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): 148 total — 2 pathogenic, 2 likely-pathogenic
• GTEx eGene: eQTL in 13 tissues, sQTL in 1 (q < 0.05)
• Drug target: yes — 3 curated mechanism-of-action drugs; 3 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 2 — Pemetrexed, Pemetrexed Dipotassium
• Cancer dependency (DepMap): dependent in 32.4% of screened cell lines
• Constraint (gnomAD): pLI 0.96 (loss-of-function intolerant), LOEUF 0.50 (moderately constrained)
• MANE Select transcript: NM_000819
• Interaction hub: 4,482 STRING partners (top 1% of genes corpus-wide)
• Notable: 148 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 70 — 49 protein_coding, 13 nonsense_mediated_decay, 6 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000381815

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 2: 2, TSL 3: 8, TSL 5: 2

ENST00000381815, ENST00000361093, ENST00000366093, 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, ENST00000979070, ENST00000979071, ENST00000979072, ENST00000979073, ENST00000979074, ENST00000979075, ENST00000979076, ENST00001036575, ENST00001036576, ENST00001036577, ENST00001036578, ENST00001036581, ENST00001036582, ENST00001036584, ENST00001036585, ENST00001036586, ENST00001036588, ENST00001036589, ENST00001062275, ENST00001062276, ENST00001062277, ENST00001106268, ENST00001106269, ENST00001106270, ENST00001106273, ENST00001116095, ENST00001116096, ENST00001116097, ENST00001116098, ENST00001116099, ENST00001116100, ENST00001116101, ENST00001131427

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.

Highest expression (Bgee): ventricular zone, ganglionic eminence, rectum, cortical plate, adrenal tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

GART is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.4e-04	+0.12	21:33549183:A:ATTGT
Cells EBV-transformed lymphocytes	eqtl	1.7e-04	+0.39	21:33762407:T:C
Brain Caudate basal ganglia	eqtl	1.2e-03	+0.23	21:33481519:T:TG
Thyroid	eqtl	7.3e-03	+0.10	21:33496187:G:C
Muscle Skeletal	eqtl	9.4e-03	+0.06	21:33495836:T:A
Pituitary	eqtl	1.8e-02	+0.78	21:33209175:A:G
Brain Cerebellar Hemisphere	eqtl	2.1e-02	+0.21	21:33653419:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.2e-02	-0.35	21:33340490:C:G
Adipose Subcutaneous	eqtl	2.3e-02	+0.08	21:33640413:G:C
Brain Cerebellum	eqtl	3.1e-02	-0.90	21:33279215:T:A
Minor Salivary Gland	eqtl	3.5e-02	-0.73	21:34034373:C:T
Testis	sqtl	3.8e-02	-1.59	21:33973514:C:T
Pancreas	eqtl	4.2e-02	+0.38	21:34373758:G:A
Adipose Visceral Omentum	eqtl	4.5e-02	+0.06	21:33867101:A:T

