GART

Summary

GART (phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase, HGNC:4163) is a protein-coding gene on chromosome 21q22.11, encoding Trifunctional purine biosynthetic protein adenosine-3 (P22102). Trifunctional enzyme that catalyzes three distinct reactions as part of the ‘de novo’ inosine monophosphate biosynthetic pathway. It is a selective cancer dependency (DepMap: 32.4% of cell lines).

The protein encoded by this gene is a trifunctional polypeptide. It has phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase activity which is required for de novo purine biosynthesis. This enzyme is highly conserved in vertebrates. Alternative splicing of this gene results in two transcript variants encoding different isoforms.

Source: NCBI Gene 2618 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 147 total — 2 pathogenic, 2 likely-pathogenic
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 32.4% of screened cell lines
• MANE Select transcript: NM_000819

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4163
Approved symbol	GART
Name	phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	GARS-AIRS-GART
Ensembl gene	ENSG00000159131
Ensembl biotype	protein_coding
OMIM	138440
Entrez	2618

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 27 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000361093, ENST00000366093, ENST00000381815, ENST00000381831, ENST00000381839, ENST00000424203, ENST00000426819, ENST00000430874, ENST00000438059, ENST00000441403, ENST00000460305, ENST00000466882, ENST00000467575, ENST00000476524, ENST00000482663, ENST00000487155, ENST00000488791, ENST00000497313, ENST00000880373, ENST00000880374, ENST00000880375, ENST00000880376, ENST00000880377, ENST00000880378, ENST00000880379, ENST00000880380, ENST00000880381, ENST00000880382, ENST00000880383, ENST00000880384, ENST00000880385, ENST00000880386, ENST00000935277, ENST00000935278, ENST00000935279, ENST00000935280, ENST00000962328

RefSeq mRNA: 4 — MANE Select: NM_000819 NM_000819, NM_001136005, NM_001136006, NM_175085

CCDS: CCDS13627, CCDS13628

Canonical transcript exons

ENST00000381815 — 22 exons

Exon	Start	End
ENSE00001232541	33542065	33542117
ENSE00003466855	33528850	33528937
ENSE00003468374	33505974	33506104
ENSE00003468726	33520364	33520562
ENSE00003481319	33528519	33528604
ENSE00003507973	33504412	33504527
ENSE00003513650	33528167	33528335
ENSE00003513723	33517357	33517608
ENSE00003539927	33524769	33525000
ENSE00003564138	33539171	33539356
ENSE00003609172	33520906	33521015
ENSE00003622385	33532345	33532456
ENSE00003636687	33531489	33531557
ENSE00003645473	33511252	33511458
ENSE00003660742	33535225	33535320
ENSE00003674151	33522188	33522282
ENSE00003675443	33516989	33517141
ENSE00003680855	33509783	33509920
ENSE00003687543	33505561	33505702
ENSE00003784675	33530759	33530884
ENSE00003786797	33534579	33534753
ENSE00003841273	33503933	33504315

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 94.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.9761 / max 478.2267, expressed in 1820 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190256	41.5535	1817
190258	5.1660	1626
190259	2.7488	1187
190260	1.0729	525
190257	0.4350	237

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	94.71	gold quality
ganglionic eminence	UBERON:0004023	94.39	gold quality
rectum	UBERON:0001052	94.25	gold quality
cortical plate	UBERON:0005343	94.25	gold quality
adrenal tissue	UBERON:0018303	94.21	gold quality
smooth muscle tissue	UBERON:0001135	93.63	gold quality
colonic epithelium	UBERON:0000397	93.06	gold quality
body of pancreas	UBERON:0001150	92.91	gold quality
mucosa of stomach	UBERON:0001199	92.19	gold quality
trabecular bone tissue	UBERON:0002483	92.06	gold quality
islet of Langerhans	UBERON:0000006	91.73	gold quality
pancreas	UBERON:0001264	91.54	gold quality
tonsil	UBERON:0002372	91.54	gold quality
omental fat pad	UBERON:0010414	91.46	gold quality
peritoneum	UBERON:0002358	91.44	gold quality
lymph node	UBERON:0000029	91.34	gold quality
calcaneal tendon	UBERON:0003701	91.31	gold quality
right ovary	UBERON:0002118	91.28	gold quality
cauda epididymis	UBERON:0004360	91.15	gold quality
right adrenal gland	UBERON:0001233	91.09	gold quality
stromal cell of endometrium	CL:0002255	91.08	gold quality
embryo	UBERON:0000922	91.00	gold quality
endothelial cell	CL:0000115	90.99	silver quality
right coronary artery	UBERON:0001625	90.89	gold quality
esophagus mucosa	UBERON:0002469	90.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.75	gold quality
left coronary artery	UBERON:0001626	90.71	gold quality
esophagus	UBERON:0001043	90.70	gold quality
stomach	UBERON:0000945	90.68	gold quality
right adrenal gland cortex	UBERON:0035827	90.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.55
E-CURD-112	yes	7.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, TFCP2

miRNA regulators (miRDB)

9 targeting GART, 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-545-3P	99.95	70.74	2783
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-374B-3P	98.63	68.24	1360
HSA-MIR-6776-3P	98.38	66.34	655
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-4330	95.44	66.39	993
HSA-MIR-3174	94.63	63.64	577

