutational (IMP) evidence for E1-alpha involvement. Supporting Evidence: PMID:10745006 The known MSUD mutations affect the functioning of E1b by interfering with the cofactor and K(+) sites, the packing of hydrophobic cores, and the precise arrangement of residues at or near several subunit interfaces. |
| 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: IDA that the purified human BCKDH complex (containing E1-alpha) carries out oxidative decarboxylation of the branched-chain 2-oxo acids to yield NADH (and, via the coupled reactions, branched-chain acyl-CoA), placing E1-alpha in this pathway. Reason: The purified complex oxidizes KIV/KIC/KMV in a CoA- and NAD-dependent reaction, the biochemical hallmark of the branched-chain 2-oxo acid decarboxylation-to-acyl-CoA pathway. Supporting Evidence: PMID:3593587 NAD and CoASH were absolutely required for the reaction. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9865121 | ACCEPT | Summary: Reactome TAS localization of the BCKDH reaction to the mitochondrial matrix. Correct and consistent with all other localization evidence. Reason: Reactome curates the BCKDH-catalyzed reaction as occurring in the mitochondrial matrix, consistent with the experimental localization of the complex. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput (HTP) mitochondrial proteome assignment. Correct but less specific than the matrix localization; retained as a broader, consistent localization. Reason: High-confidence mitochondrial proteome data place E1-alpha in the mitochondrion; this is a correct broader parent of the mitochondrial matrix localization. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:7883996 Molecular and biochemical basis of intermediate maple syrup ... | ACCEPT | Summary: IDA from a study of intermediate MSUD in which homozygous E1-alpha missense mutations (G245R, F364C) disrupt E1 heterotetrameric (alpha2-beta2) assembly and BCKAD complex function, directly demonstrating E1-alpha as a subunit of the complex. Reason: Mutant E1-alpha subunits fail to assemble the alpha2-beta2 E1 tetramer and reconstitute BCKAD activity, establishing E1-alpha membership in the BCKDH complex. Supporting Evidence: PMID:7883996 G245R and F364C mutations in the E1 alpha subunit disrupt both the E1 heterotetrameric assembly and function of the BCKAD complex |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: IDA showing the human E1 decarboxylase comprises two E1-alpha and two E1-beta subunits forming an alpha2-beta2 tetramer that is part of the BCKAD complex, with type IA MSUD E1-alpha mutations impairing assembly. Directly establishes complex membership. Reason: Reconstitution/assembly experiments define the alpha2-beta2 E1 component containing E1-alpha as part of the branched-chain ketoacid dehydrogenase complex. Supporting Evidence: PMID:9582350 The E1 decarboxylase component of the human branched-chain ketoacid dehydrogenase complex comprises two E1alpha (45.5 kDa) and two E1beta (37.5 kDa) subunits forming an alpha2 beta2 tetramer. |
| GO:0160157 branched-chain alpha-ketoacid dehydrogenase complex | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | ACCEPT | Summary: IDA from the crystal structure of the human alpha2-beta2 E1b heterotetramer, the E1 component of the BCKDH multienzyme complex, directly demonstrating E1-alpha as a structural subunit of the complex. Reason: The crystal structure resolves the alpha2-beta2 E1b heterotetramer as the E1 component of the branched-chain alpha-ketoacid dehydrogenase complex. Supporting Evidence: PMID:10745006 the 170 kDa alpha(2)beta(2) heterotetrameric E1b component of the branched-chain alpha-ketoacid dehydrogenase multienzyme complex |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | ACCEPT | Summary: IDA (contributes_to) linking E1-alpha to the branched-chain 2-oxo acid dehydrogenase molecular function of the E1 component. The contributes_to qualifier is appropriate because the activity is a property of the E1-alpha/E1-beta heterotetramer to which E1-alpha contributes catalytic residues (TPP/Mg2+ binding site). This is the core molecular function. Reason: The crystal structure with TPP, K+ and Mg2+ and characterization of MSUD variants (loss of 3-methyl-2-oxobutanoate dehydrogenase activity) establishes the contribution of E1-alpha to the branched-chain 2-oxo acid dehydrogenase activity. Supporting Evidence: PMID:10745006 The known MSUD mutations affect the functioning of E1b by interfering with the cofactor and K(+) sites |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: IDA (contributes_to) showing that E1-alpha is required for E1 and BCKAD catalytic activities; type IA MSUD E1-alpha mutations cause loss of these activities. Core molecular function to which E1-alpha contributes within the heterotetramer. Reason: In type IA MSUD the affected E1-alpha subunit results in loss of E1 and BCKAD catalytic activities, demonstrating the contribution of E1-alpha to the branched-chain 2-oxo acid dehydrogenase activity. Supporting Evidence: PMID:9582350 the E1alpha subunit is affected, resulting in the loss of E1 and branched-chain ketoacid dehydrogenase catalytic activities |