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

showing 100 of 275 tissues 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
left adrenal gland	UBERON:0001234	90.67	gold quality
body of uterus	UBERON:0009853	90.65	gold quality
adrenal gland	UBERON:0002369	90.63	gold quality
left adrenal gland cortex	UBERON:0035825	90.63	gold quality
body of stomach	UBERON:0001161	90.61	gold quality
gall bladder	UBERON:0002110	90.54	gold quality
monocyte	CL:0000576	90.52	gold quality
gastrocnemius	UBERON:0001388	90.51	gold quality
male germ cell	CL:0000015	90.47	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.46	gold quality
left ovary	UBERON:0002119	90.41	gold quality
coronary artery	UBERON:0001621	90.40	gold quality
mononuclear cell	CL:0000842	90.39	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.39	gold quality
lower esophagus	UBERON:0013473	90.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.37	gold quality
tibial artery	UBERON:0007610	90.37	gold quality
popliteal artery	UBERON:0002250	90.36	gold quality
tibial nerve	UBERON:0001323	90.35	gold quality
sperm	CL:0000019	90.30	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.30	gold quality
leukocyte	CL:0000738	90.29	gold quality
corpus epididymis	UBERON:0004359	90.18	gold quality
type B pancreatic cell	CL:0000169	90.16	gold quality
left uterine tube	UBERON:0001303	90.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.13	gold quality
muscle of leg	UBERON:0001383	90.12	gold quality
aorta	UBERON:0000947	90.09	gold quality
adrenal cortex	UBERON:0001235	90.09	gold quality
transverse colon	UBERON:0001157	90.08	gold quality
ectocervix	UBERON:0012249	90.08	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.08	gold quality
ovary	UBERON:0000992	90.07	gold quality
right testis	UBERON:0004534	90.04	gold quality
metanephros cortex	UBERON:0010533	90.00	gold quality
upper lobe of left lung	UBERON:0008952	89.95	gold quality
olfactory bulb	UBERON:0002264	89.88	gold quality
descending thoracic aorta	UBERON:0002345	89.88	gold quality
thoracic aorta	UBERON:0001515	89.84	gold quality
ascending aorta	UBERON:0001496	89.83	gold quality
skin of leg	UBERON:0001511	89.81	gold quality
endocervix	UBERON:0000458	89.77	gold quality
testis	UBERON:0000473	89.67	gold quality
right uterine tube	UBERON:0001302	89.64	gold quality
left testis	UBERON:0004533	89.61	gold quality
upper lobe of lung	UBERON:0008948	89.48	gold quality
skin of abdomen	UBERON:0001416	89.46	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.45	gold quality
vermiform appendix	UBERON:0001154	89.44	gold quality
right lobe of thyroid gland	UBERON:0001119	89.38	gold quality
vagina	UBERON:0000996	89.33	gold quality