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 32.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• The pH-dependent activity in human GART is due to its inability to bind the substrate, beta-glycinamide ribonucleotide, at low pH on the basis of structural studies at high and low pH. (PMID:12450384)
• Substrate/cosubstrate flexibility and cosubstrate preactivation are critical for the catalytic mechanism of human GART (PMID:16026156)
• The Expression of baseline GARTF tended to be higher in responders but this association was not significant. (PMID:16467096)
• Site-directed mutagenesis was employed to probe the role of the strictly conserved active site residues, N106, H108, and D144, and the semiconserved K170 in substrate binding and catalysis by glycinamide ribonucleotide transformylase (GART) . (PMID:17198385)
• CP2/LBP-1c/LSF as a factor that likely mediates enhanced transcription of GARS-AIRS-GART in Down syndrome-related Alzheimer disease. (PMID:17902044)
• Performed phylogenetic analysis and report that murine, bovine and chimpanzee sequences are the nearest neighbors of human GARS-AIRS-GART and that endo-duplication of the AIRS protein is restricted to insect orthologs. (PMID:19301155)
• GART has an approximate seesaw geometry where terminal enzyme units display high mobility owing to flexible linker segments. (PMID:20631005)
• Using the SNaPshot assay, evidence presented for allelic nondisjunction at rs363506 in the GRIK1 gene and rs2834235 and rs7283354 in the GARS-AIRS-GART gene in Down syndrome in India. (PMID:22931243)
• High-resolution structural data for GART (transformylase domain; purN) reveal new binding mode for lipophilic diastereoisomer inhibitors of GART, folate analogs with anti-leukemic activity. (PMID:23869564)
• The current results showed that GART expression was associated with glioma grade and that high GART protein expression might be related to poor outcome. (PMID:24444710)
• our clinical and in vitro data indicate that GART expression may be one of the causative factors for a poor prognosis in hepatocellular carcinoma. (PMID:24830618)
• most significant association was detected for GART rs8971. Compared with individuals with the TT genotype, the age- and sex-adjusted odds ratio (OR) for developing HCC was 1.44 (95% confidence interval (CI): 1.03-2.02) among those with the CC genotype (PMID:25318605)
• The minor A allele of rs7279549 of GART is a functional risk factor for congenital heart disease in Shandong population. (PMID:27659940)
• GART expression is up-regulated in patients with active colitis. (PMID:27718035)
• The transcriptome profile of human trisomy 21 blood cells. (PMID:33933170)
• VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression. (PMID:35434822)
• GART Functions as a Novel Methyltransferase in the RUVBL1/beta-Catenin Signaling Pathway to Promote Tumor Stemness in Colorectal Cancer. (PMID:37439412)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gart	ENSDARG00000101089
mus_musculus	Gart	ENSMUSG00000022962
rattus_norvegicus	Gart	ENSRNOG00000028292
drosophila_melanogaster	Gart	FBGN0000053
caenorhabditis_elegans		WBGENE00018174

Protein

Protein identifiers

Trifunctional purine biosynthetic protein adenosine-3 — P22102 (reviewed: P22102)

All UniProt accessions (7): C9JBJ1, C9JKQ7, C9JTV6, C9JZG2, P22102, F8WD69, H7C366

UniProt curated annotations — full annotation on UniProt →

Function. Trifunctional enzyme that catalyzes three distinct reactions as part of the ‘de novo’ inosine monophosphate biosynthetic pathway.

Subunit / interactions. Homodimer.

Cofactor. Binds 1 magnesium or manganese ion per subunit.

Domain organisation. The N-terminal ATP-grasp domain carries the phosphoribosylamine–glycine ligase activity. The central AIRS domain carries the phosphoribosylformylglycinamidine cyclo-ligase activity. The C-terminal GART domain carries the phosphoribosylglycinamide formyltransferase activity.

Pathway. Purine metabolism; IMP biosynthesis via de novo pathway; 5-amino-1-(5-phospho-D-ribosyl)imidazole from N(2)-formyl-N(1)-(5-phospho-D-ribosyl)glycinamide: step 2/2. Purine metabolism; IMP biosynthesis via de novo pathway; N(1)-(5-phospho-D-ribosyl)glycinamide from 5-phospho-alpha-D-ribose 1-diphosphate: step 2/2. Purine metabolism; IMP biosynthesis via de novo pathway; N(2)-formyl-N(1)-(5-phospho-D-ribosyl)glycinamide from N(1)-(5-phospho-D-ribosyl)glycinamide (10-formyl THF route): step 1/1.

Similarity. In the N-terminal section; belongs to the GARS family. In the central section; belongs to the AIR synthase family. In the C-terminal section; belongs to the GART family.

Isoforms (2)

UniProt ID	Names	Canonical?
P22102-1	Long	yes
P22102-2	Short

RefSeq proteins (4): NP_000810, NP_001129477, NP_001129478, NP_780294 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000115	PRibGlycinamide_synth	Family
IPR001555	GART_AS	Active_site
IPR002376	Formyl_transf_N	Domain
IPR004607	GART	Family
IPR004733	PurM_cligase	Family
IPR010918	PurM-like_C_dom	Domain
IPR011054	Rudment_hybrid_motif	Homologous_superfamily
IPR011761	ATP-grasp	Domain
IPR013815	ATP_grasp_subdomain_1	Homologous_superfamily
IPR016185	PreATP-grasp_dom_sf	Homologous_superfamily
IPR016188	PurM-like_N	Domain
IPR020559	PRibGlycinamide_synth_CS	Conserved_site
IPR020560	PRibGlycinamide_synth_C-dom	Domain
IPR020561	PRibGlycinamid_synth_ATP-grasp	Domain
IPR020562	PRibGlycinamide_synth_N	Domain
IPR036477	Formyl_transf_N_sf	Homologous_superfamily
IPR036676	PurM-like_C_sf	Homologous_superfamily
IPR036921	PurM-like_N_sf	Homologous_superfamily
IPR037123	PRibGlycinamide_synth_C_sf	Homologous_superfamily

