Hydroxymethyltransferase

Hydroxymethyltransferase is a descriptive term for enzymes that catalyze the transfer of a hydroxymethyl group (-CH2OH) from a donor to an acceptor, most commonly from serine to tetrahydrofolate (THF) to produce glycine and 5,10-methylene-THF. The best known example is serine hydroxymethyltransferase (SH MT), a pyridoxal phosphate (PLP)-dependent enzyme that operates in one-carbon metabolism.

In the canonical reaction, serine plus THF yields glycine plus 5,10-methylene-THF, a one-carbon donor used in thymidylate and purine synthesis. SHMT exists in multiple cellular compartments in eukaryotes (cytosolic and mitochondrial forms) and in bacteria as glyA, reflecting its essential role in connecting amino acid metabolism to nucleotide biosynthesis.

Mechanistically, SHMT and related hydroxymethyltransferases rely on PLP to form a Schiff base with the substrate, enabling reversible transfer of the hydroxymethyl group. Structurally, these enzymes commonly function as homodimers or homotetramers and are widespread across bacteria, archaea, and eukaryotes, illustrating the conservation of one-carbon metabolism pathways.

Biological significance lies in the integration of amino acid catabolism with folate-dependent one-carbon transfers, supporting synthesis of dTMP, purines, and S-adenosylmethionine–dependent methylation reactions. Alterations in SHMT activity or expression have been observed in various contexts, including cancer metabolism and neural development, highlighting the enzyme’s role in cellular growth and methylation potential.

Related enzymes and topics include the broader family of PLP-dependent hydroxymethyltransferases and the folate cycle, including 5,10-methylene-THF’s involvement in nucleotide biosynthesis and one-carbon transfer processes.