visceral pleura	UBERON:0002401	89.31	gold quality
minor salivary gland	UBERON:0001830	89.28	gold quality
left lobe of thyroid gland	UBERON:0001120	89.18	gold quality
small intestine	UBERON:0002108	89.17	gold quality
caecum	UBERON:0001153	89.13	gold quality
mucosa of transverse colon	UBERON:0004991	89.04	gold quality
thyroid gland	UBERON:0002046	89.00	gold quality
jejunal mucosa	UBERON:0000399	88.97	gold quality
caput epididymis	UBERON:0004358	88.94	gold quality
bone marrow cell	CL:0002092	88.88	gold quality
endometrium	UBERON:0001295	88.83	gold quality
intestine	UBERON:0000160	88.73	gold quality
right atrium auricular region	UBERON:0006631	88.69	gold quality
heart left ventricle	UBERON:0002084	88.65	gold quality
colon	UBERON:0001155	88.64	gold quality
cardiac ventricle	UBERON:0002082	88.46	gold quality
large intestine	UBERON:0000059	88.45	gold quality
female reproductive system	UBERON:0000474	88.44	gold quality
spleen	UBERON:0002106	88.36	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tonsil	tissue	36.1	medium
Thymus	tissue	32.0
Urinary bladder	tissue	30.0	medium
Lymph node	tissue	28.3	medium
Liver	tissue	27.7	medium
Testis	tissue	27.4	medium
Rectum	tissue	27.3	medium
Caudate putamen	tissue	26.9
Frontal cortex	tissue	26.4
Choroid plexus	tissue	24.6
Smooth muscle	tissue	24.5	low
Placenta	tissue	24.5	medium
Nucleus accumbens	tissue	24.0
Locus coeruleus	tissue	23.8
Postcentral gyrus	tissue	23.2
Appendix	tissue	22.8	medium
Breast	tissue	22.7	medium
Adipose tissue	tissue	22.5	low
Colon	tissue	21.7	medium
Duodenum	tissue	20.8	medium
Hippocampus	tissue	20.6	medium
Esophagus	tissue	20.4	medium
Fallopian tube	tissue	20.4	medium
Tongue	tissue	20.3
Thyroid gland	tissue	19.5	medium
Kidney	tissue	19.5	medium
Heart muscle	tissue	19.4	not detected
Retina	tissue	19.3
Skeletal muscle	tissue	19.1	low
Spleen	tissue	18.8	medium
Parathyroid gland	tissue	18.7	medium
Ovary	tissue	18.4	low
Small intestine	tissue	18.2	medium
Pancreas	tissue	17.9	medium
Bone marrow	tissue	17.6	medium
Stomach 1	tissue	17.1	medium
Endometrium 1	tissue	17.1	medium
Skin 1	tissue	16.3	medium
Epididymis	tissue	16.1	medium
Adrenal gland	tissue	16.1	medium
Vagina	tissue	15.9	medium
Corpus callosum	tissue	15.9
Prostate	tissue	15.9	medium
Salivary gland	tissue	15.8	medium
Seminal vesicle	tissue	15.7	medium
Cervix	tissue	15.4	medium
Gallbladder	tissue	14.9	medium
Lung	tissue	14.8	medium
Spinal cord	tissue	13.3
Pituitary gland	tissue	12.2
Medulla oblongata	tissue	12.0
Midbrain	tissue	11.8
Substantia nigra	tissue	11.7
Olfactory bulb	tissue	11.4
Periaqueductal gray	tissue	11.2
Ventral forebrain	tissue	11.1
Septum	tissue	11.0
Putamen	tissue	10.9
Amygdala	tissue	10.9
Thalamus	tissue	10.7

