SHMT1

Summary

SHMT1 (serine hydroxymethyltransferase 1, HGNC:10850) is a protein-coding gene on chromosome 17p11.2, encoding Serine hydroxymethyltransferase, cytosolic (P34896). 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 methio….

This gene encodes the cytosolic form of serine hydroxymethyltransferase, a pyridoxal phosphate-containing enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. This reaction provides one-carbon units for synthesis of methionine, thymidylate, and purines in the cytoplasm. This gene is located within the Smith-Magenis syndrome region on chromosome 17. A pseudogene of this gene is located on the short arm of chromosome 1. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6470 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 84 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004169

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10850
Approved symbol	SHMT1
Name	serine hydroxymethyltransferase 1
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	cSHMT, SHMT, MGC15229, MGC24556
Ensembl gene	ENSG00000176974
Ensembl biotype	protein_coding
OMIM	182144
Entrez	6470

Gene structure

Transcript identifiers

Ensembl transcripts: 66 — 61 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000316694, ENST00000354098, ENST00000395682, ENST00000395684, ENST00000579558, ENST00000580002, ENST00000582352, ENST00000582653, ENST00000583780, ENST00000886361, ENST00000886362, ENST00000886363, ENST00000886364, ENST00000886365, ENST00000886366, ENST00000886367, ENST00000886368, ENST00000886369, ENST00000886370, ENST00000886371, ENST00000886372, ENST00000886373, ENST00000886374, ENST00000886375, ENST00000886376, ENST00000886377, ENST00000886378, ENST00000886379, ENST00000886380, ENST00000886381, ENST00000886382, ENST00000886383, ENST00000886384, ENST00000886385, ENST00000886386, ENST00000886387, ENST00000886388, ENST00000886389, ENST00000886390, ENST00000886391, ENST00000886392, ENST00000886393, ENST00000886394, ENST00000886395, ENST00000886396, ENST00000886397, ENST00000886398, ENST00000886399, ENST00000886400, ENST00000886401, ENST00000886402, ENST00000886403, ENST00000886404, ENST00000886405, ENST00000886406, ENST00000886407, ENST00000926099, ENST00000926100, ENST00000926101, ENST00000926102, ENST00000926103, ENST00000926104, ENST00000951859, ENST00000951860, ENST00000951861, ENST00000951862

RefSeq mRNA: 3 — MANE Select: NM_004169 NM_001281786, NM_004169, NM_148918

CCDS: CCDS11196, CCDS11197

Canonical transcript exons

ENST00000316694 — 12 exons

Exon	Start	End
ENSE00001912602	18363372	18363550
ENSE00003473268	18327873	18328919
ENSE00003488178	18348325	18348440
ENSE00003494186	18340732	18340813
ENSE00003513105	18333166	18333288
ENSE00003527265	18335559	18335675
ENSE00003565886	18329278	18329388
ENSE00003584088	18353672	18353817
ENSE00003622560	18347496	18347656
ENSE00003655100	18355886	18356000
ENSE00003670045	18340043	18340255
ENSE00003681564	18330555	18330671

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4984 / max 599.2485, expressed in 1749 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164832	7.9204	1634
164829	5.5868	1417
164831	1.9533	767
164830	1.0379	685

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.89	gold quality
liver	UBERON:0002107	98.71	gold quality
adult mammalian kidney	UBERON:0000082	97.28	gold quality
kidney	UBERON:0002113	95.55	gold quality
duodenum	UBERON:0002114	95.37	gold quality
metanephros cortex	UBERON:0010533	95.16	gold quality
esophagus mucosa	UBERON:0002469	94.36	gold quality
lower esophagus mucosa	UBERON:0035834	93.79	gold quality
cortex of kidney	UBERON:0001225	93.12	gold quality
saliva-secreting gland	UBERON:0001044	91.19	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.02	gold quality
minor salivary gland	UBERON:0001830	90.94	gold quality
adipose tissue	UBERON:0001013	90.58	gold quality
thoracic mammary gland	UBERON:0005200	90.00	gold quality
omental fat pad	UBERON:0010414	89.85	gold quality
left lobe of thyroid gland	UBERON:0001120	89.77	gold quality
mucosa of stomach	UBERON:0001199	89.65	gold quality
thyroid gland	UBERON:0002046	89.50	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.39	gold quality
right lobe of thyroid gland	UBERON:0001119	89.23	gold quality
esophagus	UBERON:0001043	89.09	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.79	gold quality
small intestine	UBERON:0002108	88.73	gold quality
skeletal muscle tissue	UBERON:0001134	88.57	gold quality
skin of abdomen	UBERON:0001416	88.52	gold quality
zone of skin	UBERON:0000014	88.51	gold quality
skin of leg	UBERON:0001511	88.47	gold quality
mucosa of transverse colon	UBERON:0004991	88.26	gold quality
spleen	UBERON:0002106	88.22	gold quality
tibial nerve	UBERON:0001323	88.16	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

37 targeting SHMT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-5690	99.25	67.58	1012

Literature-anchored findings (GeneRIF, showing 40)

