ATIC

Summary

ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase, HGNC:794) is a protein-coding gene on chromosome 2q35, encoding Bifunctional purine biosynthesis protein ATIC (P31939). Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis. It is a selective cancer dependency (DepMap: 34.2% of cell lines).

This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. A mutation in this gene results in AICA-ribosiduria.

Source: NCBI Gene 471 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AICA-ribosiduria (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 366 total — 2 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 34.2% of screened cell lines
• MANE Select transcript: NM_004044

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:794
Approved symbol	ATIC
Name	5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	PURH, AICARFT, IMPCHASE
Ensembl gene	ENSG00000138363
Ensembl biotype	protein_coding
OMIM	601731
Entrez	471

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000236959, ENST00000413174, ENST00000426233, ENST00000427397, ENST00000435675, ENST00000442048, ENST00000443953, ENST00000444305, ENST00000446622, ENST00000459796, ENST00000467388, ENST00000478734, ENST00000479093, ENST00000488712, ENST00000856929, ENST00000856930, ENST00000856931, ENST00000939850, ENST00000939851, ENST00000939852, ENST00000939853, ENST00000939854, ENST00000939855, ENST00000957330

RefSeq mRNA: 1 — MANE Select: NM_004044 NM_004044

CCDS: CCDS2398

Canonical transcript exons

ENST00000236959 — 16 exons

Exon	Start	End
ENSE00001914660	215312059	215312161
ENSE00003478405	215333350	215333457
ENSE00003498173	215312498	215312624
ENSE00003506000	215332382	215332507
ENSE00003515480	215346759	215346941
ENSE00003542304	215325987	215326138
ENSE00003542381	215336035	215336124
ENSE00003554706	215319665	215319731
ENSE00003564427	215344779	215344871
ENSE00003573878	215325241	215325329
ENSE00003592961	215349094	215349249
ENSE00003646013	215334919	215335004
ENSE00003689178	215318157	215318233
ENSE00003689693	215338779	215338907
ENSE00003788420	215326822	215326978
ENSE00003849458	215349536	215349764

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 97.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 88.6378 / max 487.9864, expressed in 1818 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25070	88.0073	1818
25069	0.6305	393

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	97.27	gold quality
stromal cell of endometrium	CL:0002255	96.86	gold quality
rectum	UBERON:0001052	96.70	gold quality
endometrium epithelium	UBERON:0004811	96.68	gold quality
adenohypophysis	UBERON:0002196	96.35	gold quality
ventricular zone	UBERON:0003053	96.32	gold quality
right adrenal gland cortex	UBERON:0035827	96.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.21	gold quality
body of pancreas	UBERON:0001150	96.21	gold quality
right adrenal gland	UBERON:0001233	96.15	gold quality
cortical plate	UBERON:0005343	95.88	gold quality
ganglionic eminence	UBERON:0004023	95.82	gold quality
left adrenal gland cortex	UBERON:0035825	95.72	gold quality
embryo	UBERON:0000922	95.68	gold quality
left adrenal gland	UBERON:0001234	95.67	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.64	gold quality
transverse colon	UBERON:0001157	95.46	gold quality
caudate nucleus	UBERON:0001873	95.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.42	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.41	gold quality
body of uterus	UBERON:0009853	95.41	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.35	gold quality
lower esophagus	UBERON:0013473	95.34	gold quality
ectocervix	UBERON:0012249	95.33	gold quality
right ovary	UBERON:0002118	95.25	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.24	gold quality
left coronary artery	UBERON:0001626	95.23	gold quality
spleen	UBERON:0002106	95.20	gold quality
pituitary gland	UBERON:0000007	95.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	20.28
E-CURD-112	yes	8.77
E-ANND-3	yes	6.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA2, MYC

miRNA regulators (miRDB)

5 targeting ATIC, 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-12136	99.98	72.81	5713
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-9903	98.47	66.70	748

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 28)

