Branched-chain keto acid dehydrogenase kinase (BCKDK) (BCKDK)

Branched-chain keto acid dehydrogenase kinase (BCKDK) is a mitochondrial serine/threonine kinase that acts as the primary negative regulator of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex (UniProt O14874). By phosphorylating the E1-alpha subunit of the BCKD complex, BCKDK inhibits the rate-limiting step of branched-chain amino acid (BCAA) catabolism, leading to the conservation or accumulation of leucine, isoleucine, and valine (Wikipedia). Dysregulation of BCKDK is linked to several metabolic and neurological disorders; for instance, loss-of-function mutations cause a rare form of autism and epilepsy due to BCAA depletion, while its overexpression or overactivity is associated with maple syrup urine disease, obesity, type 2 diabetes, and heart failure (NIH/PubMed). In oncology, BCKDK has been shown to promote tumor progression and metastasis by activating the MAPK pathway through MEK phosphorylation (NIH/PubMed). Therapeutic strategies focus on small-molecule inhibitors like BT2 and phenylbutyrate to enhance BCAA oxidation in metabolic diseases, though care must be taken to avoid excessive BCAA depletion which can lead to neurodevelopmental issues (tandfonline.com). Additionally, research into BCKDK inhibitors must account for potential off-target effects, such as the inhibition of Mcl-1 or the displacement of tryptophan from serum albumin (biorxiv.org).

Other names

BCKDKDBDKBCKDHKIN[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrialBranched-chain alpha-ketoacid dehydrogenase kinase

Allosteric inhibition of BCKDK to prevent phosphorylation and inactivation of the BCKD complex, thereby increasing BCAA catabolism and lowering systemic BCAA levels.