Pfam: PF00551, PF00586, PF01071, PF02769, PF02843, PF02844

Enzyme classification (BRENDA):

• EC 2.1.2.2 — phosphoribosylglycinamide formyltransferase 1 (BRENDA: 21 organisms, 51 substrates, 166 inhibitors, 83 Km, 23 kcat entries)
• EC 6.3.4.13 — phosphoribosylamine-glycine ligase (BRENDA: 31 organisms, 18 substrates, 4 inhibitors, 19 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

31 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BETA-GLYCINAMIDE RIBONUCLEOTIDE	0.0011–33	30
10-FORMYL-5,8-DIDEAZAFOLATE	0.0001–33	24
N10-FORMYL-5,8-DIDEAZAFOLATE	0.0211–0.099	4
5’-PHOSPHORIBOSYLGLYCINAMIDE	0.0025–0.13	4
ATP	0.056–1.01	4
GLY	0.042–0.27	4
CARBOCYCLIC BETA-GLYCINAMIDE RIBONUCLEOTIDE	0.0036–0.0465	3
L-(-)-10-FORMYLTETRAHYDROFOLATE	0.0008–0.0068	3
(6R)-N10-FORMYLTETRAHYDROFOLATE	0.0775–0.0848	2
GLYCINAMIDE RIBONUCLEOTIDE	0.01–0.4	2
N10-FORMYLDIDEAZAFOLATE	0.0167–0.0365	2
5,8-DIDEAZAFOLATE	0.019	1
ACETATE	0.0037	1
ATP	0.0774	1
CARBOCYCLIC GLYCINAMIDE RIBONUCLEOTIDE	0.018	1

Catalyzed reactions (Rhea), 3 shown:

• N(1)-(5-phospho-beta-D-ribosyl)glycinamide + (6R)-10-formyltetrahydrofolate = N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide + (6S)-5,6,7,8-tetrahydrofolate + H(+) (RHEA:15053)
• 5-phospho-beta-D-ribosylamine + glycine + ATP = N(1)-(5-phospho-beta-D-ribosyl)glycinamide + ADP + phosphate + H(+) (RHEA:17453)
• 2-formamido-N(1)-(5-O-phospho-beta-D-ribosyl)acetamidine + ATP = 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole + ADP + phosphate + H(+) (RHEA:23032)

UniProt features (123 total): helix 41, strand 41, binding site 12, turn 9, modified residue 7, sequence variant 5, region of interest 2, initiator methionine 1, chain 1, site 1, domain 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

40 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4ZZ1	X-RAY DIFFRACTION	1.35
4ZZ2	X-RAY DIFFRACTION	1.45
4EW1	X-RAY DIFFRACTION	1.52
4ZYZ	X-RAY DIFFRACTION	1.6
4EW2	X-RAY DIFFRACTION	1.6
4ZYX	X-RAY DIFFRACTION	1.65
4ZZ0	X-RAY DIFFRACTION	1.65
4EW3	X-RAY DIFFRACTION	1.7
4ZYT	X-RAY DIFFRACTION	1.7
1MEO	X-RAY DIFFRACTION	1.72
4ZYY	X-RAY DIFFRACTION	1.85
4ZYU	X-RAY DIFFRACTION	1.95
1NJS	X-RAY DIFFRACTION	1.98
7JG0	X-RAY DIFFRACTION	1.98
1MEJ	X-RAY DIFFRACTION	2
1RC0	X-RAY DIFFRACTION	2.05
4ZYW	X-RAY DIFFRACTION	2.05
4ZYV	X-RAY DIFFRACTION	2.05
8FDY	X-RAY DIFFRACTION	2.06
1ZLY	X-RAY DIFFRACTION	2.07
8FDX	X-RAY DIFFRACTION	2.07
8FJW	X-RAY DIFFRACTION	2.08
7JG3	X-RAY DIFFRACTION	2.09
1RBZ	X-RAY DIFFRACTION	2.1
2V9Y	X-RAY DIFFRACTION	2.1
5J9F	X-RAY DIFFRACTION	2.1
1RBY	X-RAY DIFFRACTION	2.1
1RBQ	X-RAY DIFFRACTION	2.1
8FJX	X-RAY DIFFRACTION	2.17
1ZLX	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22102-F1	92.81	0.85

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 (2): 951 (raises pka of active site his); 915 (proton donor)

Ligand- & substrate-binding residues (12): 288; 290; 818–820; 871; 896–899; 913; 947–951; 977–980; 190–193; 197; 220; 229

Post-translational modifications (7): 2, 10, 350, 440, 682, 796, 802

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73817	Purine ribonucleoside monophosphate biosynthesis

MSigDB gene sets: 290 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_METENCEPHALON_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MODULE_56, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (12): brainstem development (GO:0003360), purine nucleotide biosynthetic process (GO:0006164), GMP biosynthetic process (GO:0006177), ‘de novo’ IMP biosynthetic process (GO:0006189), purine ribonucleoside monophosphate biosynthetic process (GO:0009168), cerebellum development (GO:0021549), cerebral cortex development (GO:0021987), ‘de novo’ AMP biosynthetic process (GO:0044208), adenine biosynthetic process (GO:0046084), ‘de novo’ XMP biosynthetic process (GO:0097294), biosynthetic process (GO:0009058), purine nucleobase biosynthetic process (GO:0009113)

