One-carbon metabolism: SAMe, DNA methylation, and gene regulation

Andrea Fuso, PhD, is an Associate Professor of Clinical Biochemistry and Clinical Molecular Biology at the Department of Experimental Medicine, Sapienza University of Rome, and member of the Interdepartmental Center for Research in Neurobiology “Daniel Bovet” (CRiN) at Sapienza.

He is also 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.

In this interview, Dr. Andrea Fuso explains that one‑carbon metabolism (the methionine–SAM–homocysteine cycle) fuels DNA methylation, a key epigenetic mechanism that typically silences genes, and that age‑related or disease‑related declines in this methylation capacity can lead to abnormal gene expression relevant to neurodegeneration.

Transcript

Nutritional Outlook: Can you explain what one-carbon metabolism and DNA methylation are, and how they relate to one another?

Andrea Fuso: Yes, of course. Let's start from one-carbon metabolism. It is a metabolic cycle, and I would say it is a quite underrated metabolic pathway, because people say that it has few reactions related to ATP, for example. So it's a very relevant metabolic pathway, but not so much studied. You may know it by other names, maybe homocysteine cycle or methionine cycle, depending on the sensor molecule one is interested in, but one-carbon metabolism is for sure the more the most neutral definition, and we can start describing it by methionine, which is an essential amino acid introduced by diet. Methionine is complexed with ATP to form SAMe, S-adenosyl-L-methionine, which is the methyl donor in all the so called transmethylation reactions, which means that SAMe gives its methyl group to a number of substrates, including DNA, RNA protein, lipids and so on. Besides being involved in other reactions, it's a precursor of nucleic acids, it's a precursor of neurotransmitters and so on.

When transmethylation occurs, SAMe is transformed in S-Adenosyl-L-homocysteine, SAH, and SAH is an inhibitor of transmethylation, but SAH is rapidly hydrolyzed to homocysteine and adenosine in the reaction, which is the only reversible reaction. But in turn, homocysteine does not accumulate because it's rapidly scavenged by the urinary tract, for example, or it's transformed in the transsulfuration pathway in the end, leading to the formation of glutathione, which is one of the major antioxidant cells, and on the other side, is remethylated to methionine. So giving the methyl group by SAMe is the transmethylation reaction, the methylation to homocysteine to methionine is the remethylation. This is the metabolic cycle. And so the relationship between DNA methylation and carbon metabolism is the SAMe molecule, which can give this methyl group to many substrates, but in particular, it is known for DNA methylation.

DNA methylation is the first described and the most studied epigenetic modification. Epigenetics is the study of how a few changes, not mutation, but changes on the DNA chain can alter the expression of the genes, which means that epigenetic modification regulates how one gene is read, how one gene is transformed into mRNA: full, nothing, or half way.