One-carbon metabolism, fetal growth and long-term consequences

Abstract

One-carbon metabolism, or methyl transfer, is critical for metabolism in all cells, is involved in the synthesis of purines, pyrimidines, in the methylation of numerous substrates, proteins, DNA and RNA, and in the expression of a number of genes. Serine is the primary endogenous methyl donor to the one carbon pool. Perturbations in methyl transfer due to nutrient and hormonal changes can have profound effect on cell function, growth and proliferation. It is postulated that at critical stages in development, nutrient and environmental influences by their effect on methyl transfer can impair fetal growth, reprogram metabolism and cause long-term morbidity in the offspring. The potential for their effects is underscored by the unique gestation-related changes in methyl transfer in healthy women, the late expression of transsulfuration cascade in the fetus and the unique metabolism of glycine and serine in the fetus. Dietary protein restriction in animal models and protein malnutrition in humans causes remarkable changes in the methyl transfer in vivo. Although the specific consequences of perturbation in maternal and fetal methyl transfer remain to be determined, a profound influence is suggested by the demonstrated relationship between maternal folate and B12 insufficiency and metabolic programming.

Figure 1

One carbon metabolism or methyl transfers in-vivo; shown are folate cycle (black), methionine transmethylation cycle (blue), and the methionine transsulfuration cascade(orange) The flow of methyl groups from serine to methyltransferase is shown in red. THF: tetrahydrofolate; 5 CH₃THF: 5 methyl tetrahydrofolate; MS:methionine synthase; SAM: s-adenosyl methionine; SAH: s-adenosylhomocysteine; CβS: cystathionine beta synthase; CγL: cystathionine gamma lyase.

Figure 2

Effect of isocaloric protein restriction on methyl transfer in the rat. Rats were placed on a casein based 6% protein diet for 7 to 10 days, controls were on a 24% protein diet and were pair fed. Dietary protein restriction resulted in a marked upregulation (red boxes) of 3-phosphoglycerate dehydrogenase (3PGDH), phosphoserineaminotransferase (PSAT), glutamate-cysteine ligase (GCL),and cysteinesulfinic acid decarboxylase (CSAD).The activity of cystathionine beta synthase (CβS) and cystathionine gamma lyase (CγL) was decreased ( blue boxes). Tracer dilution measured rate of appearance of serine and the rate of transmethylation of methionine ware increased (heavy arrows). Figure reproduced from Kalhan et al, Journal of Biological Chemistry 286:5266-5277,2011.