SHMT1
entrez
6470
canonical
uniprot
P34896
canonical
ensembl
ENSG00000176974
resolver
ensembl
ENSG00000284320
resolver
ensp
ENSP00000318805
resolver
ensp
ENSP00000318868
resolver
ensp
ENSP00000462041
resolver
ensp
ENSP00000556420
resolver
ensp
ENSP00000556423
resolver
ensp
ENSP00000556425
resolver
ensp
ENSP00000556438
resolver
ensp
ENSP00000556439
resolver
ensp
ENSP00000621920
resolver
genesymbol
SHMT1
resolver
hgnc
HGNC:10850
resolver
uniprot
B4DPM9
resolver
uniprot
D3DXD0
resolver
uniprot
Q96HY0
resolver
uniprot
Q9UMD1
resolver
uniprot
Q9UMD2
resolver
uniprot_entry
GLYC_HUMAN
resolver
uniprot_sec
B4DPM9
resolver
uniprot_sec
D3DXD0
resolver
uniprot_sec
Q96HY0
resolver
uniprot_sec
Q9UMD1
resolver
uniprot_sec
Q9UMD2
resolver
activity_regulation
ACTIVITY REGULATION: Inhibited by tetrahydrofolate concentrations above 40 uM (PubMed:24698160). RNA binding specifically inhibits the SHMT1-catalyzed serine cleavage reaction, thereby promoting the glycine-to-serine conversion in the cytosol and consequently increasing the tetrahydrofolate (THF) and serine pools available for mitochondrial SHMT2-dependent one-carbon metabolism (PubMed:38996576). RNA binding induces a conformational reorganization of SHMT1 tetrameric subunits, resulting in distinct combinations of open and closed active site conformations (PubMed:38996576). {ECO:0000269|PubMed:24698160, ECO:0000269|PubMed:38996576}.
uniprot
proteins
amino_acid_sequence
MTMPVNGAHKDADLWSSHDKMLAQPLKDSDVEVYNIIKKESNRQRVGLELIASENFASRAVLEALGSCLNNKYSEGYPGQRYYGGTEFIDELETLCQKRALQAYKLDPQCWGVNVQPYSGSPANFAVYTALVEPHGRIMGLDLPDGGHLTHGFMTDKKKISATSIFFESMPYKVNPDTGYINYDQLEENARLFHPKLIIAGTSCYSRNLEYARLRKIADENGAYLMADMAHISGLVAAGVVPSPFEHCHVVTTTTHKTLRGCRAGMIFYRKGVKSVDPKTGKEILYNLESLINSAVFPGLQGGPHNHAIAGVAVALKQAMTLEFKVYQHQVVANCRALSEALTELGYKIVTGGSDNHLILVDLRSKGTDGGRAEKVLEACSIACNKNTCPGDRSALRPSGLRLGTPALTSRGLLEKDFQKVAHFIHRGIELTLQIQSDTGVRATLKEFKERLAGDKYQAAVQALREEVESFASLFPLPGLPDF
uniprot
proteins
ec_number
2.1.2.1
uniprot
proteins
function
FUNCTION: Pyridoxal phosphate (PLP)-dependent enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene THF, serving as a critical component of the folate cycle and facilitating one-carbon biosynthetic reactions essential for methionine, purine, and pyrimidine synthesis (PubMed:24698160, PubMed:30035852, PubMed:38996576). While its central activity involves serine cleavage, the detailed catalytic mechanisms remain under study, including both retro-aldol cleavage of the PLP-serine C(alpha)-C(beta) bond followed by formaldehyde condensation with THF, and alternative nucleophilic displacement mechanisms of the C(alpha) atom of PLP-serine aldimine involving THF's N5 atom (By similarity). Also catalyzes the cleavage of various 3-hydroxy amino acids, such as L-allo-threonine, L-threonine and 3-phenylserine, forming glycine and the corresponding aldehyde through a retro-aldol process; additionally, it catalyzes the formation of 5-formyltetrahydrofolate from 5,10-methenyltetrahydrofolate (PubMed:38615009). Also functions as a hydroxytrimethyllysine aldolase (HTMLA) catalyzing the second step of the carnitine biosynthesis pathway and exhibits substrate preference with the erythro (S,S) configuration, and more efficiency with L-allo-threonine (PubMed:38615009). In the nucleus, first functions as a lamin-binding scaffold protein that is essential for assembling the de novo thymidylate synthesis complex by co-localizing DHFR and TYMS with the nuclear lamina and anchoring the complex to DNA replication sites (PubMed:22235121). Subsequently, provides one-carbon substrates, specifically (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, in situ for de novo dTMP synthesis to sustain DNA replication and repair during cell proliferation (PubMed:30035852). Importantly, possesses RNA-binding capability, forming complexes that selectively regulate SHMT2 mRNA translation and dynamically modulate cytosolic and mitochondrial serine and glycine concentrations, thus influencing cellular metabolic status (PubMed:38996576). {ECO:0000250|UniProtKB:P07511, ECO:0000269|PubMed:22235121, ECO:0000269|PubMed:24698160, ECO:0000269|PubMed:30035852, ECO:0000269|PubMed:38615009, ECO:0000269|PubMed:38996576}.
