SHMT

SHMT stands for serine hydroxymethyltransferase, a pyridoxal phosphate–dependent enzyme that participates in folate-mediated one-carbon metabolism. It catalyzes the reversible transfer of a hydroxymethyl group from serine to tetrahydrofolate (THF), producing glycine and methylene-THF (CH2-THF). The methylene-THF generated acts as a one-carbon donor in the synthesis of thymidylate and purines, linking serine catabolism to nucleotide biosynthesis and cellular methylation reactions.

In humans, there are two major isoforms with different cellular localizations: SHMT1 is cytosolic, and SHMT2 is mitochondrial. Both contribute to the cellular one-carbon pool that feeds folate metabolism. The enzyme uses PLP as a cofactor, forming a Schiff base with a lysine residue. The catalytic cycle involves formation of an external aldimine with serine, transfer to THF to form CH2-THF, and regeneration of the active PLP form.

SHMT activity is central to the folate cycle and interfaces with downstream enzymes such as thymidylate synthase. The CH2-THF produced can be used directly for thymidylate synthesis or can be further metabolized to other folate forms that participate in nucleotide biosynthesis and methylation pathways.

Biological and clinical relevance: SHMT supports the nucleotide biosynthesis required by rapidly proliferating cells, linking metabolism to DNA synthesis. SHMT2, in particular, is often upregulated in certain cancers and under hypoxic stress, and inhibitors of SHMT are being explored as potential anticancer therapies. Disruptions in SHMT function or folate metabolism can impact DNA synthesis and genomic stability.