Abstract
Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are increased in starvation and diabetes mellitus. However, the pathogenesis has not been explained.
It has been shown that BCAA catabolism occurs mostly in muscles due to high activity of BCAA aminotransferase, which converts BCAA and α-ketoglutarate (α-KG) to branched-chain keto acids (BCKAs) and glutamate. The loss of α-KG from the citric cycle (cataplerosis) is attenuated by glutamate conversion to α-KG in ALT and AST reactions, in which glycolysis is the main source of amino group acceptors, pyruvate and oxaloacetate.
Irreversible oxidation of BCKA by BCKA dehydrogenase is sensitive to BCKA supply and ratios of NADH to NAD+ and acyl-CoA to CoA-SH. It is hypothesized that decreased glycolysis and increased fatty acid oxidation, characteristic features of starvation and diabetes, cause in muscles alterations resulting in increased BCAA levels.
The main alterations include (i) decreased supply of α-KG by the citric acid cycle; (ii) impaired conversion of glutamate to α-KG due to decreased supply of pyruvate and oxaloacetate, and (iii) inhibitory influence of NADH and acyl-CoAs produced in fatty acid oxidation on BCKA dehydrogenase. The studies supporting the hypothesis and pros and cons of elevated BCAA concentrations are discussed in the article.