The role of B6, B12, and folate in one-carbon metabolism and SAMe synthesis

Andrea Fuso, PhD, is an Associate Professor of Clinical Biochemistry and Clinical Molecular Biology at the Department of Experimental Medicine, Sapienza University of Rome. In this interview clip, he explains how B vitamins play a central role in sustaining one-carbon metabolism, a critical biochemical pathway that supports methylation and the production of S-adenosyl-L-methionine (SAMe).

Fuso highlights how inadequate B vitamin status—particularly common in older adults due to dietary insufficiency or impaired absorption—can lead to homocysteine and S-adenosylhomocysteine (SAH) accumulation.

He is also a member of the Interdepartmental Center for Research in Neurobiology “Daniel Bovet” (CRiN) at Sapienza, an associate editor for Frontiers in Molecular Biosciences and Frontiers in Epigenetics and Epigenomics, review editor for Frontiers in Nutrition, and member of the editorial board of Clinical Epigenetics and Epigenomes.

Transcript

Nutritional Outlook: You recently did a presentation about how B vitamins sustain one-carbon metabolism to make S-Adenosyl-L-methionine (SAMe). How does one lead to the other?

Andrea Fuso: When I described the one-carbon metabolism, I told you that homocysteine can be transformed by two ways: the transsulfuration leading to glutathione synthesis is mediated by vitamin B6. B vitamins are enzymatic factor, so vitamin B6 is a cofactor of one of the enzymes responsible for the transformation of homocysteine to glutathione. In the remethylation of homocysteine to methionine, we have vitamin B12 and folate, which is the vitamin B9, again as cofactors. The folate in particular, is the methyl donor for the remethylation homocysteine to methionine. So this is the link.

The enzymes responsible for homocysteine remethylation transsulfuration need B12, B6, and folate to be active. But B vitamins are co factor of many other enzymes. In this specific case, they can avoid homocysteine accumulation, that can prevent homocysteine accumulation, and can lead to the production of antioxidants, can lead to the production of methionine, and therefore of SAMe.

In fact, another observation in elderly subjects is that there's minor availability of B vitamins due to nutritional deficiency, due to problems with the absorption in the gastrointestinal tract, there can be a lowering in B vitamins, and therefore this can bring to homocysteine accumulation. Homocysteine accumulation means SAH accumulation. SAH accumulation means methylation inhibition. This is the link.