• The kinetic mechanism of the human bifunctional enzyme ATIC (PMID:11948179)
• crystal structure of ATIC (PMID:14966129)
• Deficiency in AICAR transformylase is associated with severe neurological defects and congenital blindness (PMID:15114530)
• Polymorphisms of reduced folate carrier,aminoimidazole carboxamide ribonucleotide transformylase,and thymidylate synthase genes contribute to the therapeutic response in rheumatoid arthritis patients to methotrexate. (PMID:15457444)
• AS160 is a common target of insulin, IGF-1, EGF, PMA and AICAR, these stimuli induce distinctive patterns of phosphorylation and 14-3-3 binding, mediated by at least four protein kinases. (PMID:17617058)
• ATIC associated with nucleophosmin-ALK, and its phosphorylation required ALK activity. ALK-mediated ATIC phosphorylation enhanced its enzymatic activity. (PMID:18845790)
• Results proved in cultured skin fibroblasts from patients with AICA-ribosiduria that various mutations of ATIC destabilize to various degrees purinosome assembly. (PMID:22180458)
• study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment (PMID:24967362)
• MTHFR, DHFR and ATIC genetic variants can be considered as pharmacogenetic markers of outcome in RA patients under MTX monotherapy. (PMID:25084201)
• genotyping of ATIC rs2372536 and ITPA rs1127354 variants or measuring ITPA activity could be useful to predict methotrexate response in children with juvenile idiopathic arthritis. (PMID:25240429)
• Single nucleotide polymorphisms in ATIC gene is associated with acute graft-versus-host disease. (PMID:25425682)
• Our data show that ATIC is in complex with insulin receptor (IR)and siRNA-mediated partial knockdown of ATIC in HEK293 cells, decreases IR tyrosine phosphorylation and regulates IR endocytosis. Insulin stimulation and ATIC knockdown readily increase level of AMPK-Thr172 phosphorylation in IR complexes.ATIC depletion delayed insulin response of Glut2 translocation in HEK293 cells and decreased AKT-Ser473 phosphorylation. (PMID:25687571)
• PTPLAD1 and AMPK are rapidly compartmentalized within the plasma membrane (PM) and Golgi/endosome fractions after insulin stimulation and that ATIC later accumulates in the Golgi/endosome fraction. (PMID:25687571)
• This study shows that polymorphisms on genes related to the metabolic pathway of pemetrexed, especially, ATIC and GGH genes, would have a therapeutic implication in pemetrexed-treated patients with lung adenocarcinoma (PMID:25823786)
• ATIC 347C>G gene polymorphism may be associated with the development of MTX induced gastrointestinal adverse events. (PMID:26799664)
• The ATIC 347 C/G polymorphism may be associated with non-responsiveness to and or toxicity of methotrexate in Caucasian rheumatoid arthritis patients. (PMID:27379764)
• Pediatric Osteosarcoma patients with ATIC 347C>G exhibited a good histologic response to chemotherapy (PMID:28267080)
• The AICARFT site is capable of independently binding both nucleotide and folate substrates with high affinity however no evidence for positive cooperativity in binding could be detected using the model ligands employed in this study. (PMID:29042184)
• ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling (PMID:29246230)
• AICA-ribosiduria due to ATIC deficiency: Delineation of the phenotype with three novel cases, and long-term update on the first case. (PMID:32557644)
• Upregulation of ATIC in multiple myeloma tissues based on tissue microarray and gene microarrays. (PMID:33226193)
• Identification and Validation of a Prognostic Model Based on Three Autophagy-Related Genes in Hepatocellular Carcinoma. (PMID:33778066)
• Polymorphism of genes involved in methotrexate pathway: Predictors of response to methotrexate therapy in Indian rheumatoid arthritis patients. (PMID:33780152)
• Impact of Variants in the ATIC and ARID5B Genes on Therapeutic Failure with Imatinib in Patients with Chronic Myeloid Leukemia. (PMID:35205374)
• CircATIC Contributes to Multiple Myeloma Progression via miR-324-5p-Dependent Regulation of HGF. (PMID:35579772)
• Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients. (PMID:36584330)
• A meta-analysis of the association between the ATIC 347 C/G polymorphism and methotrexate responsiveness and toxicity in rheumatoid arthritis. (PMID:38071832)
• LncRNA ZFAS1 regulates ATIC transcription and promotes the proliferation and migration of hepatocellular carcinoma through the PI3K/AKT signaling pathway. (PMID:39001904)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atic	ENSDARG00000016706
mus_musculus	Atic	ENSMUSG00000026192
rattus_norvegicus	Atic	ENSRNOG00000015511
drosophila_melanogaster	CG11089	FBGN0039241
caenorhabditis_elegans		WBGENE00016957

Protein

Protein identifiers

Bifunctional purine biosynthesis protein ATIC — P31939 (reviewed: P31939)

Alternative names: AICAR transformylase/inosine monophosphate cyclohydrolase

All UniProt accessions (6): P31939, C9JLK0, F2Z3E8, F8WEF0, H7C1S2, V9HWH7

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis. Acts as a transformylase that incorporates a formyl group to the AMP analog AICAR (5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide) to produce the intermediate formyl-AICAR (FAICAR). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction. Also catalyzes the cyclization of FAICAR to inosine monophosphate (IMP). Is able to convert thio-AICAR to 6-mercaptopurine ribonucleotide, an inhibitor of purine biosynthesis used in the treatment of human leukemias. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization.