• These results indicate that cSHMT is a metabolic switch that, when activated, gives dTMP synthesis higher metabolic priority than S-adenosylmethionine synthesis. (PMID:12161434)
• Associations between polymorphisms in the thymidylate synthase and SHMT1 genes and susceptibility to malignant lymphoma. (PMID:12604405)
• The region missing in the shorter isoform is relatively short and is located on the cell surface. (PMID:12615003)
• SHMT1 is a zinc-inducible gene, which provides the first mechanism for the regulation of folate-mediated one-carbon metabolism by zinc (PMID:15531579)
• The low activity of SHMT in the human and rat placenta suggests that, unlike in the sheep, placental conversion of serine to glycine is not a major source of fetal glycine in these species. (PMID:15598699)
• increased expression of truncated cSHMT, Tbx3 and utrophin in plasma samples obtained from patients at early stages of ovarian cancer and breast cancer (PMID:16049973)
• Possibility of a direct or indirect role for the SHMT1(1420)T variant in spontaneous preterm or SGA births. (PMID:17074544)
• study demonstrates an association of the MTHFR C677T and SHMT(1) C1420T polymorphism with the risk of esophageal squamous cell carcinoma and gastric cardia adenocarcinoma (PMID:17206530)
• Subjects carrying the combined 3+ risk variant genotypes of SHMT1 had an increased risk of lung cancer. (PMID:17420066)
• Results describe the mechanism for the preferential partitioning of cytoplasmic serine hydroxymethyltransferase (cSHMT)-derived methylenetetrahydrofolate to de novo thymidylate biosynthesis (PMID:17446168)
• vitamin B(6) restriction decreases the activity and stability of SHMT (PMID:17482557)
• our study provides support to account for the preferential role of cytosolic serine hydroxymethyltransferase polymorphism to lower risk of female breast cancer (PMID:17896178)
• For cSHMT 1420 CC genotype, particulates <2.5 were associated with significant decreases in normal-to-normal std deviation & heart rate, but not for CT/TT. For PM2.5 level. Interaction with C1420T cSHMT genotype was statistically significant for both. (PMID:18378616)
• SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis (PMID:19513116)
• No evidence for an association between the cSHMT genotype and breast cancer was observed. There was also no evidence of a gene-gene interaction between cSHMT and MTHFR. (PMID:19707223)
• Interactions between the 5’-UTR and 3’-UTR achieve maximal internal ribosome entry site-mediated translation of SHMT1. (PMID:19734143)
• No asssociation between SHMT1 single nucleotide polymorphism 1420C > T and both, follicular lymphoma and diffuse, large B-Cell lymphoma was observed in a cohort of swedish patients. (PMID:19751277)
• Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk. (PMID:19776626)
• SHMT1 1420 and MTHFR 677 polymorphisms are associated only with development of rectal and not colon cancer (PMID:20920350)
• SHMT1 levels are found to be higher in schizophrenic brains compared to controls. (PMID:20977478)
• Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR, C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in West Siberian Region of Russia (PMID:21090237)
• there was an interaction between SHMT1 and MTHFR such that the association of the MTHFR rs1801133 CT genotype with an increased CVD risk was stronger in the presence of SHMT1 rs1979277 TT genotype. (PMID:21178087)
• A protective role for the genotypes SHMT-1420 CC and CT on maternal risk for Down syndrome. (PMID:21687976)
• MTRR A66G and cSHMT C1420T polymorphisms influence CpG island methylator phenotype of BNIP3, thus epigenetically regulating BNIP3 in breast cancer (PMID:21987236)
• The univariate and multivariate analyses demonstrated that the SHMT1 1420T allele was associated with better response (P=0.025) and longer progression-free survival (PFS) (P=0.00004) and overall survival (OS) (PMID:22044939)
• SUMO and ubiquitin modification of SHMT1 occurs on the same lysine residue and determine the localization and accumulation of SHMT1 in the nucleus. (PMID:22194612)
• The present study not only describes individual genetic variation that directly affects SHMT1 and SHMT2 activity, but provided insight into the overall regulation of the Folate and Methionine Cycles. (PMID:22220685)
• No statistically significant association with prostate cancer was detected for the polymorphic locus C1420T of SHMT1 gene. (PMID:22803112)
• geography-specific effects of the SHMT1 polymorphism that render Europeans susceptible to colorectal caner, but not Americans. (PMID:23322534)
• There is an association between DHFR DD/SHMT TT and DHFR II/SHMT TT combined genotypes and folate and MMA concentrations in individuals with Down syndrome. (PMID:23421317)
• The link between mitochondrial serine hydroxymethyltransferase activity and heme biosynthesis represents an important aspect of the whole picture of cancer cell metabolism. (PMID:23474074)
• SHMT1 C1420T and DNMT3B C46359T polymorphisms are not associated with HNC development in Brazilian population, however, SHMT1 C1420T polymorphism is less frequent in patients with primary site of tumor in larynx (PMID:24362509)
• serine hydroxymethyltransfarase C1420T reduces risk for both acute lymphoblastic leukemia and acute myeloid leukemia and influences disease progression in acute lymphoblastic leukemia (PMID:24641398)
• SHMT1 C1420T polymorphism is not associated with overall cancer development. (PMID:24716966)
• found evidence for association of SHMT1 C1420T polymorphism with significantly reduced risk of breast cancer in Asians (PMID:24789272)
• In this meta-analysis, SHMT1 C1420T polymorphism did not have a significant association with the risk of cancer overall. (PMID:25194438)
• SHMT1 knockdown in lung cancer cells leads to cell cycle arrest and to p53-dependent apoptosis. (PMID:25412303)
• SHMT1 exists in solution as a tetramer, both in the absence and presence of PLP, while SHMT2 undergoes a dimer-to-tetramer transition. (PMID:25619277)
• our meta-analysis suggested that the SHMT1 C1420T polymorphism was associated with decreased risk of breast cancer. (PMID:26125758)
• an association between MTRR 66 and SHMT1 1420 polymorphisms and spaceflight-induced vision changes (PMID:26316272)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	shmt1	ENSDARG00000052816
mus_musculus	Shmt1	ENSMUSG00000020534
rattus_norvegicus	Shmt1	ENSRNOG00000005275
drosophila_melanogaster	Shmt	FBGN0029823
caenorhabditis_elegans		WBGENE00003214

Paralogs (1): SHMT2 (ENSG00000182199)

Protein

Protein identifiers

Serine hydroxymethyltransferase, cytosolic — P34896 (reviewed: P34896)

Alternative names: Glycine hydroxymethyltransferase, L-allo-threonine/L-threonine aldolase SHMT1, Serine methylase

All UniProt accessions (3): P34896, J3KRK5, J3KRZ5

UniProt curated annotations — full annotation on UniProt →

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. 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. 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. 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. 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. 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. 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.

Subunit / interactions. Homotetramer comprising two obligate dimers. Identified in complex with ABRAXAS2 and the other subunits of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Part of the de novo thymidylate synthesis complex composed at least by SHMT1, DHFR and TYMS. Interacts with DHFR and TYMS; this interaction is DNA-dependent and mediates TYMS and DHFR co-localization with LMNB1.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Ubiquitination at Lys-39 leads to proteasomal degradation. UBE2N/UBC13-mediated ubiquitination stabilize SHMT1 within the nucleus and signals nuclear export of SHMT1 through ‘Lys-63’-specific ubiquitin linkage. ‘Lys-63’ polyubiquitination is cell cycle- and compartment-specific. Modification by UBE2I/UBC9 or UBE2N/UBC13 compete for SHMT1 modification, leading to either degradation in the nucleus or nuclear export, respectively. In the cytoplasm, SHMT1 degradation is facilitated by ‘Lys-48’ ubiquitin linkages, whereas in the nucleus, ‘Lys-63’-linked ubiquitination prevents degradation. Sumoylated at either Lys-38 or Lys-39. 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. UBE2I-mediated conjugation to SUMO2/3 in the nucleus allows nuclear degradation. Deamidation of asparagine produces alternatively aspartate or isoaspartate, which in turn can be converted to aspartate through carboxylmethylation/demethylation.

Activity regulation. Inhibited by tetrahydrofolate concentrations above 40 uM. 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. RNA binding induces a conformational reorganization of SHMT1 tetrameric subunits, resulting in distinct combinations of open and closed active site conformations.

Domain organisation. The main RNA docking site includes a flap motif and the C-terminal domain.

Pathway. One-carbon metabolism; tetrahydrofolate interconversion. Amino-acid degradation.

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

Similarity. Belongs to the SHMT family.

Isoforms (4)

UniProt ID	Names	Canonical?
P34896-1	1	yes
P34896-2	2
P34896-3	3
P34896-4	4

RefSeq proteins (3): NP_001268715, NP_004160, NP_683718 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001085	Ser_HO-MeTrfase	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR019798	Ser_HO-MeTrfase_PLP_BS	Binding_site
IPR039429	SHMT-like_dom	Domain
IPR049943	Ser_HO-MeTrfase-like	Family

Pfam: PF00464

Enzyme classification (BRENDA):

• EC 2.1.2.1 — glycine hydroxymethyltransferase (BRENDA: 81 organisms, 196 substrates, 226 inhibitors, 227 Km, 174 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-SERINE	0.0044–65.3	78
TETRAHYDROFOLATE	0.003–3.4	71
L-SER	0.13–11.2	17
5,10-METHYLENETETRAHYDROFOLATE	0.18–0.98	12
GLYCINE	0.25–5.87	11
(6S)-TETRAHYDROFOLATE	0.002–0.021	4
DL-PHENYLSERINE	0.27–131.6	4
D-SERINE	0.071–55	3
DL-3-PHENYLSERINE	57.86–61.95	2
SERINE	0.43–1.6	2
TETRAHYDROMETHANOPTERIN	0.1	1

Catalyzed reactions (Rhea), 6 shown:

• (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + glycine + H2O = (6S)-5,6,7,8-tetrahydrofolate + L-serine (RHEA:15481)
• L-threonine = acetaldehyde + glycine (RHEA:19625)
• L-threo-3-phenylserine = benzaldehyde + glycine (RHEA:21712)
• L-allo-threonine = acetaldehyde + glycine (RHEA:26209)
• (6R)-5,10-methenyltetrahydrofolate + H2O = (6S)-5-formyl-5,6,7,8-tetrahydrofolate + H(+) (RHEA:34767)
• (3S)-3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine = 4-(trimethylamino)butanal + glycine (RHEA:79695)