| GO:0009083 branched-chain amino acid catabolic process | IMP PMID:9582350 Impaired assembly of E1 decarboxylase of the branched-chain ... | ACCEPT | Summary: IMP evidence that E1-alpha function is required for branched-chain ketoacid dehydrogenase activity, the committed step of BCAA catabolism; type IA MSUD E1-alpha mutations abolish this activity. Core biological process. Reason: Loss of E1-alpha function in type IA MSUD abolishes BCKAD catalytic activity, the committed step of BCAA catabolism, providing mutational evidence for involvement in the process. Supporting Evidence: PMID:9582350 the E1alpha subunit is affected, resulting in the loss of E1 and branched-chain ketoacid dehydrogenase catalytic activities |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: High-throughput direct assay (HDA) mitochondrial phosphoproteome localization. Correct but broader than the matrix localization; consistent supporting evidence. Reason: Phosphoproteomic analysis of functional mitochondria localizes E1-alpha to the mitochondrion, a correct broader parent of the mitochondrial matrix localization. Supporting Evidence: PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated from resting human muscle |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693148 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix. Correct and consistent with all other localization evidence. Reason: Reactome curates the BCKDH reaction/subunits to the mitochondrial matrix, consistent with experimental localization. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5693153 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix. Correct; duplicate of the well-supported matrix localization. Reason: Consistent Reactome-curated matrix localization for the BCKDH complex. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859148 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix (BCKDHA:BCKDHB tetramer decarboxylates KIC, KMVA, KIV reaction). Correct localization of the E1-catalyzed step. Reason: Reactome localizes the E1 (BCKDHA:BCKDHB) decarboxylation reaction to the mitochondrial matrix, consistent with experimental data. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859163 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix. Correct; consistent with all other localization evidence. Reason: Consistent Reactome-curated matrix localization for the BCKDH complex. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9859172 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix (DLD dimer dehydrogenates dihydrolipoyl step of the BCKDH complex). Correct localization; annotated to E1-alpha as part of the same complex. Reason: Consistent Reactome-curated matrix localization for the BCKDH complex. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9865115 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix. Correct; consistent duplicate of the matrix localization. Reason: Consistent Reactome-curated matrix localization for the BCKDH complex. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9907572 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix. Correct; consistent duplicate of the matrix localization. Reason: Consistent Reactome-curated matrix localization for the BCKDH complex. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912480 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix. Correct; consistent duplicate of the matrix localization. Reason: Consistent Reactome-curated matrix localization for the BCKDH complex. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9912527 | ACCEPT | Summary: Reactome TAS localization to the mitochondrial matrix (H139Hfs13* PPM1K does not dephosphorylate BCKDH). Correct localization of the regulated BCKDH reaction. Reason: Consistent Reactome-curated matrix localization for the BCKDH complex. |
| GO:0003863 branched-chain 2-oxo acid dehydrogenase activity | IDA PMID:7883996 Molecular and biochemical basis of intermediate maple syrup ... | ACCEPT | Summary: IDA (enables) that E1-alpha is required for branched-chain 2-oxo acid dehydrogenase activity; intermediate MSUD E1-alpha mutations (G245R, F364C) abolish reconstitution of BCKAD activity. This is the core molecular function of the gene product. Reason: Both intermediate-MSUD E1-alpha mutant subunits fail to reconstitute BCKAD activity, demonstrating the requirement of E1-alpha for the branched-chain 2-oxo acid dehydrogenase activity. Supporting Evidence: PMID:7883996 both G245R and F364C mutant E1 alpha subunits were unable to significantly reconstitute BCKAD activity |
| GO:0009083 branched-chain amino acid catabolic process | IDA PMID:7883996 Molecular and biochemical basis of intermediate maple syrup ... | ACCEPT | Summary: IDA that E1-alpha function is required for BCKAD complex activity, the committed step of BCAA catabolism, whose loss (via E1-alpha mutation) causes intermediate MSUD. Core biological process. Reason: E1-alpha mutations that abolish BCKAD activity cause MSUD (a BCAA catabolic defect), demonstrating involvement of E1-alpha in branched-chain amino acid catabolism. Supporting Evidence: PMID:7883996 G245R and F364C mutations in the E1 alpha subunit disrupt both the E1 heterotetrameric assembly and function of the BCKAD complex |