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Parieto-temporal junction (white matter) (30.1), Corpus callosum, genu (white matter) (29.2), Lateral funiculus (white matter) (29.1), Cerebellar white matter (28.8), Anterior funiculus (white matter) (28.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, TFCP2

miRNA regulators (miRDB)

Targeting GART by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

9 miRNAs:

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

gnomAD constraint: pLI 0.956, LOEUF 0.496, missense Z 1.44 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000381815 — one region, missense o/e 0.92. DepMap (CRISPR cell-line fitness): dependent in 32.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SU-DHL-8 (-2.244), TFK-1 (-1.906), SNU-1 (-1.886), SU-DHL-10 (-1.868), SU-DHL-5 (-1.858), COLO 205 (-1.845), OCI-AML3 (-1.724), AsPC-1 (-1.639), OCI-LY-19 (-1.601), PC-14 (-1.564), Reh (-1.543), VMRC-LCD (-1.504), SUP-T1 (-1.471), KARPAS-299 (-1.444), SUP-M2 (-1.423).

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95654) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	1
embryonic lethality prior to tooth bud stage	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Brucella ovis ATCC 25840	A5VPP4	100.0%	Diamond
Brucella canis ATCC 23365	A9MA84	100.0%	Diamond
Brucella suis ATCC 23445	B0CL36	100.0%	Diamond
Brucella abortus S19	B2S4W8	100.0%	Diamond
Brucella melitensis ATCC 23457	C0RI52	100.0%	Diamond
Mycobacterium tuberculosis variant bovis AF2122/97	P0A5T7	100.0%	Diamond
Streptococcus pyogenes MGAS315	P0DD58	100.0%	Diamond
Streptococcus pyogenes SSI-1	P0DD59	100.0%	Diamond
Staphylococcus aureus subsp. aureus Mu50	P65895	100.0%	Diamond
Staphylococcus aureus subsp. aureus N315	P65896	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WHM2	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WHM3	100.0%	Diamond
Brucella abortus 2308	Q2YN59	100.0%	Diamond
Brucella abortus bv. 1 str. 9-941	Q57E30	100.0%	Diamond
Staphylococcus epidermidis RP62A	Q5HQ96	100.0%	Diamond
Campylobacter jejuni RM1221	Q5HTL1	100.0%	Diamond
Staphylococcus epidermidis ATCC 12228	Q8CT26	100.0%	Diamond
Brucella suis 1330	Q8G1K5	100.0%	Diamond
Brucella melitensis bv. 1 str. 16M	Q8YGB9	100.0%	Diamond
Campylobacter jejuni subsp. jejuni NCTC 11168 = ATCC 700819	Q9PN47	100.0%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	P26977	99.8%	Diamond
Staphylococcus aureus subsp. aureus MSSA476	Q6GAD9	99.8%	Diamond
Leptospira interrogans serovar Copenhageni str. Fiocruz L1-130	Q72V31	99.8%	Diamond
Leptospira interrogans serovar Lai str. 56601	Q8EZT7	99.8%	Diamond
Staphylococcus aureus subsp. aureus MW2	Q8NX87	99.8%	Diamond
Salmonella enterica subsp. enterica serovar Typhi	Q8Z334	99.8%	Diamond
Vibrio vulnificus YJ016	Q7MGT4	99.5%	Diamond
Vibrio vulnificus CMCP6	Q8DD07	99.5%	Diamond
Streptococcus pyogenes serotype M1	Q9A1Y7	99.3%	Diamond
Neisseria meningitidis Z2491	Q9JWU6	99.1%	Diamond
Neisseria meningitidis MC58	Q9JXA3	99.1%	Diamond
Staphylococcus aureus subsp. aureus COL	Q5HH10	99.0%	Diamond
Streptococcus pyogenes MGAS10394	Q5XEF0	98.8%	Diamond
Streptococcus pyogenes MGAS8232	Q8P308	98.8%	Diamond
Escherichia coli CFT073	Q8FB69	98.6%	Diamond
Escherichia coli O157:H7	Q8X612	98.6%	Diamond
Escherichia coli K-12	P15640	98.4%	Diamond
Staphylococcus aureus subsp. aureus MRSA252	Q6GI10	98.3%	Diamond
Streptococcus pneumoniae R6	Q8DRM0	98.1%	Diamond
Streptococcus pneumoniae TIGR4	Q97T98	98.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR6501	ncRNA	102465248
DONSON	protein-coding	29980
DNAJC28	protein-coding	54943
SON	protein-coding	6651
CRYZL1	protein-coding	9946
ITSN1	protein-coding	6453
IFNAR1	protein-coding	3454
IFNGR2	protein-coding	3460
TMEM50B	protein-coding	757

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-like	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)

• 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 (130 total): helix 47, strand 41, binding site 12, turn 10, 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)

showing 30 of 40 structures by resolution:

PDB	Title	Method	Resolution (Å)
4ZZ1	HUMAN GAR TRANSFORMYLASE IN COMPLEX WITH GAR AND …	X-RAY DIFFRACTION	1.35
4ZZ2	HUMAN GAR TRANSFORMYLASE IN COMPLEX WITH GAR AND …	X-RAY DIFFRACTION	1.45
4EW1	High resolution structure of human glycinamide ribonucleotide transformylase in apo form.	X-RAY DIFFRACTION	1.52
4ZYZ	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	1.6
4EW2	The structure of human glycinamide ribonucleotide transformylase in complex with …	X-RAY DIFFRACTION	1.6
4ZYX	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	1.65
4ZZ0	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	1.65
4EW3	The structure of human glycinamide ribonucleotide transformylase in complex with …	X-RAY DIFFRACTION	1.7
4ZYT	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	1.7
1MEO	human glycinamide ribonucleotide Transformylase at pH 4.2	X-RAY DIFFRACTION	1.72
4ZYY	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	1.85
4ZYU	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	1.95
1NJS	human GAR Tfase in complex with hydrolyzed form of …	X-RAY DIFFRACTION	1.98
7JG0	Human GAR transformylase in complex with GAR substrate and AGF102 inhibitor	X-RAY DIFFRACTION	1.98
1MEJ	Human Glycinamide Ribonucleotide Transformylase domain at pH 8.5	X-RAY DIFFRACTION	2
1RC0	Human GAR Tfase complex structure with polyglutamated …	X-RAY DIFFRACTION	2.05
4ZYW	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	2.05
4ZYV	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	2.05
8FDY	Human GAR transformylase in complex with GAR substrate and AGF132 inhibitor	X-RAY DIFFRACTION	2.06
1ZLY	The structure of human glycinamide ribonucleotide transformylase in complex with …	X-RAY DIFFRACTION	2.07
8FDX	AGF271 and GAR in complex with human recombinant GARFTase, ligase, purine biosynthesis …	X-RAY DIFFRACTION	2.07
8FJW	Human GAR transformylase in complex with GAR substrate and AGF347 inhibitor	X-RAY DIFFRACTION	2.08
7JG3	Human GAR transformylase in complex with GAR substrate and AGF103 inhibitor	X-RAY DIFFRACTION	2.09
1RBZ	Human GAR Tfase complex structure with polyglutamated …	X-RAY DIFFRACTION	2.1
2V9Y	Human aminoimidazole ribonucleotide synthetase	X-RAY DIFFRACTION	2.1
5J9F	Human GAR transformylase in complex with GAR and …	X-RAY DIFFRACTION	2.1
1RBY	Human GAR Tfase complex structure with …	X-RAY DIFFRACTION	2.1
1RBQ	Human GAR Tfase complex structure with …	X-RAY DIFFRACTION	2.1
8FJX	Human GAR transformylase in complex with GAR substrate and AGF320 inhibitor	X-RAY DIFFRACTION	2.17
1ZLX	The apo structure of human glycinamide ribonucleotide transformylase	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Ligase, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, FDA approved drug targets, Small molecule drugs, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; mitochondria

Antibody reliability (HPA): IH approved · IF approved

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)

Position	Role
951	raises pka of active site his
915	proton donor

Ligand- & substrate-binding residues (12)

Position	Role
288	Mg(2+)
290	Mg(2+)
818–820	N(1)-(5-phospho-beta-D-ribosyl)glycinamide
871	(6R)-10-formyltetrahydrofolate
896–899	(6R)-10-formyltetrahydrofolate
913	(6R)-10-formyltetrahydrofolate
947–951	(6R)-10-formyltetrahydrofolate
977–980	N(1)-(5-phospho-beta-D-ribosyl)glycinamide
190–193	ATP
197	ATP
220	ATP
229	ATP

Post-translational modifications (7)

Type	Positions
N-acetylalanine	2
Phosphoserine	10, 440, 796, 802
N6-acetyllysine	350
Phosphothreonine	682

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-73817	Purine ribonucleoside monophosphate biosynthesis	curated
R-HSA-1430728	Metabolism	—
R-HSA-15869	Metabolism of nucleotides	—
R-HSA-8956320	Nucleotide 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

3 top-level categories:

Category	Pathways
Nucleotide biosynthesis	1
Metabolism	1
Metabolism of nucleotides	1

GO top-level categories

35 GO namespaces:

Category	Terms
animal gross anatomical part developmental process	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
anion 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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
‘de novo’ AMP biosynthetic process	BP	direct assay
‘de novo’ IMP biosynthetic process	BP	direct assay
‘de novo’ XMP biosynthetic process	BP	direct assay
GMP biosynthetic process	BP	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
phosphoribosylformylglycinamidine cyclo-ligase activity	MF	direct assay
phosphoribosylglycinamide formyltransferase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 4,482 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GART	PPAT	Q06203	961
GART	PFAS	O15067	957
GART	DONSON	Q9NYP3	921
GART	MTHFD1	P11586	917
GART	MTHFD2	P13995	907
GART	PAICS	P22234	877
GART	ATIC	P31939	843
GART	TYMS	P04818	838
GART	DHFR2	Q86XF0	815
GART	DHFR	P00374	812
GART	ALDH1L1	O75891	746
GART	ADSL	P30566	743
GART	GSDMC	Q9BYG8	675
GART	FPGS	Q05932	670
GART	SHMT1	P34896	666

