Metabolic consequences of variation in supply and demand of methyl groups in a piglet model
Methionine is an essential amino acid that in addition to protein synthesis, can be adenylated to form SAM, the universal methyl donor in over 50 transmethylation reactions including creatine and phosphatidylcholine synthesis as well as DNA methylation. These reactions are especially important during early development when growth and pool expansion of transmethylation products puts a high demand on methionine. Furthermore, DNA methylation patterns that regulate gene expression are established during development and have been shown to be susceptible to alterations in methyl availability. These epigenetic modifications have been implicated in the developmental origins of adult diseases hypothesis, which describes how an insult to the developing fetus or neonate can result in a higher susceptibility to chronic diseases in later life. It is important to understand how methionine is partitioned during growth and to ask the question: does this partitioning change during increased methyl demand or as a consequence of an early nutritional insult? Moreover, can providing methylation products, such as creatine, spare methyl groups for other methylation reactions? These questions were addressed by detecting incorporation of methyl-3H into protein and methylation products following an infusion of methyl-3H-methionine in pigs. Although transmethylation places a considerable demand on methionine, the ultimate end product of these reactions, homocysteine, can be methylated to reform methionine via provision of a methyl group from either choline/betaine or folate. The question of whether these methyl donors can be used to spare methionine for protein synthesis was investigated in piglets using a constant infusion of 13C-phenylalanine to determine the change in amino acid oxidation following supplementation of these methyl donors to a methionine deficient diet. This research enhances the understanding of how variation in both the supply and demand of methyl groups can impact the utilization of methionine for its various functions.