Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis (PubMed:24075985, PubMed:29364879, PubMed:33015733 PubMed:25619277, PubMed:33015733). Serine provides the major source of folate one-carbon in cells by catalyzing the transfer of one carbon from serine to tetrahydrofolate (PubMed:25619277). Contributes to the de novo mitochondrial thymidylate biosynthesis pathway via its role in glycine and tetrahydrofolate metabolism: thymidylate biosynthesis is required to prevent uracil accumulation in mtDNA (PubMed:21876188). Also required for mitochondrial translation by producing 5,10-methylenetetrahydrofolate; 5,10-methylenetetrahydrofolate providing methyl donors to produce the taurinomethyluridine base at the wobble position of some mitochondrial tRNAs (PubMed:29452640, PubMed:29364879). Associates with mitochondrial DNA (PubMed:18063578). In addition to its role in mitochondria, also plays a role in the deubiquitination of target proteins as component of the BRISC complex: required for IFNAR1 deubiquitination by the BRISC complex (PubMed:24075985). (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + glycine + H2O = (6S)-5,6,7,8-tetrahydrofolate + L-serine Hydroxymethyltransferase is inhibited by succinylation at Lys-280. One-carbon metabolism; tetrahydrofolate interconversion. Homotetramer; in the presence of bound pyridoxal 5'-phosphate (PubMed:29180469, PubMed:25619277). Homodimer; in the absence of bound pyridoxal 5'-phosphate (PubMed:29180469, PubMed:25619277). Pyridoxal 5'-phosphate binding mediates an important conformation change that is required for tetramerization (PubMed:25619277). Interacts with ABRAXAS2; the interaction is direct. Identified in a complex with ABRAXAS2 and the other subunits of the BRISC complex, at least composed of the ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Identified in a complex with ABRAXAS2 and IFNAR1 (PubMed:24075985). Interacts with KIRREL3 (PubMed:25902260). Mainly localizes in the mitochondrion. Also found in the cytoplasm and nucleus as part of the BRISC complex (PubMed:24075985). Succinylation at Lys-280 inhibits the hydroxymethyltransferase activity. Desuccinylation by SIRT5 restores the activity, leading to promote cell proliferation. The disease is caused by variants affecting the gene represented in this entry. In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one. Belongs to the SHMT family.