Subunit / interactions. Homodimer. Associates with internalized INSR complexes on Golgi/endosomal membranes. Interacts with INSR; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Present in the heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas.

Disease relevance. AICA-ribosuria due to ATIC deficiency (AICAR) [MIM:608688] A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. Clinical features include profound intellectual disability, epilepsy, dysmorphic features and congenital blindness. AICAR inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. AMP and XMP inhibit AICAR formyltransferase activity. AICAR formyltransferase activity is inhibited by N-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5- [(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), which acts as a tumor suppression in cancer cell lines.

Domain organisation. The IMP cyclohydrolase activity resides in the N-terminal region.

Pathway. Purine metabolism; IMP biosynthesis via de novo pathway; 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide (10-formyl THF route): step 1/1. Purine metabolism; IMP biosynthesis via de novo pathway; IMP from 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide: step 1/1.

Miscellaneous. The de novo purine synthesis pathway includes 10 sequential steps, beginning with phosphoribosyl pyrophosphate and ending with inosine monophosphate (IMP), the first purine compound of the pathway.

Similarity. Belongs to the PurH family.

Isoforms (2)

UniProt ID	Names	Canonical?
P31939-1	1	yes
P31939-2	2

RefSeq proteins (1): NP_004035* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002695	PurH-like	Family
IPR011607	MGS-like_dom	Domain
IPR016193	Cytidine_deaminase-like	Homologous_superfamily
IPR024050	AICAR_Tfase_insert_dom_sf	Homologous_superfamily
IPR024051	AICAR_Tfase_dup_dom_sf	Homologous_superfamily
IPR036914	MGS-like_dom_sf	Homologous_superfamily

Pfam: PF01808, PF02142

Enzyme classification (BRENDA):

• EC 2.1.2.3 — phosphoribosylaminoimidazolecarboxamide formyltransferase (BRENDA: 23 organisms, 43 substrates, 186 inhibitors, 50 Km, 10 kcat entries)
• EC 3.5.4.10 — IMP cyclohydrolase (BRENDA: 16 organisms, 13 substrates, 24 inhibitors, 26 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
5-FORMAMIDO-1-(5-PHOSPHORIBOSYL)IMIDAZOLE-4-CARB	0.0009–0.115	20
10-FORMYLTETRAHYDROFOLATE	0.0043–0.2	10
5-AMINO-1-(5-PHOSPHO-D-RIBOSYL)IMIDAZOLE-4-CARBO	0.01–0.3243	10
5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOTIDE	0.0005–0.0168	6
5-FORMAMIDO-1-(5-PHOSPHO-D-RIBOSYL)IMIDAZOLE-4-C	0.0016–0.21	5
5-FORMAMIDO-1-(5-PHOSPHO-D-RIBOSYL)IMIDAZOLE-4-C	0.0021–0.03	2
N10-FORMYLTETRAHYDROPTEROYLHEPTAGLUTAMATE	0.0018–0.0031	2
N10-FORMYLTETRAHYDROPTEROYLHEXAGLUTAMATE	0.0016–0.0019	2
N10-FORMYLTETRAHYDROPTEROYLMONOGLUTAMATE	0.0016–0.353	2
N10-FORMYLTETRAHYDROPTEROYLPENTAGLUTAMATE	0.0021–0.0026	2
N10-FORMYLTETRAHYDROPTEROYLTETRAGLUTAMATE	0.001–0.0011	2
N10-FORMYLTETRAHYDROPTEROYLTRIGLUTAMATE	0.006–0.674	2
(6R,6S)-10-FORMYLTETRAHYDROFOLIC ACID	0.0602	1
10-FORMYLDIHYDROFOLATE	0.245	1
10-FORMYLDIHYDROFOLIC ACID PENTAGLUTAMATE	0.0005	1

Catalyzed reactions (Rhea), 4 shown:

• IMP + H2O = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide (RHEA:18445)
• (6R)-10-formyltetrahydrofolate + 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide + (6S)-5,6,7,8-tetrahydrofolate (RHEA:22192)
• 10-formyldihydrofolate + 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide + 7,8-dihydrofolate (RHEA:59144)
• 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-thiocarboxamide + 10-formyldihydrofolate = 6-thio-IMP + 7,8-dihydrofolate + H2O (RHEA:62676)