uniprot
proteins
mass_dalton
53083
uniprot
proteins
mutagenesis
MUTAGEN 38; /note="K->R: Does not affect ubiquitination level. Impairs sumoylation in vitro."; /evidence="ECO:0000269|PubMed:17446168, ECO:0000269|PubMed:22194612"; MUTAGEN 39; /note="K->R: Significantly decreases ubiquitination level. Impairs sumoylation in vitro."; /evidence="ECO:0000269|PubMed:17446168, ECO:0000269|PubMed:22194612"; MUTAGEN 82; /note="Y->A: Does not affect protein homotetramerization; when associated with F-83 and Q-257. Loss of glycine hydroxymethyltransferase activity; when associated with F-83 and Q-257. Does not affect location at nucleus; when associated with F-83 and Q-257. Reduces the proliferation rate of almost 60% after 48h; when associated with F-83 and Q-257. Reduces the cytoplasmic incorporation of SHMT1-derived one-carbon units into methionine synthesis; when associated with F-83 and Q-257. Enhances the nucleus incorporation of SHMT1-derived one-carbon units into de novo thymidylate synthesis; when associated with F-83 and Q-257."; /evidence="ECO:0000269|PubMed:22235121, ECO:0000269|PubMed:38996576"; MUTAGEN 83; /note="Y->F: Does not affect protein homotetramerization; when associated with A-82 and Q-257. Loss of glycine hydroxymethyltransferase activity; when associated with A-82 and Q-257. Does not affect location at nucleus; when associated with A-82 and Q-257. Reduces the proliferation rate of almost 60% after 48h; when associated with A-82 and Q-257. Reduces the cytoplasmic incorporation of SHMT1-derived one-carbon units into methionine synthesis; when associated with F-82 and Q-257. Enhances the nucleus incorporation of SHMT1-derived one-carbon units into de novo thymidylate synthesis; when associated with F-82 and Q-257."; /evidence="ECO:0000269|PubMed:22235121, ECO:0000269|PubMed:38996576"; MUTAGEN 135; /note="H->N: Does not affect protein homotetramerization; when associated with A-137 and N-168. Loss of protein homotetramerization; when associated with A-137. Slightly decreases pyridoxal-5'-phosphate binding; when associated with A-137 and N-168. Decreases pyridoxal-5'-phosphate binding; when associated with A-137. Loss of glycine hydroxymethyltransferase activity; when associated A-137. Does not affect location at nucleus; when associated with A-137 and N-168. Does not affect location at nucleus; when associated with A-137. Does not affect cell proliferation; when associated with A-137. Does not affect cell proliferation; when associated with A-137 and N-168."; /evidence="ECO:0000269|PubMed:38996576"; MUTAGEN 137; /note="R->A: Does not affect protein homotetramerization; when associated with N-135 and N-168. Loss of protein homotetramerization; when associated with N-135. Slightly decreases pyridoxal-5'-phosphate binding; when associated with N-135 and N-168. Decreases pyridoxal-5'-phosphate binding; when associated with N-135. Loss of glycine hydroxymethyltransferase activity; when associated with N-135. Does not affect location at nucleus; when associated with N-135 and N-168. Does not affect location at nucleus; when associated with N-135. Does not affect cell proliferation; when associated with N-135. Does not affect cell proliferation; when associated with N-135 and N-168."; /evidence="ECO:0000269|PubMed:38996576"; MUTAGEN 168; /note="E->N: Does not affect protein homotetramerization; when associated with N-135 and A-137. Slightly decreases pyridoxal-5'-phosphate binding; when associated with A-135 and A-137. Does not affect location at nucleus; when associated with A-135 and A-137.Does not affect cell proliferation rate of almost 60% after 48h; when associated with A-137. Does not affect cell proliferation; when associated with N-135. Does not affect cell proliferation; when associated with N-135 and N-168."; /evidence="ECO:0000269|PubMed:38996576"; MUTAGEN 257; /note="K->Q: Does not affect protein homotetramerization; when associated with A-82 and F-83. Loss of glycine hydroxymethyltransferase activity; when associated with A-82 and F-83. Does not affect location at nucleus; when associated with A-82 and F-83. Reduces the proliferation rate of almost 60% after 48h; when associated with A-82 and F-83. Reduces the cytoplasmic incorporation of SHMT1-derived one-carbon units into methionine synthesis; when associated with F-82 and F-83. Enhances the nucleus incorporation of SHMT1-derived one-carbon units into de novo thymidylate synthesis; when associated with F-82 and F-83."; /evidence="ECO:0000269|PubMed:22235121, ECO:0000269|PubMed:38996576"; MUTAGEN 279; /note="K->S: Loss of RNA binding. Decreases ability of RNA