BRANCHED CHAIN AMINO ACIDS AT THE EDGE BETWEEN MENDELIAN AND COMPLEX DISORDERS

Abstract

Branched chained amino acids (BCAA) are essential components of the human diet and important nutrient signals, which regain particular interest in recent years with the avenue of metabolomics studies suggesting their potential role as biomarkers. There is now compelling evidence for predictive role of BCAA in progression of diabetes, but causality relationship is still debated concerning insulin resistance and genetic versus non-genetic pathogenesis. Mendelian randomization studies in large cohorts of diabetes indicated pathogenic role of PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) on Chr 4q22.1 gene, encoding for a phosphatase that activates BCKDH (branched chain keto acid dehydrogenase) complex. Recent studies indicated that insulin rapidly and dose-dependently regulates gene expression of the same complex, but the relationship with systemic insulin resistance and glucose levels is complex. Rare genetic syndromes due to Mendelian mutations in key genes in BCAA catabolism may be good models to understand potential role of gene of BCAA catabolism. However, in studying complex disorders geneticists are faced to complete new aspects of metabolic regulation complicating understanding genetics of obesity, diabetes or metabolic syndrome. A review of genetic syndromes of BCAA metabolism suggests that insulin resistance is not present, except rare cases of methylmalonic aciduria due to MUT (methylmalonyl-coA mutase) gene on Chr 6p12.3. Another aspect that complicates understanding is the new role of central nervous system (CNS) in insulin resistance. For a long time the hypothalamic hunger/satiety neuronal system was considered a key site of nutrient regulation. Genes may also affect the brain rewarding system (BRS) that would regulate food intake by modulating the motivation to obtain food and considering hedonic properties. Nutrigenomic and nutrigenetic investigations taking into account concurrently BCAA intake, metabolic regulation and gene variation have large perspectives to merge genetic and nutritional understanding in complex disorders.

Keywords: BCAA; brain rewarding; branched chain amino acids; gene, Mendelian syndromes; insulin resistance; nutrigenomics.

Figure 1.

Major steps in the catabolism of BCAA. The first step in BCAA catabolism is determined by reversible transamination by the BCAT enzymes followed by irreversible oxidation by the BCKDH complex. Downstream metabolism is then independent for three amino acids, ketogenic for leucine and isoleucine (aceto acetate and acetyl Co-A) and glucogenic for valine with the formation of propionyl-CoA. Acetyl Co-A and succinyl-CoA enter then in the Krebs cycle for energy generation and gluconeogenesis or as precursors of lipogenesis and ketone bodies formation. Not indicated in the figure is AACS (acetoacetyl-CoA synthetase) located on Chr 12q24.31, which is a ketone body-utilizing ligase with a role in lipid synthesis through the non-oxidative pathway.

Figure 2.

Major Mendelian diseases and location of related genes in the catabolism of BCAA. Mendelian diseases can be classified as function of genes involved in four steps: 1) gene involved in reversible transamination; 2) irreversible oxidation by the BCKDH complex including the BCKD kinase and PPM1K; 3) a series of rare diseases of intermediates in leucine, isoleucine and valine pathways; 4) genes involved in the distal phase of BCAA metabolism like the MUT gene.