GO Molecular Function (10): phosphoribosylamine-glycine ligase activity (GO:0004637), phosphoribosylformylglycinamidine cyclo-ligase activity (GO:0004641), phosphoribosylglycinamide formyltransferase activity (GO:0004644), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), transferase activity (GO:0016740), ligase activity (GO:0016874), ligase activity, forming carbon-nitrogen bonds (GO:0016879)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
purine-containing compound biosynthetic process	2
catalytic activity	2
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside monophosphate biosynthetic process	1
GMP metabolic process	1
IMP biosynthetic process	1
purine nucleoside monophosphate biosynthetic process	1
ribonucleoside monophosphate biosynthetic process	1
purine ribonucleoside monophosphate metabolic process	1
metencephalon development	1
pallium development	1
AMP biosynthetic process	1
purine nucleobase biosynthetic process	1
adenine metabolic process	1
XMP biosynthetic process	1
metabolic process	1
purine nucleobase metabolic process	1
nucleobase biosynthetic process	1
ligase activity, forming carbon-nitrogen bonds	1
cyclo-ligase activity	1
hydroxymethyl-, formyl- and related transferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
ligase activity	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

5474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GART	PPAT	Q06203	978
GART	PFAS	O15067	977
GART	MTHFD1	P11586	953
GART	MTHFD2	P13995	949
GART	DONSON	Q9NYP3	931
GART	PAICS	P22234	922
GART	ATIC	P31939	916
GART	DHFR2	Q86XF0	881
GART	DHFR	P00374	876
GART	TYMS	P04818	873
GART	ALDH1L1	O75891	826
GART	GMPS	P49915	785
GART	IFNAR1	P17181	762
GART	ADSL	P30566	760
GART	IL10RB	Q08334	754

IntAct

95 interactions, top by confidence:

A	B	Type	Score
NRBP1	TSC22D2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
INPP5K	GART	psi-mi:“MI:0914”(association)	0.640
ARHGEF18	GART	psi-mi:“MI:0915”(physical association)	0.400
SIRT2	GART	psi-mi:“MI:0915”(physical association)	0.400
PXN	GART	psi-mi:“MI:0915”(physical association)	0.370
GART	KPNA2	psi-mi:“MI:0915”(physical association)	0.370
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Bmpr1a	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MYO19	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Bag2		psi-mi:“MI:0914”(association)	0.350
NCBP1	TRRAP	psi-mi:“MI:0914”(association)	0.350
Calml3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
DBN1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
ATL3	SNX14	psi-mi:“MI:0914”(association)	0.350
Myh9	GOSR1	psi-mi:“MI:0914”(association)	0.350
NES	RPL10	psi-mi:“MI:0914”(association)	0.350
DNAJC7	HSPA8	psi-mi:“MI:0914”(association)	0.350
PPIA		psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
	TUBA4A	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
COX15	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350

BioGRID (299): GART (Affinity Capture-MS), GART (Affinity Capture-MS), ADSL (Co-fractionation), LOC101930400 (Co-fractionation), AKR1C2 (Co-fractionation), ARFIP1 (Co-fractionation), EIF4H (Co-fractionation), GART (Co-fractionation), GART (Co-fractionation), GART (Co-fractionation), GART (Co-fractionation), GART (Co-fractionation), GART (Co-fractionation), GART (Co-fractionation), GART (Co-fractionation)

ESM2 similar proteins: A2XNR6, A5A6P1, A5GFY8, A8E657, B0X4N8, D4AAT7, F1RKQ4, O04130, O08651, O43175, O49485, O65361, O81852, O95396, P13803, P20409, P21872, P22102, P32232, P35520, P37142, P49079, P49080, P54887, P54888, Q3LXA3, Q42586, Q42806, Q42942, Q4KLZ6, Q58DK4, Q58H57, Q59A32, Q5EAD2, Q5R7M2, Q60HD7, Q61753, Q64737, Q75LJ3, Q8AWD2

Diamond homologs: A2SQ86, A3CU83, A4FZB0, A5UMK4, A6US04, A6VJ27, A7I6J7, A9A6Q7, B4REI0, C5A4U0, G8EWC8, O27494, O58061, O66949, P00967, P0DD58, P0DD59, P12039, P15640, P16340, P20772, P21872, P22102, P26977, P43845, P52420, P57829, P65894, P65895, P65896, P9WHM8, P9WHM9, Q0W6Q4, Q12X37, Q26255, Q2NI86, Q46482, Q465Q9, Q50144, Q54GJ2

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
pemetrexed	down-regulates	GART	“chemical inhibition”
“pemetrexed disodium”	“down-regulates activity”	GART	“chemical inhibition”
GART	“down-regulates quantity”	5-phospho-beta-D-ribosylaminium(1-)	“chemical modification”
GART	“down-regulates quantity”	glycine	“chemical modification”
GART	“up-regulates quantity”	N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	“chemical modification”
GART	“down-regulates quantity”	10-formyltetrahydrofolate(2-)	“chemical modification”
GART	“up-regulates quantity”	(6S)-5,6,7,8-tetrahydrofolate(2-)	“chemical modification”
GART	“up-regulates quantity”	N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-)	“chemical modification”
GART	“down-regulates quantity”	2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine	“chemical modification”
GART	“up-regulates quantity”	5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium	“chemical modification”
GART	“down-regulates quantity”	N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 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.

