Serine hydroxymethyltransferase, cytosolic (SHMT1)

Serine hydroxymethyltransferase, cytosolic (SHMT1) is a fundamental pyridoxal phosphate-dependent enzyme that catalyzes the reversible conversion of L-serine and tetrahydrofolate into glycine and 5,10-methylene-tetrahydrofolate (UniProt P34896). This reaction is a primary entry point for one-carbon units into the folate cycle, providing the essential building blocks for the de novo synthesis of purines and thymidylate required for DNA replication and repair (NCBI Gene 6470). While primarily localized in the cytoplasm, SHMT1 can translocate to the nucleus during the S and G2 phases of the cell cycle to facilitate localized nucleotide production at the replication fork (PubMed: 22561383). In many cancers, SHMT1 is upregulated to support the metabolic demands of rapid cell proliferation, making it an attractive target for antimetabolite therapy (PubMed: 30108180). Although traditional antifolates like pemetrexed inhibit SHMT1 indirectly by depleting folate pools, specific small-molecule inhibitors such as SHIN1 are being developed to selectively disrupt its activity (PubMed: 28583440). Furthermore, genetic polymorphisms in SHMT1 have been linked to an increased risk of neural tube defects and certain leukemias, highlighting its critical role in maintaining genomic stability (PubMed: 11555305).

Other names

SHMT1CSHMTSerine methylaseGlycine hydroxymethyltransferaseSerine hydroxymethyltransferase 1

Competitive inhibition of the serine or tetrahydrofolate binding sites, preventing the transfer of a one-carbon unit and subsequently halting the production of 5,10-methylene-tetrahydrofolate required for nucleotide synthesis.