| GO:0005739 mitochondrion | TAS PMID:11839747 Solution structure and dynamics of the lipoic acid-bearing d... | ACCEPT | Summary: TAS (HGNC-UCL) mitochondrial localization derived from a study of the human BCKD complex (E2 lipoyl-bearing domain). Correct but broader than the matrix localization; the paper concerns the E2/DBT lipoyl domain rather than E1-alpha specifically, and is used here as curator-transferred general localization for the complex. Reason: Mitochondrial localization of the BCKD complex is correct; retained as a broader parent of the mitochondrial matrix localization. Supporting Evidence: PMID:11839747 the human branched-chain alpha-keto acid dehydrogenase complex |
| GO:0016831 carboxy-lyase activity | TAS PMID:11839747 Solution structure and dynamics of the lipoic acid-bearing d... | MARK AS OVER ANNOTATED | Summary: TAS (HGNC-UCL) carboxy-lyase activity, a generic parent capturing the decarboxylation (CO2-releasing) chemistry of the E1 reaction. The reference is actually an NMR study of the E2 lipoyl domain, so this is a curator-assigned broad term rather than a direct assay of E1-alpha carboxy-lyase activity. The specific molecular function is GO:0003863. Reason: Carboxy-lyase activity is a correct but overly general description of the E1 decarboxylation step; the precise molecular function branched-chain 2-oxo acid dehydrogenase activity (GO:0003863) is already annotated with experimental evidence and better represents the role of E1-alpha. |
| GO:0030976 thiamine pyrophosphate binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: Not present in the seeded GOA but strongly supported. The crystal structure of human E1b resolves thiamine diphosphate bound at the E1-alpha/E1-beta interface, and UniProt annotates multiple TPP-binding residues on E1-alpha (positions 158, 159, 207, 239, 240, 265 and 336 of the P12694 precursor, each flagged "ligand shared with beta subunit"). Added as a NEW core molecular function for the essential cofactor. Reason: E1-alpha provides the diphosphate-binding residues of the shared thiamine diphosphate cofactor, which is essential for the decarboxylation reaction; this MF is documented crystallographically and by UniProt binding features but is missing from the current GOA. Supporting Evidence: PMID:10745006 One of these ions assists a loop that is close to the cofactor to adopt the proper conformation. file:human/BCKDHA/BCKDHA-deep-research-falcon.md The E1 component requires thiamine pyrophosphate (ThDP/TPP) as an essential cofactor |
| GO:0000287 magnesium ion binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: Not present in the seeded GOA but supported by the crystal structure and UniProt binding features. Mg2+ is a required cofactor coordinated by E1-alpha residues 238, 267 and 269 of the P12694 precursor (UniProt BINDING features with ECO:0000269|PubMed:10745006) together with the diphosphate moiety of thiamine diphosphate. Added as a NEW core molecular function. Reason: E1-alpha coordinates the catalytically required Mg2+ that anchors the diphosphate of thiamine diphosphate; documented crystallographically and by UniProt binding features but missing from the current GOA. Supporting Evidence: file:human/BCKDHA/BCKDHA-uniprot.txt Name=Mg(2+) |
| GO:0030955 potassium ion binding | IDA PMID:10745006 Crystal structure of human branched-chain alpha-ketoacid deh... | NEW | Summary: Not present in the seeded GOA. The 2.7 A crystal structure of human E1b located two structural K+ ions in the heterotetramer, one of which orders a loop adjacent to the thiamine diphosphate cofactor; UniProt records four corresponding structural K+ BINDING sites on E1-alpha (positions 206, 208, 211 and 212 of the P12694 precursor). Added as a NEW, non-core molecular function. Reason: The K+ sites are experimentally located in the human E1b structure and are required for the correct conformation of the cofactor-proximal loop; MSUD mutations are noted to act partly by disturbing them. This is a structural rather than catalytic cofactor, so it is added as supporting detail and not as a core function. Supporting Evidence: PMID:10745006 The position of two important potassium (K(+)) ions was determined. PMID:10745006 One of these ions assists a loop that is close to the cofactor to adopt the proper conformation. |
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Download this section (compressed HTML)Q: Beyond the canonical alpha2-beta2 E1 heterotetramer, are there physiologically distinct assemblies or partners of E1-alpha (e.g. the BCAT2-BCKDH metabolon) that alter substrate channeling or flux in specific tissues?
Q: Does phosphorylation of E1-alpha at Ser337 by BCKDK versus dephosphorylation by PPM1K act purely as an on/off switch, or does it also modulate substrate specificity among the three branched-chain 2-oxo acids?
Experiment: Cryo-EM of the intact human BCKDH complex (E1/E2/E3 on the DBT core) in phosphorylated versus dephosphorylated states to resolve how E1-alpha phosphorylation-loop conformation gates the reductive acylation step.
Experiment: Reconstitution assays comparing kcat/Km of wild-type versus MSUD1A E1-alpha variants for KIC, KMV and KIV to test whether specific mutations differentially affect the three physiological substrates.
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