to interfere with folate binding. Significantly impairs the ability of RNA to inhibit serine hydroxymethyltransferase activity. Decreases serine hydroxymethyltransferase activity. Does not affect SHMT2 protein expression."; /evidence="ECO:0000269|PubMed:38996576"; MUTAGEN 282; /note="K->S: Decreases RNA binding. Decreases ability of RNA to interfere with folate binding. Decreases the ability of RNA to inhibit serine hydroxymethyltransferase activity. Decreases serine hydroxymethyltransferase activity."; /evidence="ECO:0000269|PubMed:38996576"; MUTAGEN 393; /note="R->S: Decreases RNA binding; when associated with S-397. Decreases ability of RNA to interfere with folate binding; when associated with S-397. Decreases the ability of RNA to inhibit serine hydroxymethyltransferase activity; when associated with S-397. Decreases serine hydroxymethyltransferase activity; when associated with S-397."; /evidence="ECO:0000269|PubMed:38996576"; MUTAGEN 397; /note="R->S: Decreases RNA binding; when associated with S-393. Decreases ability of RNA to interfere with folate binding; when associated with S-393. Decreases the ability of RNA to inhibit serine hydroxymethyltransferase activity; when associated with S-393. Decreases serine hydroxymethyltransferase activity; when associated with S-393."; /evidence="ECO:0000269|PubMed:38996576
uniprot
proteins
pathway_participation
PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion. {ECO:0000269|PubMed:24698160, ECO:0000269|PubMed:30035852, ECO:0000269|PubMed:38996576}.; PATHWAY: Amino-acid degradation. {ECO:0000269|PubMed:38615009}.
uniprot
proteins
post_translational_modification
PTM: Ubiquitination at Lys-39 leads to proteasomal degradation (PubMed:22194612). UBE2N/UBC13-mediated ubiquitination stabilize SHMT1 within the nucleus and signals nuclear export of SHMT1 through 'Lys-63'-specific ubiquitin linkage (PubMed:22194612). 'Lys-63' polyubiquitination is cell cycle- and compartment-specific (PubMed:22194612). Modification by UBE2I/UBC9 or UBE2N/UBC13 compete for SHMT1 modification, leading to either degradation in the nucleus or nuclear export, respectively (PubMed:22194612). In the cytoplasm, SHMT1 degradation is facilitated by 'Lys-48' ubiquitin linkages, whereas in the nucleus, 'Lys-63'-linked ubiquitination prevents degradation (PubMed:22194612). {ECO:0000269|PubMed:22194612}.; PTM: Sumoylated at either Lys-38 or Lys-39 (PubMed:17446168). SUMO1 conjugation by UBE2I/UBC9 occurs at the nuclear pore during S,G2/M phases of the cell cycle and triggers the RAN-dependent nuclear import of SHMT1 (PubMed:17446168, PubMed:22194612). UBE2I-mediated conjugation to SUMO2/3 in the nucleus allows nuclear degradation (PubMed:22194612). {ECO:0000269|PubMed:17446168, ECO:0000269|PubMed:22194612}.; PTM: Deamidation of asparagine produces alternatively aspartate or isoaspartate, which in turn can be converted to aspartate through carboxylmethylation/demethylation. {ECO:0000250|UniProtKB:P07511}.
uniprot
proteins
protein_family
SHMT family
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16625196
uniprot
proteins
pubmed
17446168
uniprot
proteins
pubmed
19608861
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22194612
uniprot
proteins
pubmed
22235121
uniprot
proteins
pubmed
24075985
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24698160
uniprot
proteins
pubmed
25619277
uniprot
proteins
pubmed
30035852
uniprot
proteins
pubmed
38615009
uniprot
proteins
pubmed
38996576
uniprot
proteins
pubmed
8505317
uniprot
proteins
pubmed
9056951
uniprot
proteins
pubmed
9753690
uniprot
proteins
sequence_length
483
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17446168}. Nucleus {ECO:0000269|PubMed:17446168, ECO:0000269|PubMed:30035852, ECO:0000305|PubMed:22235121}. Note=Nuclear translocation is RAN-dependent and is independent from both the oligomerization state and the catalytic activity (PubMed:30035852). In the cytoplasm, SHMT1 degradation is facilitated by 'Lys-48'-linked ubiquitination, whereas in the nucleus, 'Lys-63'-linked ubiquitination prevents degradation (PubMed:22194612). Predominantly sumoylated and localized to the nucleus in S phase cells and remains in the nucleus during the G2/M phase of the cell cycle (PubMed:17446168). Sumoylation occurs at the nuclear pore and is linked to nuclear import (PubMed:17446168). As a component of the de novo thymidylate synthesis complex, localizes specifically to replication forks during DNA synthesis (PubMed:22235121). {ECO:0000269|PubMed:17446168, ECO:0000269|PubMed:22194612, ECO:0000269|PubMed:22235121, ECO:0000269|PubMed:30035852}.
uniprot
proteins