UniProt features (96 total): helix 28, strand 25, binding site 16, mutagenesis site 7, turn 5, chain 2, modified residue 2, sequence variant 2, region of interest 2, active site 2, initiator methionine 1, site 1, splice variant 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5UZ0	X-RAY DIFFRACTION	1.79
1PKX	X-RAY DIFFRACTION	1.9
5UY8	X-RAY DIFFRACTION	2.39
1P4R	X-RAY DIFFRACTION	2.55
1PL0	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31939-F1	97.46	0.99

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 (3): 266 (transition state stabilizer); 137 (proton donor/acceptor; for faicar cyclization activity); 267 (proton acceptor; for aicar formyltransferase activity)

Ligand- & substrate-binding residues (16): 64–67; 101–102; 125–126; 207–208 (in other chain); 267 (in other chain); 316 (in other chain); 339 (in other chain); 431; 451; 452; 541; 546 …

Post-translational modifications (2): 1, 199

Mutagenesis-validated functional residues (7):

Position	Phenotype
66	decreased affinity to faicar; no change in faicar cyclization activity.
104	decreased faicar cyclization activity; no change in affinity to faicar.
125	decreased faicar cyclization activity; no change in affinity to faicar.
137	decreased affinity to faicar; no change in faicar cyclization activity.
137	decreased faicar cyclization activity; no change in affinity to faicar.
213	loss of aicar transformylase activity.
267	loss of aicar transformylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-73817	Purine ribonucleoside monophosphate biosynthesis
R-HSA-9725370	Signaling by ALK fusions and activated point mutants

MSigDB gene sets: 317 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GNF2_CKS1B, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_RESPONSE_TO_PEPTIDE, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, HSIAO_HOUSEKEEPING_GENES, GOBP_REGENERATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_FOREBRAIN_DEVELOPMENT

GO Biological Process (13): brainstem development (GO:0003360), nucleobase-containing compound metabolic process (GO:0006139), GMP biosynthetic process (GO:0006177), ‘de novo’ IMP biosynthetic process (GO:0006189), cerebellum development (GO:0021549), cerebral cortex development (GO:0021987), animal organ regeneration (GO:0031100), ‘de novo’ AMP biosynthetic process (GO:0044208), dihydrofolate metabolic process (GO:0046452), tetrahydrofolate biosynthetic process (GO:0046654), ‘de novo’ XMP biosynthetic process (GO:0097294), cellular response to interleukin-7 (GO:0098761), purine nucleotide biosynthetic process (GO:0006164)

GO Molecular Function (7): IMP cyclohydrolase activity (GO:0003937), phosphoribosylaminoimidazolecarboxamide formyltransferase activity (GO:0004643), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), catalytic activity (GO:0003824), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

GO Cellular Component (5): cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Nucleotide biosynthesis	1
Signaling by ALK in cancer	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
cellular anatomical structure	3
catalytic activity	2
primary metabolic process	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside monophosphate biosynthetic process	1
GMP metabolic process	1
IMP biosynthetic process	1
metencephalon development	1
pallium development	1
regeneration	1
animal organ development	1
AMP biosynthetic process	1
folic acid-containing compound metabolic process	1
dicarboxylic acid metabolic process	1
folic acid-containing compound biosynthetic process	1
tetrahydrofolate metabolic process	1
XMP biosynthetic process	1
cellular response to cytokine stimulus	1
response to interleukin-7	1
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
purine-containing compound biosynthetic process	1
cyclohydrolase activity	1
hydroxymethyl-, formyl- and related transferase activity	1
identical protein binding	1
protein dimerization activity	1
cell adhesion molecule binding	1
molecular_function	1
cytoplasm	1
membrane	1
cell periphery	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3709 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATIC	MTHFD1	P11586	943
ATIC	GART	P22102	916
ATIC	SHMT1	P34896	897
ATIC	ALK	Q9UM73	867
ATIC	DHFR	P00374	863
ATIC	GMPS	P49915	818
ATIC	ADSL	P30566	811
ATIC	TYMS	P04818	795
ATIC	PFAS	O15067	791
ATIC	MTHFD2	P13995	790
ATIC	FPGS	Q05932	767
ATIC	MTHFD1L	Q6UB35	766
ATIC	PPAT	Q06203	762
ATIC	MTHFD2L	Q9H903	743
ATIC	PAICS	P22234	736
ATIC	MTHFR	P42898	736