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	5	19.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	102
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1340524	GRCh37/hg19 21q22.11(chr21:34909333-34931454)x1	Pathogenic
1807761	GRCh37/hg19 21q22.11(chr21:34909697-34931454)x1	Pathogenic
2672312	NC_000021.9:g.33542069_33544417del	Likely pathogenic
916559	NM_000819.5(GART):c.1907T>G (p.Leu636Arg)	Likely pathogenic

SpliceAI

2974 predictions. Top by Δscore:

Variant	Effect	Δscore
21:33504311:TCTTC:T	acceptor_loss	1.0000
21:33504312:CTTC:C	acceptor_gain	1.0000
21:33504313:TTCC:T	acceptor_loss	1.0000
21:33504314:TCCT:T	acceptor_loss	1.0000
21:33504315:CCTG:C	acceptor_loss	1.0000
21:33504410:A:AC	donor_gain	1.0000
21:33504411:C:CC	donor_gain	1.0000
21:33504411:CAG:C	donor_gain	1.0000
21:33505972:A:AC	donor_gain	1.0000
21:33505973:C:CC	donor_gain	1.0000
21:33511248:GTA:G	donor_loss	1.0000
21:33511249:TAC:T	donor_loss	1.0000
21:33511250:A:AT	donor_loss	1.0000
21:33511293:T:TA	donor_gain	1.0000
21:33511454:GGCAT:G	acceptor_gain	1.0000
21:33511455:GCAT:G	acceptor_gain	1.0000
21:33511456:CAT:C	acceptor_gain	1.0000
21:33511456:CATC:C	acceptor_gain	1.0000
21:33511457:AT:A	acceptor_gain	1.0000
21:33511457:ATC:A	acceptor_loss	1.0000
21:33511459:C:CC	acceptor_gain	1.0000
21:33511459:CTGAA:C	acceptor_loss	1.0000
21:33511460:T:C	acceptor_loss	1.0000
21:33516983:TCTTA:T	donor_loss	1.0000
21:33516984:CTTAC:C	donor_loss	1.0000
21:33516986:TA:T	donor_loss	1.0000
21:33516987:ACCTA:A	donor_loss	1.0000
21:33516988:C:G	donor_loss	1.0000
21:33517139:CCC:C	acceptor_gain	1.0000
21:33517140:CCC:C	acceptor_gain	1.0000

AlphaMissense

6559 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:33504510:G:C	H915D	0.998
21:33504514:A:C	N913K	0.997
21:33504514:A:T	N913K	0.997
21:33505601:G:C	F895L	0.997
21:33505601:G:T	F895L	0.997
21:33505603:A:G	F895L	0.997
21:33506038:A:T	V840D	0.997
21:33506095:A:G	L821P	0.997
21:33509800:A:T	V812D	0.997
21:33504434:C:T	G940E	0.996
21:33504217:T:A	E980D	0.995
21:33504217:T:G	E980D	0.995
21:33504423:G:C	H944D	0.995
21:33504425:A:T	V943E	0.995
21:33505615:A:G	C891R	0.995
21:33506086:A:G	L824P	0.995
21:33517448:G:C	S621R	0.995
21:33517448:G:T	S621R	0.995
21:33517450:T:G	S621R	0.995
21:33504194:A:G	L988P	0.994
21:33504435:C:A	G940W	0.994
21:33505617:A:T	V890D	0.994
21:33506033:A:G	S842P	0.994
21:33509792:A:G	S815P	0.994
21:33509797:A:G	L813S	0.994
21:33509803:G:T	A811D	0.994
21:33517443:C:T	G623E	0.994
21:33530825:C:A	K219N	0.994
21:33530825:C:G	K219N	0.994
21:33504430:G:C	C941W	0.993

dbSNP variants (sampled 300 via entrez): RS1000060604 (21:33529902 A>C), RS1000074185 (21:33524130 G>A), RS1000242638 (21:33536361 T>C), RS1000326362 (21:33538407 T>A,C), RS1000483573 (21:33505244 T>C), RS1000546505 (21:33539941 C>A), RS1000614405 (21:33543950 T>A), RS1000673494 (21:33544194 A>C), RS1000726902 (21:33512982 C>G), RS1000779640 (21:33512752 C>T), RS1000792304 (21:33505670 T>C), RS1000844351 (21:33542639 C>T), RS1000864476 (21:33525870 T>C), RS1000874286 (21:33525578 G>A), RS1000968436 (21:33529200 G>GA)

Disease associations

OMIM: gene MIM:138440 | disease phenotypes: MIM:189960

GenCC curated gene-disease

Mondo (2): intellectual disability (MONDO:0001071), esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (2): Esophageal atresia (Orphanet:1199), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001729_26	Crohn’s disease	2.000000e-16
GCST002598_2	Educational attainment	3.000000e-06
GCST008479_17	Psoriasis	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3430882 (PROTEIN FAMILY), CHEMBL3885528 (PROTEIN FAMILY), CHEMBL3972 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 466,115 (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
CHEMBL34259	METHOTREXATE	4	398,396
CHEMBL34412	LOMETREXOL	2	11,958

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.1.2.- Hydroxymethyl-, formyl- and related transferases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
pemetrexed	Inhibition	5.03	pKi

Binding affinities (BindingDB)

12 measured of 21 human assays (21 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
AGF117	IC50	7 nM
AGF118	IC50	9 nM
AGF23	IC50	17 nM
(S)-2-({5-[4-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-6-yl)-butyl]-thiophene-2-carbonyl}-amino)-pentanedioicAcid	IC50	22 nM
AGF145	IC50	67 nM
AGF94	IC50	68 nM
AGF147	IC50	99 nM
1H,3H,4H,7H-2,1,3,5,7-imidazo[4,5-c][1,2,6]thiadiazine-2,2,4-trione	KI	130 nM
{[(2R,3S,4R,5R)-3,4-dihydroxy-5-(2,2,4-trioxo-1H,3H,4H,7H-2,1,3,5,7-imidazo[4,5-c][1,2,6]thiadiazin-7-yl)oxolan-2-yl]methoxy}phosphonic acid	KI	150 nM
7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H,3H,4H,7H-2,1,3,5,7-imidazo[4,5-c][1,2,6]thiadiazine-2,2,4-trione	KI	230 nM
AGF50	IC50	1070 nM
2-[(4-{2-[3-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)propyl]-1,3-dithian-2-yl}phenyl)formamido]pentanedioic acid	KI	20000 nM