UniProt features (96 total): helix 24, binding site 20, strand 17, mutagenesis site 12, turn 7, cross-link 4, modified residue 3, splice variant 3, sequence variant 2, initiator methionine 1, chain 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7RJP	X-RAY DIFFRACTION	1.25
7RJL	X-RAY DIFFRACTION	1.5
1BJ4	X-RAY DIFFRACTION	2.65
6M5W	X-RAY DIFFRACTION	3.1
8R7H	ELECTRON MICROSCOPY	3.29
8XND	X-RAY DIFFRACTION	3.45
8A11	ELECTRON MICROSCOPY	3.52
6FL5	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P34896-F1	96.68	0.95

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 75 (proton donor/acceptor)

Ligand- & substrate-binding residues (20): 120; 121; 147; 148; 148; 149; 158; 203; 228; 231; 256; 303 …

Post-translational modifications (7): 6, 257, 6–7, 38, 39, 39, 271

Mutagenesis-validated functional residues (12):

Position	Phenotype
38	does not affect ubiquitination level. impairs sumoylation in vitro.
39	significantly decreases ubiquitination level. impairs sumoylation in vitro.
82	does not affect protein homotetramerization; when associated with f-83 and q-257. loss of glycine hydroxymethyltransfera
83	does not affect protein homotetramerization; when associated with a-82 and q-257. loss of glycine hydroxymethyltransfera
135	does not affect protein homotetramerization; when associated with a-137 and n-168. loss of protein homotetramerization;
137	does not affect protein homotetramerization; when associated with n-135 and n-168. loss of protein homotetramerization;
168	does not affect protein homotetramerization; when associated with n-135 and a-137. slightly decreases pyridoxal-5’-phosp
257	does not affect protein homotetramerization; when associated with a-82 and f-83. loss of glycine hydroxymethyltransferas
279	loss of rna binding. decreases ability of rna to interfere with folate binding. significantly impairs the ability of rna
282	decreases rna binding. decreases ability of rna to interfere with folate binding. decreases the ability of rna to inhibi
393	decreases rna binding; when associated with s-397. decreases ability of rna to interfere with folate binding; when assoc
397	decreases rna binding; when associated with s-393. decreases ability of rna to interfere with folate binding; when assoc

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-196757	Metabolism of folate and pterines
R-HSA-71262	Carnitine synthesis

MSigDB gene sets: 348 (showing top): MORF_MTA1, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, HORIUCHI_WTAP_TARGETS_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_RESPONSE_TO_PEPTIDE, ZHAN_MULTIPLE_MYELOMA_MF_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, MORF_RAD21, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP

GO Biological Process (18): dTMP biosynthetic process (GO:0006231), glycine metabolic process (GO:0006544), L-serine metabolic process (GO:0006563), L-serine catabolic process (GO:0006565), one-carbon metabolic process (GO:0006730), purine nucleobase biosynthetic process (GO:0009113), negative regulation of translation (GO:0017148), obsolete glycine biosynthetic process from L-serine (GO:0019264), tetrahydrofolate interconversion (GO:0035999), carnitine biosynthetic process (GO:0045329), tetrahydrofolate metabolic process (GO:0046653), folic acid metabolic process (GO:0046655), protein homotetramerization (GO:0051289), cellular response to tetrahydrofolate (GO:1904482), cellular response to leukemia inhibitory factor (GO:1990830), regulation of translation (GO:0006417), proteolysis (GO:0006508), protein deubiquitination (GO:0016579)

GO Molecular Function (18): mRNA regulatory element binding translation repressor activity (GO:0000900), glycine hydroxymethyltransferase activity (GO:0004372), threonine aldolase activity (GO:0004793), lamin binding (GO:0005521), aldehyde-lyase activity (GO:0016832), pyridoxal phosphate binding (GO:0030170), small molecule binding (GO:0036094), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), mRNA 5’-UTR binding (GO:0048027), molecular adaptor activity (GO:0060090), serine binding (GO:0070905), hydroxytrimethyllysine aldolase activity (GO:0120567), cysteine-type deubiquitinase activity (GO:0004843), protein binding (GO:0005515), peptidase activity (GO:0008233), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), extracellular exosome (GO:0070062), intracellular organelle lumen (GO:0070013)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	3
proteinogenic amino acid metabolic process	2
translation	2
folic acid-containing compound metabolic process	2
mRNA binding	2
aldehyde-lyase activity	2
protein binding	2
catalytic activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
pyrimidine deoxyribonucleoside monophosphate biosynthetic process	1
pyrimidine deoxyribonucleotide biosynthetic process	1
dTMP metabolic process	1
L-amino acid metabolic process	1
L-serine metabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
small molecule metabolic process	1
purine nucleobase metabolic process	1
nucleobase biosynthetic process	1
purine-containing compound biosynthetic process	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
one-carbon metabolic process	1
tetrahydrofolate metabolic process	1
amino-acid betaine biosynthetic process	1
carnitine metabolic process	1
dicarboxylic acid metabolic process	1
protein homooligomerization	1
protein tetramerization	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to tetrahydrofolate	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
protein metabolic process	1

Protein interactions and networks

STRING

3444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHMT1	MTHFD1	P11586	974
SHMT1	MTRR	Q9UBK8	927
SHMT1	MTHFR	P42898	913
SHMT1	MTR	Q99707	909
SHMT1	ATIC	P31939	897
SHMT1	TYMS	P04818	879
SHMT1	H7C2H4	H7C2H4	872
SHMT1	DHFR	P00374	869
SHMT1	GAPDH	P00354	864
SHMT1	P0DN79	P0DN79	863
SHMT1	MTHFD2	P13995	860
SHMT1	MTHFD1L	Q6UB35	839
SHMT1	DHFR2	Q86XF0	815
SHMT1	MTHFD2L	Q9H903	815
SHMT1	PSPH	P78330	807

IntAct

62 interactions, top by confidence:

A	B	Type	Score
SHMT1	MAPK9	psi-mi:“MI:0915”(physical association)	0.780
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
SHMT1	SHMT1	psi-mi:“MI:0915”(physical association)	0.670
DCAF7	PFDN6	psi-mi:“MI:0914”(association)	0.570
SULT1A3	SHMT1	psi-mi:“MI:0915”(physical association)	0.560
SHMT1	SULT1A3	psi-mi:“MI:0915”(physical association)	0.560
SHMT1	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
DDX6	SHMT1	psi-mi:“MI:0915”(physical association)	0.560
SHMT1	MDFI	psi-mi:“MI:0915”(physical association)	0.560
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
SAMTOR	PER1	psi-mi:“MI:0914”(association)	0.530
IDH3A	SHMT1	psi-mi:“MI:0915”(physical association)	0.460
SHMT1	IDH3A	psi-mi:“MI:0915”(physical association)	0.460
SHMT1	IDH3A	psi-mi:“MI:0403”(colocalization)	0.460
SHMT1	DEDD	psi-mi:“MI:0915”(physical association)	0.370
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NBEAL2	HAX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (115): SHMT1 (Two-hybrid), SHMT1 (Two-hybrid), SULT1A3 (Two-hybrid), ARFIP1 (Co-fractionation), ATIC (Co-fractionation), HSPE1 (Co-fractionation), ITPA (Co-fractionation), PGK2 (Co-fractionation), SHMT1 (Co-fractionation), SHMT1 (Co-fractionation), SHMT1 (Co-fractionation), SHMT1 (Co-fractionation), SHMT1 (Co-fractionation), SHMT2 (Affinity Capture-MS), DPYSL5 (Affinity Capture-MS)

ESM2 similar proteins: A0B5D0, A0R2V7, A1A1V0, A2SQB8, A2SSS7, A3CVZ3, A4FWT8, A4IPA1, A6L7E4, A6UPN9, A6UUU3, A6VGH9, A7I757, A7I9Z8, A9AA73, B7GTL3, O13426, O13972, O23254, O30207, P07511, P34896, P34898, P35623, P37291, P45545, Q0W2L3, Q0W486, Q0W896, Q12W26, Q12XS4, Q1IUW9, Q2F5L3, Q2FLN5, Q2FTY4, Q46C09, Q4WXF4, Q54Z26, Q59072, Q5E9P9

Diamond homologs: A0B8J6, A1AE82, A1WVG6, A4J9B1, A4XL61, A5CYB7, A5N7P5, A7ZPZ4, A8A359, A9KSH6, B0K631, B0K742, B1I6M4, B1IVS6, B1LNK7, B1XB26, B2TXW4, B5YFZ0, B5Z123, B6I5C4, B7LDE3, B7M8A7, B7MIN5, B7MYI0, B7N6D8, B7NRK2, B7UGZ1, B8I2N8, B9E156, B9MR57, C4ZH69, C4ZXC6, O13425, O13426, O13972, O23254, O62585, P07511, P0A825, P0A826

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
MYC	“up-regulates quantity by expression”	SHMT1	“transcriptional regulation”
SHMT1	“up-regulates quantity”	glycine	“chemical modification”
SHMT1	“up-regulates quantity”	(6R)-5,10-methylenetetrahydrofolate(2-)	“chemical modification”
SHMT1	“down-regulates quantity”	3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine	“chemical modification”
SHMT1	“up-regulates quantity”	4-trimethylammoniobutanal	“chemical modification”
SHMT1	“up-regulates quantity”	“glycine zwitterion”	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cellular responses to stress	7	7.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

84 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	7
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

2320 predictions. Top by Δscore:

