BCKDK

Structure

BCKDK's structure consists of a characteristic nucleotide-binding domain along with a four-helix bundle domain similar to certain aspects of protein histidine kinases, which are involved in two-component signal transduction systems. BCKDK is also a dimer with a Leu389 residue located between the dimers and this dimerization is seen to be essential for its kinase activity and protein stability. Moreover, it is made up of 382 amino acids and has a molecular weight of 43 kDa. The gene BCKDK is located at 16p11.2, has an exon count of 11, and it lacks a TATA-box and an initiator element.

Function

BCKDK regulates the activity of branched-chain α-ketoacid dehydrogenase complex (BCKD) through phosphorylation and inactivation. This inactivation results in increased branched-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. As stated earlier, BCKDK concentrations vary depending on the type of tissue that is observed, whereas BCKD's concentration is the same in any tissue. 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.

Clinical significance

Abnormalities in BCKD activity often leads to pathological conditions which is why BCKDK is needed to regulate it. Often, mutations in the BCKDK gene occur creating the deviation in BCKD behavior. Exceedingly high BCKD complex activity increases branched-chain amino acid catabolism and protein 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 to mental retardation, brain edema, seizures, coma, and death if not treated correctly by lifelong limitation of branched-chain amino acid intake. 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. 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.

Deficiency of BCKDK, first described in 2012, 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.

Therapeutics development

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. A variant of this molecule, PF-07328948, was disclosed in 2024 and is being evaluated as a clinical candidate for heart failure.

Interactions

BCKDK has been seen to interact with:

• BCKD

References

References

1. "Entrez Gene: BCKDK branched chain ketoacid dehydrogenase kinase".
2. (Jul 1992). "Branched-chain alpha-ketoacid dehydrogenase kinase. Molecular cloning, expression, and sequence similarity with histidine protein kinases". The Journal of Biological Chemistry.
3. (Oct 2004). "Tissue-specific translation of murine branched-chain alpha-ketoacid dehydrogenase kinase mRNA is dependent upon an upstream open reading frame in the 5'-untranslated region". The Journal of Biological Chemistry.
4. (Apr 2014). "Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients". Human Mutation.
5. (Jul 2014). "Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase". The Journal of Biological Chemistry.
6. (Jun 2013). "Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase". Proceedings of the National Academy of Sciences of the United States of America.
7. (July 2025). "BCKDK gene mutations as a rare condition responsible for comorbid neurodevelopmental delay, autism, and epilepsy: a case series of four patients". Annals of Medicine and Surgery.
8. (October 2012). "Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy". Science.
9. (October 2012). "Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy". Science.
10. (2023-08-09). "Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels". Nature Communications.
11. {{ClinicalTrialsGov. NCT05654181. A First-in-human Study of Single Doses of PF-07328948 Which is Given to Healthy Adult Participants
12. {{ClinicalTrialsGov. NCT05807490. A Study to Learn How Different Amounts of the Study Medicine Called PF-07328948 Are Tolerated and Act in the Body in Healthy Adults