Dr. Patrick Stover, PhD, the Director of the Division of Nutritional Sciences at Cornell University, provides a great overview of the key role of folate in one-carbon metabolism, and DNA methylation in nutrition.
Folate, Nutrition, and DNA Methylation Regulation
There’s a long history in the whole field of folate metabolism, one-carbon metabolism, that outcomes associated with disruptions in the pathway had genomic impacts. So folate is a B vitamin, and you need folate both to synthesize DNA – 3 out of the 4 nucleotides needed to synthesize DNA require a one-carbon that’s carried by folate – and the methyl groups that are used to regulate gene expression that converts cytosine to methylcytosine also come out of one-carbon metabolism, or folate metabolism. So this is a metabolic pathway that is intimately tied to the genome and effects both genome stability as well as these at these epigenetic marks that are on DNA that then affect gene expression.
So long clinical history in folate: ever since it was first discovered, it was almost immediately identified as a nutrient that affected cancer risk, and later that affected birth defect risk. Beyond that, neurological disorders. So you have major, common public health pathologies or diseases that are associated with this individual nutrient. The problem is, it’s been decades and decades and decades of research and we still cannot identify a causal pathway where alterations either in diet or the utilization of this vitamin, how it affects the genome in a way, mechanistically, that leads to these pathologies.
And the reason is because it’s such a complex problem. Because it involves the entire genome. It involves genome stability. It involves methylation throughout the genome. So the real challenge for us has been trying to link how a dietary exposure, whether overnutrition or undernutrition affects metabolism, physiology, and then how those changes in metabolism either impact the genome or are sensed by the genome, and then how those changes in the genome affect disease. We’re not there yet, but that’s the goal of this whole field.
Folate is a metabolic co-factor. So it’s a vitamin, it’s a nutrient. And it’s in fresh fruits and vegetables. You see folate deficiency around the world because if you cook your food, you destroy your folate. So the best sources of natural folate are from fresh fruits and vegetables. So if you cook your food, you destroy the vitamin. You see vitamin deficiencies, except in populations that take supplements or that have food that’s been fortified with that nutrient, and a stable form that doesn’t degrade when you cook it.
So you have folate in the diet, when it gets into the cell it’s processed into a metabolic co-factor. And what it does is it carries and chemically activates single carbons, one-carbon. And it does that at three oxidation states, the oxidation of formate, formaldehyde, and menthanol. So it carries and chemically activates that one-carbon for a biosynthetic reaction. So the best analogy is with ATP. ATP carries and chemically activates a phosphate group for phosphorylation reactions. Folate carries and chemically activates a single carbon.
Now, in the processing of that one-carbon between the different oxidation states of the one-carbon, you need other vitamins. You need niacin, you need riboflavin, you need vitamin B12. Furthermore, you need sources of the one-carbons. The sources of those one-carbons, most of them coming out of glycolysis in the form of serine and glycine or from protein, but you also have other nutrients or metabolites that can provide a one-carbon including choline and it’s degradation products butane, dimethylglycine, sarcosine.
So you need both sources of one-carbons that come out of, essentially, glycolysis, or it can come from protein, then the folate, the vitamin, carries that one-carbon, then requires these other vitamins to process it so can enter the right biosynthetic pathway, whether it’s going to make nucleotides for DNA, or is it going to make methyl groups to regulate the genome.