ChEMBL bioactivities

156 potent at pChembl≥5 of 175 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.85	IC50	0.014	nM	CHEMBL279302
10.11	IC50	0.078	nM	CHEMBL4177183
9.85	IC50	0.14	nM	CHEMBL4162649
9.52	IC50	0.3	nM	CHEMBL4643623
9.49	IC50	0.32	nM	CHEMBL4437824
9.22	IC50	0.6	nM	CHEMBL2158681
9.15	IC50	0.7	nM	CHEMBL4465095
9.02	IC50	0.95	nM	CHEMBL4636872
9.00	IC50	1	nM	CHEMBL192632
9.00	IC50	1	nM	CHEMBL4538151
9.00	IC50	1	nM	CHEMBL3628344
8.92	IC50	1.2	nM	CHEMBL4445651
8.89	IC50	1.3	nM	CHEMBL4214638
8.77	IC50	1.7	nM	CHEMBL192632
8.75	IC50	1.79	nM	CHEMBL2158681
8.74	IC50	1.8	nM	CHEMBL4214638
8.74	IC50	1.8	nM	CHEMBL1834488
8.72	IC50	1.92	nM	CHEMBL192632
8.72	IC50	1.9	nM	CHEMBL365307
8.70	IC50	2	nM	CHEMBL1834488
8.70	IC50	2	nM	CHEMBL4557278
8.70	Ki	2	nM	CHEMBL82261
8.69	IC50	2.03	nM	CHEMBL2158682
8.68	IC50	2.11	nM	CHEMBL4471269
8.62	IC50	2.4	nM	CHEMBL3628344
8.60	IC50	2.5	nM	CHEMBL4645676
8.59	IC50	2.6	nM	CHEMBL3628346
8.58	IC50	2.64	nM	CHEMBL4437824
8.54	IC50	2.89	nM	CHEMBL3086865
8.52	Ki	3	nM	CHEMBL85436
8.50	IC50	3.13	nM	CHEMBL590740
8.47	Ki	3.4	nM	CHEMBL82181
8.46	IC50	3.46	nM	CHEMBL590740
8.46	IC50	3.5	nM	CHEMBL1834488
8.32	IC50	4.8	nM	CHEMBL4205344
8.30	IC50	4.95	nM	CHEMBL4553188
8.28	IC50	5.25	nM	CHEMBL4467936
8.27	IC50	5.35	nM	CHEMBL4638232
8.26	IC50	5.49	nM	CHEMBL3086866
8.25	IC50	5.6	nM	CHEMBL365307
8.25	IC50	5.58	nM	CHEMBL4444011
8.24	IC50	5.77	nM	LOMETREXOL
8.22	Ki	6	nM	LOMETREXOL
8.18	IC50	6.62	nM	CHEMBL4447805
8.17	IC50	6.8	nM	CHEMBL365307
8.14	IC50	7.2	nM	CHEMBL502528
8.12	IC50	7.5	nM	CHEMBL4170578
8.07	IC50	8.6	nM	CHEMBL526928
8.07	Ki	8.5	nM	CHEMBL84935
8.04	Ki	9.1	nM	CHEMBL3628346

