Regulation of homocysteine remethylation cycle

We studied the regulation of homocysteine remethylation cycle by investigating the function of two human folate-metabolizing enzymes: methionine synthase and cytosolic serine hydroxymethyl transferase (cSHMT).; Homocysteine remethylation is a key step for both folate and homocysteine metabolism. Methionine synthase and cytosolic serine hydroxymethyl transferase are two important enzymes in the homocysteine remethylation cycle. Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTD). The observations that homocysteine, vitamin B6 and vitamin B12 levels are independent predictors of NTD risk suggested that genetic variation of methionine synthase and cytosolic SHMT could be associated with the developments of NTDs. The possible linkage between genetic defects of MS and cSHMT genes and development of NTDs was investigated. Our results suggested that inherited variations in cSHMT and methionine synthase genes do not contribute to NTD risk in this population.; To test the impact of variations in vitamin B₆ status on the homocysteine remethylation metabolic flux, we designed a metabolite labeling study to compare the differences in flux rate through the remethylation pathway under different conditions of vitamin B6 status using CHO cells as a model system. We found that decreasing B₆ concentration could partially block availability of the one carbon source for the de novo synthesis of methionine and slows down homocysteine remethylation because of the decreased cSHMT activity.; Nutritional factors that effect human methionine synthase gene expression were also investigated. Some nutritional factors, such as low and high levels methionine and low level of folate, affect methionine synthase gene expression at the mRNA level.