IntAct

Human interaction partners of GART in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
INPP5K	association	0.640	2
ARHGEF18	physical association	0.400	1
SIRT2	physical association	0.400	1
KPNA2	physical association	0.370	1
PXN	physical association	0.370	1
SYN3	association	0.350	1
ARF6	physical association	0.000	1
IKBKG	physical association	0.000	1

BioGRID (304 interactions; top human partners by supporting records): CUL3 (Affinity Capture-MS; 3 records), INPP5K (Affinity Capture-MS; 3 records), PARK2 (Affinity Capture-MS; 3 records), AGR2 (Proximity Label-MS; 2 records), AIFM1 (Co-fractionation; 2 records), ATP1B3 (Cross-Linking-MS (XL-MS); 2 records), DNAJC7 (Affinity Capture-MS; 2 records), EEF1A1 (Co-fractionation; 2 records), ENO1 (Cross-Linking-MS (XL-MS); 2 records), GAPDH (Cross-Linking-MS (XL-MS); 2 records), HNRNPU (Cross-Linking-MS (XL-MS); 2 records), KCNA3 (Proximity Label-MS; 2 records), PAICS (Co-fractionation; 2 records), PPAT (Co-fractionation; 2 records), PRKAR1A (Affinity Capture-MS; 2 records)

SIGNOR signaling

11 signaling 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”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ GART homodimer	1	GART

Disease & clinical

Genetic variants

Variant evidence for GART: 148 ClinVar records (4 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

148 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)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1807761	GRCh37/hg19 21q22.11(chr21:34909697-34931454)x1	Pathogenic	criteria provided, single submitter	1
2672312	NC_000021.9:g.33542069_33544417del	Likely pathogenic	criteria provided, single submitter	1
916559	NM_000819.5(GART):c.1907T>G (p.Leu636Arg)	Likely pathogenic	no assertion criteria provided	1
1340524	GRCh37/hg19 21q22.11(chr21:34909333-34931454)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore GART’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 39 predictions of 1,602):

Position(s)	Effect	Δscore	Sites
21:33511250–33511251	donor_loss	1.0000	5
21:33511459–33511460	acceptor_loss	1.0000	5
21:33516987–33516988	donor_loss	1.0000	5
21:33517142–33517143	acceptor_loss	1.0000	6
21:33517146	acceptor_gain	1.0000
21:33517503	donor_gain	1.0000
21:33517609–33517610	acceptor_loss	1.0000	4
21:33517624	acceptor_gain	1.0000
21:33520904–33520905	donor_loss	1.0000	5
21:33521016–33521017	acceptor_loss	1.0000	6

AlphaMissense

2,059 missense substitutions predicted likely pathogenic (of 6,559 scored), across 566 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M896	9	0.882	0.988
M233	9	0.795	0.907
D951	8	0.975	0.990
D515	8	0.974	0.990
D523	8	0.969	0.992
H944	8	0.962	0.995
N913	8	0.960	0.997
H915	8	0.958	0.998
N689	8	0.957	0.993
D217	8	0.923	0.973
D584	8	0.913	0.939
H620	8	0.912	0.978
D875	8	0.912	0.986
F534	8	0.892	0.969
D494	8	0.886	0.961
D536	8	0.882	0.935
F903	8	0.878	0.958
D295	8	0.876	0.943
H680	8	0.866	0.975
D967	8	0.849	0.948

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000299
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000372
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000432
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000585

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)

GWAS associations

3 associations:

Study	Trait	p-value
GCST001729_23	Crohn’s disease	2e-16
GCST008479_17	Psoriasis	2e-7
GCST002598_28	Educational attainment	3e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004784	self reported educational attainment

MeSH disease descriptors

2 disease descriptors:

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)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the GART protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

3 curated-mechanism drugs:

Drug	Modality	Max phase
PEMETREXED	Small molecule	4
PEMETREXED DIPOTASSIUM	Small molecule	4
PELITREXOL	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 470,942 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL225072	PEMETREXED	4	56,714
CHEMBL34259	METHOTREXATE	4	402,177
CHEMBL34412	LOMETREXOL	2	12,051

