The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology

Abstract

Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.

The Role of Branched-Chain Amino Acids and Branched-Chain α-Keto Acid Dehydrogenase Kinase in Metabolic Disorders

“…BCAAs metabolize into acetyl coenzyme A and propionyl coenzyme A, which are substrates for lipid synthesis. Excess carbon produced by catabolism of BCAA may lead to an increase in the rate of adipogenesis ( 29 ). Research has reported that fat accumulation in the liver was reduced after BCAAs supplementation in a rat experiment.…”

The Biochemical Assessment of Mitochondrial Respiratory Chain Disorders

“…Patients with a deficiency in the enzyme pyruvate dehydrogenase (PDH) have shown a significantly larger increase in plasma alanine levels compared to those with mitochondrial disease [20]. Mitochondrial disease criteria (MDC) scoring systems, such as the modified Walker criteria [21], define abnormal metabolic studies, such as high alanine levels, as a minor criterion of mitochondrial dysfunction. According to the Nijmegan protocol, a plasma alanine level of >450 mM in patients is used to help determine the likelihood of mitochondrial dysfunction [21].…”

“…Mitochondrial disease criteria (MDC) scoring systems, such as the modified Walker criteria [21], define abnormal metabolic studies, such as high alanine levels, as a minor criterion of mitochondrial dysfunction. According to the Nijmegan protocol, a plasma alanine level of >450 mM in patients is used to help determine the likelihood of mitochondrial dysfunction [21]. However, an increase in serum alanine concentrations has been identified in other conditions, such as sepsis, hyperinsulinism and chronic thiamine deficiency [22].…”

“…Research conducted by Dimou and colleagues in 2022 [21] provides further information about the relationship between MRC dysfunction and the increased circulatory levels of BCAAs. There are similarities between the present study and those described by Clark et al, 2013 [18], including how the accumulation of BCAAs-more specifically, leucine-inhibits the function of the enzymes (α-ketoglutarate dehydrogenase, pyruvate dehydrogenase and those of the MRC) and, in turn, provides further scientific evidence and support to older studies.…”

“…There are similarities between the present study and those described by Clark et al, 2013 [18], including how the accumulation of BCAAs-more specifically, leucine-inhibits the function of the enzymes (α-ketoglutarate dehydrogenase, pyruvate dehydrogenase and those of the MRC) and, in turn, provides further scientific evidence and support to older studies. The focus of recent literature has shifted towards BCAA homeostasis and how it holds great importance for brain function and its correlation with severe neurological diseases [21]. Therefore, a greater understanding of the mechanisms connecting the central nervous system to increasing levels of BCAA may aid novel therapeutic approaches to mitochondrial disorders.…”