107 Roles of Amino Acids in One-carbon Metabolism and Nutition.

Abstract

The critical importance of non-essential and conditionally-essential amino acids for physiological function is perhaps best exemplified in one-carbon metabolism (OCM), a complex metabolic process whereby chemical groups containing a single carbon atom are used as biosynthetic building blocks. OCM is required for the synthesis of three of the building blocks of nucleic acids (adenine, guanine, thymidine). In addition, OCM provides methyl groups for many methyltransferases. OMC involves two vitamins (folate, Vitamin B12) and amino acids such as serine and glycine which serve as sources of the one-carbon groups. As much as 70% of the whole-body labile methyl groups (S-adenosylmethionine) produced by OMC in piglets is utilized for creatine synthesis. Formate plays a critical role in OCM. Formate, produced in mitochondria from serine and other substrates is released to the cytosol where it is incorporated into 10-formyl-THF. This may be directly incorporated into purines or reduced to 5,10-methylene-THF which is used either for thymidine synthesis or for the production of methyl groups. We have measured formate in serum from a variety of animals (mice, rats, sheep, pigs, humans) and find substantial concentrations, (25–50 µM), in all cases. An important exception is in late pregnant fetal lambs and fetal rats, where we found very high formate concentrations (200–400 µM) in the fetal circulation. Serine concentrations in the fetal circulation are also very high almost 10-fold higher than in the pregnant ewe. Formate concentrations in the human umbilical cord are 70% higher than in the mother. These data suggest an important role for formate in fetal development. We examined this possibility by examining the fate of formate in fetal sheep. Label from 13C-formate infused into the fetal circulation is incorporated into methionine. This requires that formate serves as a substrate for OCM in fetal sheep. Formate is a new frontier in OCM.