Mammalian Tolerance to Amino Acid Heterochirality

Organisms use amino acids predominantly in l-configuration. In contrast, a series of studies show that a variety of d-amino acids also occur in mammals, and amino acid homochirality is not complete. Mammals de novo synthesize most amino acids with l-configuration, but serine and aspartate are converted from l- to d-configuration by endogenous enzymes. In addition to endogenous syntheses of d-amino acids, symbiotic bacteria in mammals chiral-convert amino acids, including alanine, glutamate, proline, and leucine in the intestine, creating a heterochiral inner environment. d-amino acids are distributed in distinctive patterns among organs and have physiological roles in the central nervous, endocrine, and immune systems. Mammals manage such diverse d-amino acids with catabolism and excretion into urine at individual levels. In contrast, at the cellular levels an enantioselection mechanism to regulate chiral homeostasis of amino acids has remained unclear. In protein synthesis, the ribosome has a sophisticated system to eliminate d-amino acids, whereas non-ribosomal synthesis also utilizes d-amino acids. Furthermore, amino acid residues in proteins/peptides can be isomerized post-translationally through enzymatic or spontaneous processes. This manuscript overviews how the chiral balance of free amino acids or residues in proteins is maintained in mammals at the individual and cellular levels.