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Details on Person UniProt:O14874 BCKDK

Class:Id	ReferenceGeneProduct:50756
_chainChangeLog	transit peptide:1-30 added on Fri February 6 2015;chain:31-412 added on Fri February 6 2015
_displayName	UniProt:O14874 BCKDK
_timestamp	2025-02-21 19:15:54
chain	transit peptide:1-30 chain:31-412
checksum	AC97CF5D151FEFB4
comment	FUNCTION Serine/threonine-protein kinase component of macronutrients metabolism. Forms a functional kinase and phosphatase pair with PPM1K, serving as a metabolic regulatory node that coordinates branched-chain amino acids (BCAAs) with glucose and lipid metabolism via two distinct phosphoprotein targets: mitochondrial BCKDHA subunit of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex and cytosolic ACLY, a lipogenic enzyme of Krebs cycle (PubMed:24449431, PubMed:29779826, PubMed:37558654). Phosphorylates and inactivates mitochondrial BCKDH complex a multisubunit complex consisting of three multimeric components each involved in different steps of BCAA catabolism: E1 composed of BCKDHA and BCKDHB, E2 core composed of DBT monomers, and E3 composed of DLD monomers. Associates with the E2 component of BCKDH complex and phosphorylates BCKDHA on Ser-337, leading to conformational changes that interrupt substrate channeling between E1 and E2 and inactivates the BCKDH complex (PubMed:29779826, PubMed:37558654). Phosphorylates ACLY on Ser-455 in response to changes in cellular carbohydrate abundance such as occurs during fasting to feeding metabolic transition. Refeeding stimulates MLXIPL/ChREBP transcription factor, leading to increased BCKDK to PPM1K expression ratio, phosphorylation and activation of ACLY that ultimately results in the generation of malonyl-CoA and oxaloacetate immediate substrates of de novo lipogenesis and glucogenesis, respectively (PubMed:29779826). Recognizes phosphosites having SxxE/D canonical motif (PubMed:29779826).CATALYTIC ACTIVITY L-seryl-[3-methyl-2-oxobutanoate dehydrogenase] + ATP = O-phospho-L-seryl-[3-methyl-2-oxobutanoate dehydrogenase] + ADP + H(+)CATALYTIC ACTIVITY L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)ACTIVITY REGULATION Allosterically inhibited by certain thiazoles and thiophenes: thiazoles increase interaction with DBT/BCKDH-E2, whereas thiophenes reduce this interaction. Inhibited by 3,6- dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) (PubMed:37558654). The ATP binding is mediated by both potassium and magnesium ions (PubMed:37558654).PATHWAY Protein modification.SUBUNIT Homodimer. Homotetramer (By similarity). Dimerizes through interaction of two opposing nucleotide-binding domains. Interacts with E2 component of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. Competes with BCKDK for binding to the E2 component; this interaction is modulated by branched-chain alpha-keto acids. At steady state, BCKDH holoenzyme contains BCKDK and BCKDHA is phosphorylated. In response to high levels of branched-chain alpha-keto acids, the inhibitory BCKDK is replaced by activating PPM1K leading to BCKDHA dephosphorylation and BCAA degradation (PubMed:22589535, PubMed:37558654).INTERACTION Detected in the cytosolic compartment of liver cells.ALTERNATIVE PRODUCTS Ubiquitous.PTM Autophosphorylated.DISEASE The disease is caused by variants affecting the gene represented in this entry. A diet enriched in branched amino acids (BCAAs) allows to normalize plasma BCAA levels. This suggests that it may be possible to treat patients with mutations in BCKDK with BCAA supplementation.SIMILARITY Belongs to the PDK/BCKDK protein kinase family.ONLINE INFORMATION The silence within - Issue 147 of March 2013
description	recommendedName: fullName evidence="13"Branched-chain alpha-ketoacid dehydrogenase kinase shortName evidence="12"BCKDH kinase shortName: BCKDHKIN shortName evidence="13"BDK ecNumber evidence="7 8"2.7.11.1 alternativeName: fullName evidence="15"[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrial ecNumber evidence="7 8 9"2.7.11.4
geneName	BCKDK
identifier	O14874
isSequenceChanged	FALSE
keyword	3D-structure Acetylation Alternative splicing ATP-binding Autism Autism spectrum disorder Disease variant Epilepsy Intellectual disability Kinase Mitochondrion Nucleotide-binding Phosphoprotein Proteomics identification Reference proteome Transferase Transit peptide
modified	[InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21
name	BCKDK
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:9001039] ENSEMBL:ENSG00000103507 BCKDK [Homo sapiens]
secondaryIdentifier	BCKD_HUMAN A8MY43 Q6FGL4 Q96G95 Q96IN5
sequenceLength	412
species	[Species:48887] Homo sapiens
(isoformParent)	[ReferenceIsoform:8967313] UniProt:O14874-1 BCKDK [Homo sapiens] [ReferenceIsoform:8967314] UniProt:O14874-2 BCKDK [Homo sapiens] [ReferenceIsoform:8967315] UniProt:O14874-3 BCKDK [Homo sapiens]
(referenceEntity)	[EntityWithAccessionedSequence:5693129] BCKDK [mitochondrial matrix] [Homo sapiens] [EntityWithAccessionedSequence:9912461] L389P BCKDK [mitochondrial matrix] [Homo sapiens] [EntityWithAccessionedSequence:9912465] R156* BCKDK [mitochondrial matrix] [Homo sapiens] [EntityWithAccessionedSequence:9912466] R224P BCKDK [mitochondrial matrix] [Homo sapiens] [EntityWithAccessionedSequence:9912469] R174Gfs1* BCKDK [mitochondrial matrix] [Homo sapiens]
(referenceSequence)	[ReplacedResidue:9912460] L-arginine 224 replaced with L-proline [ReplacedResidue:9912462] L-leucine 389 replaced with L-proline [FragmentReplacedModification:9912463] Replacement of residues 174 to 174 by G [NonsenseMutation:9912468] Nonsense mutation at L-arginine 156
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No pathways have been reviewed or authored by UniProt:O14874 BCKDK (50756)