BCKDK's structure consists of a characteristicnucleotide-binding domain along with afour-helix bundle domain similar to certain aspects of protein histidine kinases, which are involved in two-component signaltransduction systems. BCKDK is also adimer with a Leu389 residue located between the dimers and this dimerization is seen to be essential for its kinase activity andprotein stability.[8] Moreover, it is made up of 382amino acids and has amolecular weight of 43kDa.[6] The geneBCKDK is located at 16p11.2, has anexon count of 11, and it lacks aTATA-box and aninitiator element.[5][7]
BCKDK regulates the activity ofbranched-chain α-ketoacid dehydrogenase complex (BCKD) throughphosphorylation andinactivation. This inactivation results in increasedbranched-chain amino acids (BCAA), which is seen to reduce oxidative stress; however, having too much BCAA has been proven to be toxic to humans. Therefore, BCKDK is a vital tool to assist with BCAA homeostasis.[9][10] As stated earlier, BCKDK concentrations vary depending on the type of tissue that is observed, whereas BCKD's concentration is the same in anytissue. Although BCKD concentration is constant, the amount of BCKDK determines the activity of the dehydrogenase complex. Since liver tissue is seen to have the lowest concentration of BCKDK, the activity of BCKD is seen to be the highest, delineating the fact that the BCKD kinase inversely affects the BCKD activity.[7]
Abnormalities in BCKD activity often leads topathological conditions which is why BCKDK is needed to regulate it. Often,mutations in theBCKDK gene occur creating the deviation in BCKD behavior. Exceedingly high BCKD complex activity increases branched-chain amino acid catabolism andprotein degradation in skeletal muscle, which is a distinctive feature for cachexia. Deficiencies in BCKD activity have been the main cause in the rare metabolism maple syrup urine disease that can lead tomental retardation,brain edema,seizures,coma, anddeath if not treated correctly by lifelong limitation of branched-chain amino acid intake.[7] Because BCKDK regulates BCKD which in turn catalyzes BCAA, BCKDK is one of the factors that determines the concentration of BCAA levels. High BCAA levels can lead to insulin resistance and can be a potential marker for type 2 diabetes.[10] The amalgamation of BCAA can also lead to congenital heart diseases and heart failure. Furthermore, low levels of BCAA have been described as a cause of comorbid intellectual disability, autism, and epilepsy.[8]
Deficiency of BCKDK, first described in 2012,[11] is a disorder that could be considered as the "opposite" of maple syrup disease, because patients have decreased levels of branched-chain amino acids, instead of increased levels. The condition may present as autism with epileptiform abnormalities on EEG and seizures.
In 2023, Pfizer reported the development of the thiophene PF-07208254 as an allosteric BCKDK inhibitor that also promotes BCKDK degradation by promoting BCKDK interaction with BCKDH-E2.[12] A variant of this molecule, PF-07328948, was disclosed in 2024 and is being evaluated as a clinical candidate for heart failure.[13][14]
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