SHMT2

SHMT2, short for serine hydroxymethyltransferase 2, is a mitochondrial enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and methylene-tetrahydrofolate, with water produced as a byproduct. It is a pyridoxal phosphate–dependent enzyme and plays a key role in mitochondrial one-carbon metabolism, supplying one-carbon units for nucleotide biosynthesis and related pathways.

In humans, SHMT2 is encoded by the SHMT2 gene and exists as multiple isoforms produced by alternative splicing. The two major isoforms are SHMT2α, which contains a mitochondrial targeting sequence and localizes to the mitochondrial matrix, and SHMT2β, which lacks this sequence and is found in the cytosol. The enzyme thus functions in both mitochondrial and, to a lesser extent, cytosolic contexts depending on the isoform.

Biological function and metabolism: The methylene-tetrahydrofolate generated by SHMT2 feeds into mitochondrial folate metabolism, supporting de novo synthesis of thymidylate and purines and contributing to the generation of formate, a one-carbon source for cytosolic folate reactions. Through these pathways, SHMT2 links serine catabolism to DNA synthesis, mitochondrial DNA maintenance, and overall cellular proliferation, particularly in cells with high metabolic demand.

Regulation and clinical relevance: SHMT2 expression is influenced by cellular metabolic state and environmental conditions; it is notably upregulated in several cancers, especially under hypoxic stress, where it supports tumor growth and survival. As a result, SHMT2 is studied as a potential target for cancer therapy, with ongoing research into selective inhibitors and the broader role of mitochondrial one-carbon metabolism in disease.

See also: SHMT1, one-carbon metabolism, folate cycle.