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Cyclo-ligases

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

Ligand	Action	Affinity	Parameter
pemetrexed	Inhibition	5.03	pKi

Binding affinities (BindingDB)

116 measured of 139 human assays (151 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(R)-2-({5-[2-(2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-thiophene-2-carbonyl}-amino)-pentanedioic acid	KD	0.0005 nM
2-{4-[3-(2-Amino-4-oxo-3,4,5,6,7,8-hexahydro-pteridin-6-yl)-2-methyl-propyl]-benzoylamino}-pentanedioic acid	IC50	0.001 nM
2-{4-[2-(2-Amino-4-oxo-3,4,5,6,7,8-hexahydro-pteridin-6-yl)-ethylamino]-benzoylamino}-pentanedioic acid	IC50	0.001 nM
2-{4-[3-(2-Amino-4-oxo-3,4,7,8-tetrahydro-pteridin-6-yl)-2-methyl-propyl]-benzoylamino}-pentanedioic acid	IC50	0.001 nM
2-{4-[2-(2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-benzoylamino}-pentanedioic acid	KD	0.002 nM
(S)-2-({5-[2-(2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-thiophene-2-carbonyl}-amino)-pentanedioic acid	KD	0.0032 nM
CHEMBL4177183	IC50	0.078 nM
CHEMBL4162649	IC50	0.14 nM
CHEMBL4445651	IC50	0.14 nM
(S)-2-({5-[3-(2,4-Diamino-6-oxo-1,6-dihydro-pyrimidin-5-ylsulfanyl)-propyl]-thiophene-2-carbonyl}-amino)-pentanedioic acid	KD	0.153 nM
CHEMBL4643623	IC50	0.3 nM
AGF94	IC50	0.31 nM
CHEMBL3628344	IC50	0.33 nM
CHEMBL4465095	IC50	0.36 nM
(S)-2-({5-[3-(2,4-Diamino-6-oxo-1,6-dihydro-pyrimidin-5-ylsulfanyl)-propyl]-3-methyl-thiophene-2-carbonyl}-amino)-pentanedioic acid	KD	0.38 nM
CHEMBL4467936	IC50	0.51 nM
(S)-2-{[6-(2,4-Diamino-6-oxo-1,6-dihydro-pyrimidin-5-ylsulfanylmethyl)-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl]-amino}-pentanedioic acid	KD	0.57 nM
CHEMBL3628346	IC50	0.61 nM
(S)-2-({5-[2-(2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-4-methyl-thiophene-2-carbonyl}-amino)-pentanedioic acid	KD	0.69 nM
CHEMBL4557278	IC50	0.69 nM
(R)-2-({5-[2-(2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-4-methyl-thiophene-2-carbonyl}-amino)-pentanedioic acid	KD	0.95 nM
CHEMBL4636872	IC50	0.95 nM
CHEMBL4538151	IC50	1.1 nM
CHEMBL4553188	IC50	1.1 nM
CHEMBL4214638	IC50	1.3 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	1.8 nM
CHEMBL4447805	IC50	1.9 nM
CHEMBL2158681	IC50	2.5 nM
CHEMBL4645676	IC50	2.5 nM
CHEMBL3086865	IC50	2.9 nM
CHEMBL4437824	IC50	3 nM
CHEMBL4471269	IC50	3 nM
2-{3-[2-(2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-benzoylamino}-pentanedioic acid	KI	3.4 nM
CHEMBL4444011	IC50	4.9 nM
CHEMBL4638232	IC50	5.4 nM
AGF147	IC50	5.5 nM
AGF117	IC50	7 nM
N-{4-[5-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)pentyl]benzoyl}-L-glutamic Acid	IC50	7.2 nM
CHEMBL4170578	IC50	7.5 nM
N-{4-[6-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)hexyl]benzoyl}-L-glutamic Acid	IC50	8.6 nM
AGF118	IC50	9 nM
CHEMBL3335605	IC50	9.5 nM
CHEMBL3086867	IC50	9.6 nM
CHEMBL4641908	IC50	13 nM
(S)-2-({5-[3-(2,4-Diamino-6-oxo-1,6-dihydro-pyrimidin-5-ylsulfanyl)-propyl]-3-ethyl-thiophene-2-carbonyl}-amino)-pentanedioic acid	KI	14 nM
N-{4-[3-(2-Amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)-propyl]benzoyl}-L-glutamic Acid	IC50	14 nM
CHEMBL4205344	IC50	15 nM
AGF23	IC50	17 nM
N-{4-[5-(2-Amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)-pentyl]benzoyl}-L-glutamic Acid	IC50	24 nM
N-{4-[6-(2-Amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)-hexyl]benzoyl}-L-glutamic Acid	IC50	27 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	increases expression, affects expression, decreases 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	decreases expression, affects cotreatment, increases methylation, increases expression	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	increases expression, affects cotreatment, affects localization, decreases expression	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	affects binding, decreases reaction	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 210 trials:

