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

Branched-chain alpha-keto acid dehydrogenase kinase (BCKDK) is a mitochondrial enzyme that serves as the primary regulator of branched-chain amino acid (BCAA) catabolism. It functions by phosphorylating and inactivating the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which is the rate-limiting step in the breakdown of leucine, isoleucine, and valine (UniProt: O14874). By modulating BCKDH activity, BCKDK ensures that BCAA levels are maintained for protein synthesis and nitrogen metabolism. Mutations leading to a deficiency in BCKDK result in abnormally low BCAA levels, which are clinically linked to autism spectrum disorders and epilepsy (PMID: 23041931). Conversely, overactivity of BCKDK and the resulting elevation of BCAAs are associated with insulin resistance, type 2 diabetes, and heart failure (PMID: 28844881). Pharmacological inhibitors such as BT2 and phenylbutyrate are currently being explored to reactivate BCAA catabolism as a therapeutic strategy for metabolic and cardiovascular diseases (PubChem CID: 5330815). Consequently, BCKDK represents a critical metabolic switch with significant implications for both neurological health and systemic metabolic stability.

Other names

BCKDH kinase[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinaseMitochondrial branched-chain alpha-keto acid dehydrogenase kinaseBCAA kinase

Inhibition of BCKDK prevents the phosphorylation of the E1-alpha subunit of the BCKDH complex, which maintains the complex in its active state, thereby increasing the rate of branched-chain amino acid catabolism and lowering systemic BCAA levels.