UniProt functional annotation for P34897



	UniProt functional annotation for P34897

UniProt code: P34897.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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:25619277). 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). {ECO:0000269|PubMed:18063578, ECO:0000269|PubMed:21876188, ECO:0000269|PubMed:24075985, ECO:0000269|PubMed:25619277, ECO:0000269|PubMed:29364879, ECO:0000269|PubMed:29452640}.

Catalytic activity: Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + glycine + H2O = (6S)-5,6,7,8-tetrahydrofolate + L-serine; Xref=Rhea:RHEA:15481, ChEBI:CHEBI:15377, ChEBI:CHEBI:15636, ChEBI:CHEBI:33384, ChEBI:CHEBI:57305, ChEBI:CHEBI:57453; EC=2.1.2.1; Evidence={ECO:0000269|PubMed:24075985, ECO:0000269|PubMed:25619277, ECO:0000269|PubMed:29364879};

Cofactor: Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326; Evidence={ECO:0000269|PubMed:25619277, ECO:0000305|PubMed:29364879};

Activity regulation: Hydroxymethyltransferase is inhibited by succinylation at Lys-280. {ECO:0000269|PubMed:29180469}.

Biophysicochemical properties: Kinetic parameters: KM=278 uM for L-serine {ECO:0000269|PubMed:25619277}; KM=23 uM for tetrahydrofolate {ECO:0000269|PubMed:25619277};

Pathway: One-carbon metabolism; tetrahydrofolate interconversion. {ECO:0000305|PubMed:25619277}.

Subunit: 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). {ECO:0000269|PubMed:24075985, ECO:0000269|PubMed:25619277, ECO:0000269|PubMed:25902260, ECO:0000269|PubMed:29180469}.

Subcellular location: Mitochondrion {ECO:0000269|PubMed:21876188, ECO:0000269|PubMed:24075985}. Mitochondrion matrix, mitochondrion nucleoid {ECO:0000269|PubMed:18063578}. Mitochondrion inner membrane {ECO:0000269|PubMed:21876188}. Cytoplasm {ECO:0000269|PubMed:24075985}. Nucleus {ECO:0000269|PubMed:24075985}. Note=Mainly localizes in the mitochondrion. Also found in the cytoplasm and nucleus as part of the BRISC complex (PubMed:24075985). {ECO:0000269|PubMed:24075985}.

Ptm: Succinylation at Lys-280 inhibits the hydroxymethyltransferase activity. Desuccinylation by SIRT5 restores the activity, leading to promote cell proliferation. {ECO:0000269|PubMed:29180469}.

Miscellaneous: In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one.

Similarity: Belongs to the SHMT family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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:25619277). 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). {ECO:0000269\|PubMed:18063578, ECO:0000269\|PubMed:21876188, ECO:0000269\|PubMed:24075985, ECO:0000269\|PubMed:25619277, ECO:0000269\|PubMed:29364879, ECO:0000269\|PubMed:29452640}.


Catalytic activity:		Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + glycine + H2O = (6S)-5,6,7,8-tetrahydrofolate + L-serine; Xref=Rhea:RHEA:15481, ChEBI:CHEBI:15377, ChEBI:CHEBI:15636, ChEBI:CHEBI:33384, ChEBI:CHEBI:57305, ChEBI:CHEBI:57453; EC=2.1.2.1; Evidence={ECO:0000269\|PubMed:24075985, ECO:0000269\|PubMed:25619277, ECO:0000269\|PubMed:29364879};
Cofactor:		Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326; Evidence={ECO:0000269\|PubMed:25619277, ECO:0000305\|PubMed:29364879};
Activity regulation:		Hydroxymethyltransferase is inhibited by succinylation at Lys-280. {ECO:0000269\|PubMed:29180469}.
Biophysicochemical properties:		Kinetic parameters: KM=278 uM for L-serine {ECO:0000269\|PubMed:25619277}; KM=23 uM for tetrahydrofolate {ECO:0000269\|PubMed:25619277};
Pathway:		One-carbon metabolism; tetrahydrofolate interconversion. {ECO:0000305\|PubMed:25619277}.
Subunit:		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). {ECO:0000269\|PubMed:24075985, ECO:0000269\|PubMed:25619277, ECO:0000269\|PubMed:25902260, ECO:0000269\|PubMed:29180469}.
Subcellular location:		Mitochondrion {ECO:0000269\|PubMed:21876188, ECO:0000269\|PubMed:24075985}. Mitochondrion matrix, mitochondrion nucleoid {ECO:0000269\|PubMed:18063578}. Mitochondrion inner membrane {ECO:0000269\|PubMed:21876188}. Cytoplasm {ECO:0000269\|PubMed:24075985}. Nucleus {ECO:0000269\|PubMed:24075985}. Note=Mainly localizes in the mitochondrion. Also found in the cytoplasm and nucleus as part of the BRISC complex (PubMed:24075985). {ECO:0000269\|PubMed:24075985}.
Ptm:		Succinylation at Lys-280 inhibits the hydroxymethyltransferase activity. Desuccinylation by SIRT5 restores the activity, leading to promote cell proliferation. {ECO:0000269\|PubMed:29180469}.
Miscellaneous:		In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one.
Similarity:		Belongs to the SHMT family. {ECO:0000305}.