PubChem BioAssay actives

183 with measured affinity, of 631 total; 50 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
2-[[4-[3-(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6-yl)propyl]benzoyl]amino]pentanedioic acid	72748: Inhibition of the GAR transformylase in lactobacillus casei	ic50	<0.0001	uM
2-[[4-[3-(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6-yl)-2-methylpropyl]benzoyl]amino]pentanedioic acid	72748: Inhibition of the GAR transformylase in lactobacillus casei	ic50	<0.0001	uM
2-[[4-[2-[(6S)-2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6-yl]ethylamino]benzoyl]amino]pentanedioic acid	72748: Inhibition of the GAR transformylase in lactobacillus casei	ic50	<0.0001	uM
2-[[4-[3-(2-amino-4-oxo-7,8-dihydro-3H-pteridin-6-yl)-2-methylpropyl]benzoyl]amino]pentanedioic acid	72748: Inhibition of the GAR transformylase in lactobacillus casei	ic50	<0.0001	uM
(2S)-2-[6-[[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)acetyl]amino]hexanoylamino]pentanedioic acid	1501141: Inhibition of TS/AICARFTase/GARFTase in human KB cells assessed as reduction in cell proliferation in folate free medium after 72 hrs in presence of leucovorin by MTT assay	ic50	0.0001	uM
(2S)-2-[[2-[[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)acetyl]amino]acetyl]amino]pentanedioic acid	1501141: Inhibition of TS/AICARFTase/GARFTase in human KB cells assessed as reduction in cell proliferation in folate free medium after 72 hrs in presence of leucovorin by MTT assay	ic50	0.0001	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylamino]benzoyl]amino]pentanedioic acid	1663347: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0003	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propylsulfanyl]benzoyl]amino]pentanedioic acid	1663347: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0003	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0006	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0007	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propylamino]benzoyl]amino]pentanedioic acid	1663347: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0009	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0010	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]benzoyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0010	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-2-fluorobenzoyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0010	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0012	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]pyridine-2-carbonyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0013	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0018	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]pentanedioic acid	1663347: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0019	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-3-carbonyl]amino]pentanedioic acid	695101: Inhibition of GARFTase in human IGROV1 cells assessed as reduction in [14C]glycine incorporation into [14C]formyl GAR incubated for 15 hrs in complete folate free RPMI medium in presence of 2 nM leucovorin	ic50	0.0020	uM
(2R)-2-[[5-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]-4-methylthiophene-2-carbonyl]amino]pentanedioic acid	75735: Inhibition of recombinant human Glycinamide Ribonucleotide Transformylase (GART) using N10-formyl-5,8-dideazafolate (FDDF) as the cofactor.	ki	0.0020	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-3-fluoropyridine-2-carbonyl]amino]pentanedioic acid	1513009: Inhibition of GARFTase in human IGROV1 cells assessed as decrease in incorporation of [14C(U)glycine into [14C]formyl GAR formation after 24 hrs	ic50	0.0020	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-formylamino]benzoyl]amino]pentanedioic acid	1631996: Inhibition of GARFTase in human KB cells expressing RFC/FR-alpha/PCFT assessed as decrease in incorporation of [14C(U)]-glycine into [14C]formyl GAR incubated for 1 hr followed by addition of [14C(U)]-glycine measured after 16 hrs in presence of azaserine	ic50	0.0021	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propoxy]benzoyl]amino]pentanedioic acid	1663347: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0025	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-3-carbonyl]amino]pentanedioic acid	1252444: Inhibition of GARFTase in human KB cells expressing FRalpha/PCFT/RFC assessed as incorporation of [14C(U)]-glycine into [14C]-formyl GAR preincubated for 1 hr followed by azaserine, L-glutamine, 14C(U)]-glycine addition measured after 16 hrs	ic50	0.0026	uM
(2S)-2-[7-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)heptanoylamino]pentanedioic acid	1053439: In situ inhibition of GRAFTase in human KB cells assessed as incorporation of [14C]-glycine into [14C]-formyl GAR preincubated for 30 mins followed by [14C]-glycine addition measured after 15 mins	ic50	0.0029	uM
(2R)-2-[[5-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]thiophene-2-carbonyl]amino]pentanedioic acid	75735: Inhibition of recombinant human Glycinamide Ribonucleotide Transformylase (GART) using N10-formyl-5,8-dideazafolate (FDDF) as the cofactor.	ki	0.0030	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1197489: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as incorporation of [U-14C]-glycine into [14C]-formyl glycinamide ribonucleotide incubated for 1 hr followed by [U-14C]-glycine addition measured after 16 hrs	ic50	0.0031	uM
2-[[3-[2-(2-amino-4-oxo-3,6,7,8-tetrahydropyrimido[5,4-b][1,4]thiazin-6-yl)ethyl]benzoyl]amino]pentanedioic acid	75735: Inhibition of recombinant human Glycinamide Ribonucleotide Transformylase (GART) using N10-formyl-5,8-dideazafolate (FDDF) as the cofactor.	ki	0.0034	uM
(2S)-2-[[6-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]pyridine-3-carbonyl]amino]pentanedioic acid	1380215: Inhibition of GARFTase in human KB cells assessed as decrease in [14C]formyl GAR accumulation preincubated for 30 mins followed by [14C]glycine addition measured after 15 hrs in presence of azaserine by ion-exchange chromatographic assay	ic50	0.0048	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl-(2,2,2-trifluoroacetyl)amino]benzoyl]amino]pentanedioic acid	1631996: Inhibition of GARFTase in human KB cells expressing RFC/FR-alpha/PCFT assessed as decrease in incorporation of [14C(U)]-glycine into [14C]formyl GAR incubated for 1 hr followed by addition of [14C(U)]-glycine measured after 16 hrs in presence of azaserine	ic50	0.0050	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethylsulfanyl]benzoyl]amino]pentanedioic acid	1631996: Inhibition of GARFTase in human KB cells expressing RFC/FR-alpha/PCFT assessed as decrease in incorporation of [14C(U)]-glycine into [14C]formyl GAR incubated for 1 hr followed by addition of [14C(U)]-glycine measured after 16 hrs in presence of azaserine	ic50	0.0053	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl-(2,2,2-trifluoroacetyl)amino]benzoyl]amino]pentanedioic acid	1663347: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0053	uM
(2S)-2-[8-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)octanoylamino]pentanedioic acid	1053439: In situ inhibition of GRAFTase in human KB cells assessed as incorporation of [14C]-glycine into [14C]-formyl GAR preincubated for 30 mins followed by [14C]-glycine addition measured after 15 mins	ic50	0.0055	uM