Variant	Effect	Δscore
17:18329272:CCTTA:C	donor_loss	1.0000
17:18329273:CTTAC:C	donor_loss	1.0000
17:18329274:TTA:T	donor_loss	1.0000
17:18329275:TA:T	donor_loss	1.0000
17:18329277:C:CT	donor_loss	1.0000
17:18329277:CCT:C	donor_gain	1.0000
17:18329387:ACCTA:A	acceptor_loss	1.0000
17:18329389:CT:C	acceptor_loss	1.0000
17:18330549:TCTCA:T	donor_loss	1.0000
17:18330550:CTCA:C	donor_loss	1.0000
17:18330551:TCAC:T	donor_loss	1.0000
17:18330552:CA:C	donor_loss	1.0000
17:18330553:A:AC	donor_gain	1.0000
17:18330553:A:AT	donor_loss	1.0000
17:18330554:C:CC	donor_gain	1.0000
17:18330554:C:CT	donor_loss	1.0000
17:18330668:CCAC:C	acceptor_gain	1.0000
17:18330669:CAC:C	acceptor_gain	1.0000
17:18330669:CACC:C	acceptor_gain	1.0000
17:18330671:CCTG:C	acceptor_loss	1.0000
17:18330672:C:CG	acceptor_loss	1.0000
17:18330673:T:G	acceptor_loss	1.0000
17:18335585:C:A	donor_gain	1.0000
17:18335672:ACTCC:A	acceptor_loss	1.0000
17:18335673:CTCCT:C	acceptor_loss	1.0000
17:18335676:C:CA	acceptor_loss	1.0000
17:18335677:T:A	acceptor_loss	1.0000
17:18340038:CTCA:C	donor_loss	1.0000
17:18340039:TCA:T	donor_loss	1.0000
17:18340040:CA:C	donor_loss	1.0000

AlphaMissense

3142 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:18347560:C:T	G152E	1.000
17:18330565:G:C	N387K	0.999
17:18330565:G:T	N387K	0.999
17:18340086:C:A	K257N	0.999
17:18340086:C:G	K257N	0.999
17:18340087:T:A	K257M	0.999
17:18340245:G:C	C204W	0.999
17:18340248:G:C	S203R	0.999
17:18340248:G:T	S203R	0.999
17:18340250:T:G	S203R	0.999
17:18347556:G:C	F153L	0.999
17:18347556:G:T	F153L	0.999
17:18347558:A:G	F153L	0.999
17:18347561:C:A	G152W	0.999
17:18347564:G:C	H151D	0.999
17:18347571:G:C	H148Q	0.999
17:18347571:G:T	H148Q	0.999
17:18347578:C:T	G146E	0.999
17:18347587:A:T	L143H	0.999
17:18353697:A:G	Y73H	0.999
17:18353749:A:C	N55K	0.999
17:18353749:A:T	N55K	0.999
17:18353753:T:A	E54V	0.999
17:18353786:C:G	R43P	0.999
17:18329350:C:A	G404W	0.998
17:18329361:C:T	G400E	0.998
17:18330568:C:A	K386N	0.998
17:18330568:C:G	K386N	0.998
17:18330571:G:C	N385K	0.998
17:18330571:G:T	N385K	0.998

dbSNP variants (sampled 300 via entrez): RS1000004147 (17:18361372 C>A), RS1000260186 (17:18339637 T>G), RS1000321158 (17:18346757 G>A), RS1000330832 (17:18346991 C>G,T), RS1000350633 (17:18339811 C>T), RS1000470547 (17:18333975 G>A), RS1000533583 (17:18344618 C>A), RS1000576010 (17:18364072 G>C), RS1000736882 (17:18358736 T>C), RS1000821226 (17:18333671 T>C), RS1000871304 (17:18335692 A>T), RS1000890053 (17:18340358 T>G), RS1000982106 (17:18350351 T>A), RS1000983756 (17:18336020 T>A), RS1000987654 (17:18364302 C>G)

Disease associations

OMIM: gene MIM:182144 | disease phenotypes: MIM:606764

GenCC curated gene-disease

Mondo (1): gastrointestinal stromal tumor (MONDO:0011719)

Orphanet (1): Gastrointestinal stromal tumor (Orphanet:44890)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003566_4	Multiple sclerosis	7.000000e-12
GCST006585_2641	Blood protein levels	1.000000e-31
GCST008497_5	Change in neurofilament light levels	6.000000e-06
GCST90013663_25	Alanine aminotransferase levels	7.000000e-10
GCST90013664_85	Aspartate aminotransferase levels	3.000000e-08
GCST90020025_1408	Waist-to-hip ratio adjusted for BMI	1.000000e-12
GCST90020027_455	Waist-hip index	4.000000e-13
GCST90020029_477	Waist circumference adjusted for body mass index	4.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D046152	Gastrointestinal Stromal Tumors	C04.557.450.565.370; C06.301.371.308; C06.405.249.308

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1772927 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 55,761 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL225072	PEMETREXED	4	55,761

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1979277	Toxicity	3	methotrexate	Acute lymphoblastic leukemia
rs1979277	Efficacy	3	bevacizumab;fluorouracil;irinotecan;leucovorin	Colorectal Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1979277	SHMT1, SMCR8	3	4.00	2	bevacizumab;fluorouracil;irinotecan;leucovorin;methotrexate

Binding affinities (BindingDB)

15 measured of 16 human assays (16 total across all organisms); most potent 15 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynamide	IC50	0.4 nM	US-10077273: SHMT inhibitors
5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-cyanophenyl]pent-4-ynoic acid	IC50	1.7 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(4-hydroxybut-1-ynyl)-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	2 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-cyano-5-(5-hydroxypent-1-ynyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	2.4 nM	US-10077273: SHMT inhibitors
2-[5-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(trifluoromethyl)phenyl]pent-4-ynoylamino]-2-methylpropanoic acid	IC50	4 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(hydroxymethyl)-5-phenylphenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	5 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(5-aminopent-1-ynyl)-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	8 nM	US-10077273: SHMT inhibitors
6-amino-3-methyl-4-propan-2-yl-4-[3-pyrrolidin-1-yl-5-(trifluoromethyl)phenyl]-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	13 nM	US-10077273: SHMT inhibitors
2-[3-[3-(6-amino-5-cyano-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazol-4-yl)-5-(hydroxymethyl)phenyl]phenyl]acetamide	IC50	16.9 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-(hydroxymethyl)-5-(5-hydroxypent-1-ynyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	17 nM	US-10077273: SHMT inhibitors
6-amino-4-[3-chloro-5-(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	20 nM	US-10077273: SHMT inhibitors
6-amino-4-[3,5-bis(trifluoromethyl)phenyl]-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	21 nM	US-10077273: SHMT inhibitors
6-amino-4-(3,5-dichlorophenyl)-3-methyl-4-propan-2-yl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	67 nM	US-10077273: SHMT inhibitors
6-amino-4-[3,5-bis(trifluoromethyl)phenyl]-4-cyclobutyl-3-methyl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	206 nM	US-10077273: SHMT inhibitors
6-amino-4-cyclobutyl-4-(3,5-dichlorophenyl)-3-methyl-2,3,3a,7a-tetrahydro-1H-pyrano[2,3-c]pyrazole-5-carbonitrile	IC50	593 nM	US-10077273: SHMT inhibitors

ChEMBL bioactivities

77 potent at pChembl≥5 of 103 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.77	IC50	0.17	nM	CHEMBL5945752
9.40	IC50	0.4	nM	CHEMBL5747977
9.40	IC50	0.4	nM	CHEMBL6041327
9.19	IC50	0.65	nM	CHEMBL5748724
9.10	IC50	0.79	nM	CHEMBL5748724
9.10	IC50	0.8	nM	CHEMBL5951491
9.00	IC50	1	nM	CHEMBL5796912
8.85	IC50	1.4	nM	CHEMBL5747977
8.77	IC50	1.7	nM	CHEMBL6041327
8.77	IC50	1.7	nM	CHEMBL5952857
8.70	IC50	2	nM	CHEMBL5860275
8.70	IC50	2	nM	CHEMBL6026678
8.62	IC50	2.4	nM	CHEMBL5952857
8.40	IC50	4	nM	CHEMBL6026678
8.40	IC50	4	nM	CHEMBL5860275
8.30	IC50	5	nM	CHEMBL5852298
8.30	IC50	5	nM	CHEMBL6065909
8.12	IC50	7.5	nM	CHEMBL5978303
8.11	IC50	7.8	nM	CHEMBL5903310
8.10	IC50	8	nM	CHEMBL5843823
7.89	IC50	13	nM	CHEMBL4083734
7.89	IC50	13	nM	CHEMBL6065909
7.82	IC50	15	nM	CHEMBL5872419
7.77	IC50	17	nM	CHEMBL5743786
7.77	IC50	16.9	nM	CHEMBL5903310
7.72	IC50	19	nM	CHEMBL5743786
7.70	IC50	20	nM	CHEMBL6001953
7.68	IC50	21	nM	CHEMBL5852298
7.57	IC50	27	nM	CHEMBL5852298
7.46	IC50	35	nM	CHEMBL6001953
7.38	IC50	42	nM	CHEMBL5973762
7.37	IC50	43	nM	CHEMBL5843823
7.22	Ki	60	nM	CHEMBL5438587
7.18	IC50	66	nM	CHEMBL4083734
7.17	IC50	67	nM	CHEMBL5741507
7.00	IC50	100	nM	CHEMBL6001953
6.92	Ki	120	nM	CHEMBL5429283
6.88	IC50	131	nM	CHEMBL5741507
6.78	IC50	168	nM	CHEMBL5955032
6.69	IC50	206	nM	CHEMBL5955032
6.66	Ki	220	nM	CHEMBL5440815
6.40	IC50	400	nM	CHEMBL5935551
6.40	IC50	400	nM	CHEMBL5811106
6.30	IC50	500	nM	CHEMBL5749700
6.23	IC50	593	nM	CHEMBL4083506
6.12	IC50	756	nM	CHEMBL5811106
6.10	Ki	790	nM	CHEMBL5408906
6.05	Ki	900	nM	CHEMBL5431881
5.98	Ki	1040	nM	CHEMBL5417651
5.98	Ki	1040	nM	CHEMBL5402700

PubChem BioAssay actives

13 with measured affinity, of 23 total; 13 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[4-[5-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]benzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.0600	uM
(2S)-2-[[5-[5-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]thiophene-2-carbonyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.1200	uM
(2S)-2-[[4-[5-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.2200	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.7900	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]benzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.9000	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]benzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	1.0400	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	1.0400	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	1.1100	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	1.2500	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propoxy]benzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	1.5300	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2,6-difluorobenzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	3.1200	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propylsulfanyl]benzoyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	7.1000	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	2011535: Binding affinity to N-terminal 6His-tagged full length truncated SHMT1 (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	9.1900	uM