NCT	Phase	Status	Title
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	Phase 3	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	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	Phase 1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	Phase 1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03792360	Phase 1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT03479476	Phase 2/3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	Phase 1/2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	Early Phase 1	TERMINATED	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
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders
NCT02862808	Not specified	COMPLETED	Molecular Diagnosis of Syndromic or Isolated Severe Intellectual Disability Using Whole Exome Sequencing : a Pilot Study
NCT02881333	Not specified	UNKNOWN	Various Type of Genetic Events in Patients With Intellectual Disability
NCT02889068	Not specified	COMPLETED	Targeted Next Generation Sequencing and Intellectual Disability
NCT02914951	Not specified	ENROLLING_BY_INVITATION	Cognitive-Behavioral Therapy for Irritability in Children With Autism Spectrum Disorder and Intellectual Disability
NCT02919826	Not specified	COMPLETED	Dialectical Behaviour Group Therapy for Adults With Intellectual Disabilities
NCT02934854	Not specified	WITHDRAWN	Biomarker for Creatine Deficiency Syndromes (BioCDS)
NCT03033797	Not specified	UNKNOWN	Augmentative and Alternative Communication in Games With Virtual Reality in Intellectual Disabilities
NCT03135236	Not specified	COMPLETED	Parents as the Primary Sexuality Educators for Their Young Adults With Down Syndrome
NCT03139760	Not specified	COMPLETED	POWERSforID: A Telehealth Weight Management System for Adults With Intellectual Disability
NCT03203226	Not specified	COMPLETED	The Feldenkrais Method for People With Intellectual Disability
NCT03212092	Not specified	COMPLETED	Reducing Aggression Among People With an Intellectual Disability
NCT03218462	Not specified	COMPLETED	Effect of Sensory Adapted Dental Environment on Dental Anxiety of Children With Intellectual and Developmental Disabilities
NCT03234231	Not specified	UNKNOWN	Supervised Brushing Programme for Intellectual Disabled Students
NCT03348124	Not specified	UNKNOWN	Prevention Among Young People With Intellectual Disability
NCT03424772	Not specified	UNKNOWN	Whole Genome Sequencing in the Detection of Rare Undiagnosed Genetic Diseases in Children in China
NCT03426059	Not specified	COMPLETED	Mapping the Phenotype in Adults With Phelan-McDermid Syndrome
NCT03492060	Not specified	RECRUITING	Longitudinal Study of Neurogenetic Disorders
NCT03501914	Not specified	COMPLETED	A Pilot Trial of Mindfulness Based Intervention Program for People With Intellectual Disabilities in a Low Income Setting
NCT03522337	Not specified	COMPLETED	Oral Health Promotion Among Preschool Children With Special Needs

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for GART across ~30M SureChEMBL compounds — explore on Sugi Predict.