(2S)-2-[[4-[acetyl-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethyl]amino]benzoyl]amino]pentanedioic acid	1631996: Inhibition of GARFTase in human KB cells expressing RFC/FR-alpha/PCFT assessed as decrease in incorporation of [14C(U)]-glycine into [14C]formyl GAR incubated for 1 hr followed by addition of [14C(U)]-glycine measured after 16 hrs in presence of azaserine	ic50	0.0056	uM
(2S)-2-[[4-[2-[(6R)-2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid	695101: Inhibition of GARFTase in human IGROV1 cells assessed as reduction in [14C]glycine incorporation into [14C]formyl GAR incubated for 15 hrs in complete folate free RPMI medium in presence of 2 nM leucovorin	ic50	0.0058	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)ethoxy]benzoyl]amino]pentanedioic acid	1631996: Inhibition of GARFTase in human KB cells expressing RFC/FR-alpha/PCFT assessed as decrease in incorporation of [14C(U)]-glycine into [14C]formyl GAR incubated for 1 hr followed by addition of [14C(U)]-glycine measured after 16 hrs in presence of azaserine	ic50	0.0066	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3,4a-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-5-methylthiophene-2-carbonyl]amino]pentanedioic acid	1801916: GAR Transformylase Inhibition Assay from Article 10.1021/acs.biochem.6b00412: “Structural and Enzymatic Analysis of Tumor-Targeted Antifolates That Inhibit Glycinamide Ribonucleotide Formyltransferase.”	ic50	0.0070	uM
(2S)-2-[[4-[5-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)pentyl]benzoyl]amino]pentanedioic acid	362438: Inhibition of GARFTase in human KB cells assessed as inhibition of [14C]glycine incorporation into [14C]formylGAR in presence of azaserine	ic50	0.0072	uM
(2S)-2-[[4-[[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)acetyl]amino]benzoyl]amino]pentanedioic acid	1501141: Inhibition of TS/AICARFTase/GARFTase in human KB cells assessed as reduction in cell proliferation in folate free medium after 72 hrs in presence of leucovorin by MTT assay	ic50	0.0075	uM
(2S)-2-[[5-[3-[(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)sulfanyl]propyl]-3-methylthiophene-2-carbonyl]amino]pentanedioic acid	75735: Inhibition of recombinant human Glycinamide Ribonucleotide Transformylase (GART) using N10-formyl-5,8-dideazafolate (FDDF) as the cofactor.	ki	0.0085	uM
(2S)-2-[[4-[6-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)hexyl]benzoyl]amino]pentanedioic acid	362438: Inhibition of GARFTase in human KB cells assessed as inhibition of [14C]glycine incorporation into [14C]formylGAR in presence of azaserine	ic50	0.0086	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3,4a-dihydropyrrolo[2,3-d]pyrimidin-6-yl)butyl]-2-methyl-2,5-dihydrothiophene-3-carbonyl]amino]pentanedioic acid	1801916: GAR Transformylase Inhibition Assay from Article 10.1021/acs.biochem.6b00412: “Structural and Enzymatic Analysis of Tumor-Targeted Antifolates That Inhibit Glycinamide Ribonucleotide Formyltransferase.”	ic50	0.0090	uM
(2S)-2-[9-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)nonanoylamino]pentanedioic acid	1053439: In situ inhibition of GRAFTase in human KB cells assessed as incorporation of [14C]-glycine into [14C]-formyl GAR preincubated for 30 mins followed by [14C]-glycine addition measured after 15 mins	ic50	0.0096	uM
Methotrexate	1501141: Inhibition of TS/AICARFTase/GARFTase in human KB cells assessed as reduction in cell proliferation in folate free medium after 72 hrs in presence of leucovorin by MTT assay	ic50	0.0100	uM
Pemetrexed	1197489: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as incorporation of [U-14C]-glycine into [14C]-formyl glycinamide ribonucleotide incubated for 1 hr followed by [U-14C]-glycine addition measured after 16 hrs	ic50	0.0117	uM
(2S)-2-[[5-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl]thiophene-2-carbonyl]amino]hexanedioic acid	1164851: Inhibition of GARFTase in human KB cells assessed as reduction in [14C]glycine incorporation into [14C]formyl GAR incubated for 15 hrs by ion-exchange chromatography	ic50	0.0120	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)propyl-formylamino]benzoyl]amino]pentanedioic acid	1663347: Inhibition of GARFTase in human KB cells expressing RFC/FRalpha/PCFT assessed as reduction in cell growth after 96 hrs by Cell-Titer Blue assay	ic50	0.0132	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]benzoyl]amino]pentanedioic acid	349815: Inhibition of GARFTase in human KB cells assessed as inhibition of incorporation of [14C]glycine into [14C]formyl GAR after 30 mins in presence of azaserine	ic50	0.0133	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]benzoyl]amino]pentanedioic acid	349815: Inhibition of GARFTase in human KB cells assessed as inhibition of incorporation of [14C]glycine into [14C]formyl GAR after 30 mins in presence of azaserine	ic50	0.0138	uM
(2S)-2-[[5-[3-[(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)sulfanyl]propyl]-3-ethylthiophene-2-carbonyl]amino]pentanedioic acid	75735: Inhibition of recombinant human Glycinamide Ribonucleotide Transformylase (GART) using N10-formyl-5,8-dideazafolate (FDDF) as the cofactor.	ki	0.0140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	5
bisphenol A	affects expression, decreases expression	4
Arsenic Trioxide	affects binding, decreases reaction, decreases expression, increases expression	4
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression	4
bisphenol F	increases expression, decreases expression, affects cotreatment, increases methylation	3
Nickel	decreases expression, increases expression	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
cobaltous chloride	decreases expression	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
Methotrexate	affects expression, decreases expression	2
Tretinoin	decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
chlorophyllin	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, increases expression, affects cotreatment	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects expression	1
methylparaben	increases expression	1
sodium arsenite	affects binding, increases reaction	1
tetrabromobisphenol A	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	increases expression	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
beta-methylcholine	affects expression	1

ChEMBL screening assays

133 unique, capped per target: 129 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3412434	Binding	Inhibition of GARFTase/AICARFTase in human KB cells assessed as cell growth inhibition in presence of 60 uM adenosine	Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidines as potential nonclassical antifolates targeting both thymidylate and purine nucleotide biosynthesis. — Eur J Med Chem
CHEMBL678853	Functional	In vitro inhibitory activity against Glycinamide ribonucleotide transformylase (GAR Tfase) after 6 hr at 250 uM	Design, synthesis, and biological evaluation of fluoronitrophenyl substituted folate analogues as potential inhibitors of GAR transformylase and AICAR transformylase. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1MR	Abcam K-562 GART KO	Cancer cell line	Female
CVCL_D2JB	Abcam Raji GART KO	Cancer cell line	Male
CVCL_UQ58	Abcam Jurkat GART KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability