The Pediatric Methionine Requirement Should Incorporate Remethylation Potential and Transmethylation Demands

The metabolic demand for methionine is great in neonates. Indeed, methionine is the only indispensable sulfur amino acid and is required not only for protein synthesis and growth but is also partitioned to a greater extent to transsulfuration for cysteine and taurine synthesis and to >50 transmethylation reactions that serve to methylate DNA and synthesize metabolites, including creatine and phosphatidylcholine. Therefore, the pediatric methionine requirement must accommodate the demands of rapid protein turnover as well as vast nonprotein demands. Because cysteine spares the methionine requirement, it is likely that the dietary provision of transmethylation products can also feasibly spare methionine. However, understanding the requirement of methionine is further complicated because demethylated methionine can be remethylated by the dietary methyl donors folate and betaine (derived from choline). Intakes of dietary methyl donors are highly variable, which is of particular concern for newborns. It has been demonstrated that many populations have enhanced requirements for these nutrients, and nutrient fortification may exacerbate this phenomenon by selecting phenotypes that increase methyl requirements. Moreover, higher transmethylation rates can limit methyl supply and affect other transmethylation reactions as well as protein synthesis. Therefore, careful investigations are needed to determine how remethylation and transmethylation contribute to the methionine requirement. The purpose of this review is to support our hypothesis that dietary methyl donors and consumers can drive methionine availability for protein synthesis and transmethylation reactions. We argue that nutritional strategies in neonates need to ensure that methionine is available to meet requirements for growth as well as for transmethylation products.