BCKDK

Branched-chain ketoacid dehydrogenase kinase (BCKDK) is a mitochondrial serine/threonine kinase that regulates the catabolism of the Branched-Chain Amino Acids (BCAAs) valine, leucine, and isoleucine. It phosphorylates the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex, the rate-limiting enzyme in BCAA oxidation, thereby inhibiting BCKD activity and reducing the flux through the BCAA catabolic pathway. By controlling BCKD phosphorylation, BCKDK helps maintain physiologic levels of BCAAs in plasma and tissues.

Biochemical mechanism and regulation: BCKD is a multi-subunit complex whose E1 component (comprising BCKDHA and BCKDHB) becomes inactivated when phosphorylated by BCKDK. Dephosphorylation by the phosphatase PPM1K reactivates BCKD. BCKDK activity is influenced by cellular energy status, nutrient signals, and the availability of BCAAs, and it interacts with broader metabolic regulatory networks that coordinate amino acid catabolism with growth and energy needs.

Genetics and clinical significance: The BCKDK gene encodes the enzyme of this regulatory kinase. Rare loss-of-function variants in BCKDK have been linked to a neurodevelopmental disorder spectrum, including intellectual disability and autism-like features, often with low plasma BCAA levels. The condition is considered under the umbrella of BCAA metabolism disorders, and some cases have shown partial responsiveness to dietary BCAA supplementation in clinical reports.

Pharmacology and research directions: Experimental BCKDK inhibitors, such as BT2, reduce phosphorylation of BCKD, activate the complex, and lower circulating BCAA levels in animal models. This approach is studied in metabolic disease contexts where elevated BCAA levels are associated with insulin resistance or obesity, though clinical applicability requires further investigation.