BCKDHA (P12694) deep research report (falcon / Edison Scientific Literature)
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The E1 heterotetramer is thiamine-diphosphate dependent, and the two subunits divide the cofactor site between them - E1-alpha supplies the residues that bind the diphosphate moiety and the associated divalent metal, while E1-beta supplies the thiazolium-ring contacts. This informed the NEW thiamine pyrophosphate binding and magnesium ion binding annotations on BCKDHA.
"The E1α subunit provides residues critical for binding the diphosphate portion of thiamine pyrophosphate and associated divalent metal atoms, while E1β subunits contribute residues that bind the thiazolium ring portion"
UniProtKB P12694 (ODBA_HUMAN) record
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UniProt records thiamine diphosphate BINDING sites at 158, 159, 207, 239, 240, 265 and 336 (each "ligand shared with beta subunit"), Mg(2+) BINDING sites at 238, 267 and 269, and structural K(+) BINDING sites at 206, 208, 211 and 212, all in P12694 precursor numbering; the transit peptide is 1-45 and the mature chain 46-445.
"Name=Mg(2+)"
Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Combined Automated Annotation using Multiple IEA Methods
Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease.
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The 2.7 A crystal structure of the human alpha2-beta2 heterotetrameric E1b component reveals the TPP, K+ and Mg2+ sites and explains how MSUD mutations disrupt function.
"the 170 kDa alpha(2)beta(2) heterotetrameric E1b component of the branched-chain alpha-ketoacid dehydrogenase multienzyme complex"
Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex.
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NMR structure of the E2 (transacylase) lipoyl-bearing domain of the human BCKD complex; concerns the E2 lipoyl domain rather than E1-alpha directly.
"The lipoyl-bearing domain (LBD) of the transacylase (E2) subunit of the branched-chain alpha-keto acid dehydrogenase complex plays a central role in substrate channeling in this mitochondrial multienzyme complex."
Roles of His291-alpha and His146-beta' in the reductive acylation reaction catalyzed by human branched-chain alpha-ketoacid dehydrogenase: refined phosphorylation loop structure in the active site.
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Mechanistic study of the human E1b reductive acylation reaction and active-site/phosphorylation-loop structure. Source of an E1-alpha/E1-beta protein-binding IPI.
"reductive acylation reaction catalyzed by human branched-chain alpha-ketoacid dehydrogenase"
Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase.
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Links thiamine diphosphate binding to phosphorylation-loop conformation in human E1b. Source of an E1-alpha/E1-beta protein-binding IPI.
"Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase."
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation.
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Describes phosphorylation-based regulation of the human BCKDH complex. Source of an E1-alpha/E1-beta protein-binding IPI.
"Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation."
Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes.
Architecture of the human interactome defines protein communities and disease networks.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
Purification and characterization of human liver branched-chain alpha-keto acid dehydrogenase complex.
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The purified human liver BCKDH complex resolves into E1-alpha/E1-beta/E2 subunits and oxidizes KIV, KIC and KMV in a NAD- and CoA-dependent reaction.
"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."
Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1 alpha locus of Hispanic-Mexican patients.
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Homozygous E1-alpha missense mutations (G245R, F364C) disrupt alpha2-beta2 E1 assembly and abolish BCKAD activity, causing intermediate MSUD.
"G245R and F364C mutations in the E1 alpha subunit disrupt both the E1 heterotetrameric assembly and function of the BCKAD complex"
Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase complex in type IA maple syrup urine disease.
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The human E1 decarboxylase is an alpha2-beta2 tetramer of two E1-alpha and two E1-beta subunits; type IA MSUD E1-alpha mutations impair assembly and abolish E1/BCKAD catalytic activity.
"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."
BCKDK phosphorylates BCKDH
PPM1K dephosphorylates p-BCKDH
BCKDHA:BCKDHB tetramer decarboxylates KIC, KMVA, KIV
DBT transfers BCAA to CoA
DLD dimer dehydrogenates dihydrolipoyl
DBT loss-of-function mutants don't synthesize BCAA-CoA
BCKDHA or BCKDHB loss-of-function mutants don't synthesize BCAA-CoA
Loss-of-function DLD mutants don't dehydrogenate dihydrolipoyl DBT
BCKDK loss-of-function mutations do not phosphorylate BCKDH
H139Hfs13* PPM1K does not dephosphorylate BCKDH