Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders

Abstract

Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multifactorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability and seizures. Finally, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism.

Figure 1.

BCAA catabolism. The BCAAs are transaminated by BCAT to generate α-ketoacids (KIC, KMV and KIV). These α-ketoacids undergo oxidative decarboxylation by the BCKDC.

Figure 2.

BCKDC regulation. The BCKDC is regulated by phosphorylation. The BCKDK phosphorylates two serine residues of BCKDC and inactivates the enzyme complex. PPM1K (protein phosphatase, pp2c domain containing, 1k) dephosphorylates and inactivates the BCKDC.