Insights into metabolic mechanisms underlying folate-responsive neural tube defects: a minireview

Abstract

Neural tube defects (NTDs), including anencephaly and spina bifida, arise from the failure of neurulation during early embryonic development. Neural tube defects are common birth defects with a heterogenous and multifactorial etiology with interacting genetic and environmental risk factors. Although the mechanisms resulting in failure of neural tube closure are unknown, up to 70% of NTDs can be prevented by maternal folic acid supplementation. However, the metabolic mechanisms underlying the association between folic acid and NTD pathogenesis have not been identified. This review summarizes our current understanding of the mechanisms by which impairments in folate metabolism might ultimately lead to failure of neural tube closure, with an emphasis on untangling the relative contributions of nutritional deficiency and genetic risk factors to NTD pathogenesis.

Figure 1

Gene nutrient interactions in neural tube closure defects. Low folate status interacts with impairments in one-carbon metabolism (folate utilization) to create risk for neural tube defects. Both folate status and folate utilization are compromised by interactions among genetic and environmental (nutritional) factors.

Figure 2

Compartmentation of folate-mediated one-carbon metabolism in the cytoplasm and mitochondria. One-carbon metabolism in the cytoplasm is required for the de novo synthesis of purines and thymidylate and for the remethylation of homocysteine to methionine. One-carbon metabolism in mitochondria is required to generate formate for one-carbon metabolism in the cytoplasm, to generate the amino acid glycine, and to synthesize formylmethionyl-tRNA for protein synthesis in mitochondria. FTHFS, 10-formyltetrahydrofolate synthetase; MTHFC, methenyltetrahydrofolate cyclohydrolase; MTHFD, methylenetetrahydrofolate dehydrogenase; MTHFR, methylenetetrahydrofolate reductase; GARFT, phosphoribosylglycinamide formyltransferase; AICARFT, phosphoribosylaminoimidazolecarboxamide formyltransferase; cSHMT, cytoplasmic serine hydroxymethyltransferase; TS, thymidylate synthase; DHFR, dihydrofolate reductase; MS, methionine synthase; mSHMT, mitochondrial serine hydroxymethyltransferase; GCS, glycine cleavage system; SD, sarcosine dehydrogenase; DMGD, dimethylglycine dehydrogense; mMTHFD, mitochondrial methylenetetrahydrofolate dehydrogenase; mMTHFC, mitochondrial methenyltetrahydrofolate cyclohydrolase; MFT, methionyl-tRNA formyltransferase; mFTHFS, mitochondrial formyltetrahydrofolate synthetase.