Epigenetics is the relatively new science interested in the interaction between the environment and DNA. Environmental changes can influence genetic make-up through stable modification to gene expression not mediated by changes in DNA sequence. This is achieved through methylation of the DNA via methyl donors, molecules that attach a methyl (one carbon) group (-CH3,) to the DNA sequence, switching on particular genes. Such methylation of DNA, if established during pregnancy may persist for life. The methyl donors that participate in the epigenetic transfer of the methyl groups to DNA are involved in the methionine to homocysteine pathway. Methionine is adenylated to S-adenosylmethionine (SAM), which donates methyl groups for DNA methylation. This in turn forms S-adenosylhomocysteine (SAH) which is metabolised to homocysteine. One carbon donors such as methyltetrahydrofolate (MTHF) and betaine (a metabolite of choline) then convert homocysteine back to methionine (figure 1).
Figure 1. One carbon metabolism. THF = tetrahydrofolate, DMG = dimethylglycine, MTHF = Methyltetrahydrofolate, B6 = vitamin B6, B12 = vitamin B12, SAM = S-adenosyl methionine, SAH = S-adenosyl homocysteine.
The conversion of homocysteine back to methionine via donation of a methyl group from betaine and methyltetrahydrofolate are homocysteine salvage pathways. These pathways are vital because they allow continued methylation of DNA which modifies gene expression. In addition, these salvage pathways are also important because they reduce the accumulation of homocysteine in the blood. Homocysteine is now thought to be a driver of disease because it can induce oxidative stress and damage cellular components. High blood levels of homocysteine are independently associated with cardiovascular disease and dementia, brought about through homocysteine induced damage to blood vessels. Homocysteine may deplete nitric oxide from the endothelium of vessels via the generation of free radicals and this in turn leads to endothelial dysfunction which is a likely cause of vascular disease. The homocysteine salvage pathways are therefore important at reducing this process through the removal of homocysteine.
Methyltetrahydrofolate is the biologically active form of folate and is therefore reliant on dietary intake of folic acid for synthesis. Betaine (N,N,N-trimethylglycine) is a metabolite of choline, a conditionally essential element considered part of the B vitamin group. Betaine synthesis therefore relies on an appropriate intake of dietary choline. Variations in the diet is able to cause alterations to the efficiency of the methionine pathway and homocysteine salvage pathways because dietary variation can alter the synthetic rates of the one carbon donors required for flux. In a study investigating the seasonal variation in dietary intakes of nutrients involved in one carbon metabolism in African women1, it was reported that dietary intake of these nutrients varied because of seasonal variation in food supply. The variation in these nutrients then caused a switch between the betaine and methyltetrahydrofolate salvage pathways, suggesting that natural food variation is able to alter pathway flux, and that the salvage pathways interact.
In another study2, researchers investigated the interaction between the methyltetrahydrofolate and betaine salvage pathways during pregnancy. Fasting plasma concentrations of choline, betaine, dimethylglycine (DMG) and folate were measured longitudinally, and use of folic acid supplements was recorded. During the course of the pregnancy, plasma betaine decreased 35 % whereas its metabolite DMG increased 40 %, suggesting increased flux through the betaine salvage pathway. A low folate status (<27.6 nmol/L) was associated with increased flux through the betaine salvage pathway, whereas a high folate status (>27.6 nmol/L) was associated with a decreased flux. Both plasma folate and plasma betaine were inversely associated with homocysteine concentrations, and the association between betaine and homocysteine depended on the folate status. Taken as a whole these data suggests that the homocysteine salvage pathways interact and decreased flux through one pathway increases flux through the other.
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