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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The reviewed record places BCKDHA in the mitochondrial matrix.
"Mitochondrion matrix"
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The mitochondrial transit peptide occupies precursor positions 1–45.
"TRANSIT 1..45"
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The mature alpha chain spans precursor positions 46–445.
"CHAIN 46..445"
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The ThDP binding features identify a ligand shared with the beta subunit.
"/ligand_note="ligand shared with beta subunit""
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The feature at alpha-chain residue 238 identifies a magnesium contact.
"BINDING 238
FT /ligand="Mg(2+)""
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The feature at alpha-chain residue 206 identifies a potassium contact.
"BINDING 206
FT /ligand="K(+)""
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.
Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase 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.
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.
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 complex oxidizes all three branched-chain ketoacids; the abstract does not assign each gel band to a named subunit.
"effectively oxidized all of KIV, KIC, and KMV"
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.
Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase complex in type IA maple syrup urine disease.
BCKDK phosphorylates BCKDH
PPM1K dephosphorylates p-BCKDH
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The record describes activation of BCKDH by PPM1K and calls the target E1 beta; that subunit attribution is disputed in the reference review.
"PPM1K) dephosphorylates
the E1 beta subunit of BCKDH thereby regaining its active state."
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
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The record links DBT loss-of-function alleles to several clinical forms of MSUD.
"Loss-of-function alleles of DBT are associated with classic, intermittent
and thiamine-responsive forms of MSUD"
BCKDHA or BCKDHB loss-of-function mutants don't synthesize BCAA-CoA
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The record links BCKDHA interface or hydrophobic-core mutations to destabilization of BCKDH assembly.
"Mutations of residues in BCKDHA that participate in subunit associations
or that form part of the hydrophobic core destabilize the overall assembly of BCKDH"
Loss-of-function DLD mutants don't dehydrogenate dihydrolipoyl DBT
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DLD loss-of-function variants are linked to MSUD type 3, also called DLD deficiency.
"Loss-of-function mutations in DLD are associated with Maple Syrup Urine Disease
3 (MSUD3), also known as DLD deficiency."
BCKDK loss-of-function mutations do not phosphorylate BCKDH
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BCKDK variants that prevent inhibitory E1 phosphorylation permit excessive branched-chain amino acid oxidation.
"prevent the inhibitory phosphorylation of the E1 subunit of BCKDH, allowing unregulated oxidative decarboxylation of branched-chain amino acids."
H139Hfs13* PPM1K does not dephosphorylate BCKDH