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	4
bisphenol A	affects expression, decreases expression	3
sodium arsenite	decreases expression, increases expression	3
Arsenic Trioxide	increases degradation, increases expression	3
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases expression	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Cyclosporine	decreases expression	3
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
Acetaminophen	decreases expression, increases expression	2
Acrolein	increases abundance, affects cotreatment, increases expression	2
Folic Acid	affects expression, decreases expression	2
Ozone	affects cotreatment, increases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	decreases expression, increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
tert-Butylhydroperoxide	decreases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1776086	Binding	Binding affinity to human recombinant Serine hydroxymethyltransferase, cytosolic by isothermal titration calorimetry	In silico and in vitro validation of serine hydroxymethyltransferase as a chemotherapeutic target of the antifolate drug pemetrexed. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TL00	HAP1 SHMT1 (-) 1	Cancer cell line	Male
CVCL_TL01	HAP1 SHMT1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00171977	PHASE4	COMPLETED	Post-Marketing Clinical Study of Postoperative Adjuvant Therapy With Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT00510354	PHASE4	COMPLETED	Treatment of Patients With Everolimus and Imatinib Mesylate Who Have Progressive Gastro Intestinal Stromal Tumors (GIST) and Are Resistant to Imatinib Mesylate
NCT00756509	PHASE4	COMPLETED	Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT02800330	PHASE4	COMPLETED	The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib
NCT04825574	PHASE4	COMPLETED	Study for Patients Previously Treated in Avapritinib Clinical Trials
NCT00009906	PHASE3	TERMINATED	Comparison of Two Different Doses of STI571 in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00041197	PHASE3	COMPLETED	Imatinib Mesylate in Treating Patients With Primary Gastrointestinal Stromal Tumor That Has Been Completely Removed By Surgery
NCT00075218	PHASE3	COMPLETED	A Study To Assess The Safety And Efficacy Of SU11248 In Patients With Gastrointestinal Stromal Tumor(GIST)
NCT00103168	PHASE3	COMPLETED	Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor
NCT00293124	PHASE3	COMPLETED	Open-label Trial of GlivecWith Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors
NCT00324987	PHASE3	TERMINATED	Imatinib Mesylate With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00372567	PHASE3	TERMINATED	Safety And Effectiveness Of Daily Dosing With Sunitinib Or Imatinib In Patients With Gastrointestinal Stromal Tumors
NCT00471328	PHASE3	COMPLETED	Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib
NCT00685828	PHASE3	UNKNOWN	Imatinib Mesylate in Treating Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumor
NCT00688766	PHASE3	TERMINATED	Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib
NCT00751036	PHASE3	TERMINATED	Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
NCT00785785	PHASE3	COMPLETED	A Study of Nilotinib Versus Imatinib in GIST Patients
NCT00812240	PHASE3	TERMINATED	Masitinib in First Line Treatment of Gastro-Intestinal Stromal Tumor (GIST)
NCT00956072	PHASE3	TERMINATED	Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate
NCT01031628	PHASE3	TERMINATED	Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients
NCT01151852	PHASE3	COMPLETED	Rechallenge of Imatinib in GIST Having no Effective Treatment: RIGHT
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01271712	PHASE3	COMPLETED	Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
NCT01289028	PHASE3	COMPLETED	Efficacy of Nilotinib in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Imatinib and Sunitinib.
NCT01462994	PHASE3	COMPLETED	Detection of CF-DNA in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT01694277	PHASE3	COMPLETED	Masitinib in Patients With Gastrointestinal Stromal Tumour After Progression With Imatinib
NCT02260505	PHASE3	COMPLETED	Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)
NCT02576080	PHASE3	UNKNOWN	Efficacy of Imatinib in Patients With Intermediate-risk Gastrointestinal Stromal Tumor With a High-risk Genomic Grade Index
NCT02866045	PHASE3	UNKNOWN	EUS-FNB vs. Single-incision Needle-knife (SINK) Biopsy for Gastrointestinal SELs
NCT03353753	PHASE3	COMPLETED	Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies
NCT03426722	PHASE3	COMPLETED	L-carnitine vs Placebo for the Treatment of Muscle Cramps After Imatinib in Gastrointestinal Stromal Tumors
NCT03465722	PHASE3	COMPLETED	(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST
NCT03673501	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib
NCT04409223	PHASE3	TERMINATED	Efficacy and Safety of Famitinib Versus Sunitinib in the Treatment of Advanced Gastrointestinal Stromal Tumour Patients After Failure of Imatinib
NCT05208047	PHASE3	ACTIVE_NOT_RECRUITING	(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors
NCT05734105	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Patients With Advanced GIST With Specific KIT Exon Mutations Who Were Previously Treated With Imatinib
NCT06640361	PHASE3	RECRUITING	A Study of Olverembatinib in SDH-deficient GIST.
NCT07585266	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (StrateGIST Frontline)
NCT00003939	PHASE2	COMPLETED	Ecteinascidin 743 in Treating Patients With Advanced Soft Tissue Sarcoma