IntAct

64 interactions, top by confidence:

A	B	Type	Score
NFE2L2	MAFG	psi-mi:“MI:0914”(association)	0.940
EGFR	ATIC	psi-mi:“MI:0915”(physical association)	0.550
ATIC	EGFR	psi-mi:“MI:0915”(physical association)	0.550
	TK2	psi-mi:“MI:0915”(physical association)	0.400
INSR	ATIC	psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
SH3GL3	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
SHOC2	PNP	psi-mi:“MI:0914”(association)	0.350
PRKCE	PRPSAP2	psi-mi:“MI:0914”(association)	0.350
CAV1	PPM1G	psi-mi:“MI:0914”(association)	0.350
PRKCE	PAPSS1	psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
MAP3K7	ACOT7	psi-mi:“MI:0914”(association)	0.350
MYLK	ACOT7	psi-mi:“MI:0914”(association)	0.350
TP53	HGS	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ACTR2		psi-mi:“MI:0914”(association)	0.350
ARL3	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
SAR1B	UBA6	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
	SUPT5H	psi-mi:“MI:0914”(association)	0.350
	GTPBP1	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (187): ATIC (Affinity Capture-MS), ATIC (Affinity Capture-Western), ALDH16A1 (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation), ATIC (Co-fractionation)

ESM2 similar proteins: A2YII8, A8X0P0, O35567, O59736, O74940, O80585, O82191, O94460, P12628, P23368, P29696, P31335, P31939, P37222, P37223, P38795, P43279, P51615, P79023, Q01637, Q09755, Q0D8D4, Q0VCK0, Q19360, Q23623, Q25479, Q4QQY7, Q54ML1, Q54V77, Q5R5C2, Q6FXK9, Q6NUA1, Q754E7, Q7SYK1, Q84WV8, Q8RWM2, Q93714, Q941T1, Q945K7, Q99KE1

Diamond homologs: A0K4L7, A0KGJ2, A0LDB0, A0R900, A1AIH7, A1AS76, A1V068, A2S597, A3MP76, A3NDF2, A3NZ64, A3PNE9, A4JBL5, A4SR98, A4WWQ0, A7GKI2, A7MJ89, A8LMD0, A9AH70, A9GIT1, A9VRF5, B0BZH9, B0RN27, B0TEC5, B0U7A0, B1IUP1, B1JVV6, B1LPG6, B1XC09, B1YTE2, B2FJP9, B2I4L7, B2IX54, B2JGU1, B2SYJ7, B3QS62, B4EES4, B4SL92, B5Z0A3, B6I5L8

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
“pemetrexed disodium”	“down-regulates activity”	ATIC	“chemical inhibition”
ATIC	“down-regulates quantity”	10-formyltetrahydrofolate(2-)	“chemical modification”
ATIC	“up-regulates quantity”	(6S)-5,6,7,8-tetrahydrofolate(2-)	“chemical modification”
ATIC	“up-regulates quantity”	5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	“chemical modification”
ATIC	“up-regulates quantity”	IMP	“chemical modification”
ALK	“up-regulates activity”	ATIC	phosphorylation
VASP	“up-regulates activity”	ATIC	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ub-specific processing proteases	8	7.3×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	7
Uncertain significance	160
Likely benign	98
Benign	47

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
666360	NM_004044.7(ATIC):c.1654A>T (p.Lys552Ter)	Pathogenic
7811	NM_004044.7(ATIC):c.131delinsGGA (p.Ala44fs)	Pathogenic
1446036	NM_004044.7(ATIC):c.379+1G>A	Likely pathogenic
1704308	NM_212482.4(FN1):c.7144+1G>A	Likely pathogenic
2132862	NM_004044.7(ATIC):c.923-2del	Likely pathogenic
4796628	NM_004044.7(ATIC):c.371T>C (p.Ile124Thr)	Likely pathogenic
4845921	NM_004044.7(ATIC):c.1070del (p.Lys357fs)	Likely pathogenic
4849484	NM_004044.7(ATIC):c.1227+2T>C	Likely pathogenic
801894	NM_004044.7(ATIC):c.1085A>G (p.Tyr362Cys)	Likely pathogenic

SpliceAI

2391 predictions. Top by Δscore:

Variant	Effect	Δscore
2:215312621:TCAGG:T	donor_loss	1.0000
2:215312622:CAGGT:C	donor_loss	1.0000
2:215312623:AGG:A	donor_loss	1.0000
2:215312624:GGT:G	donor_loss	1.0000
2:215312625:GTAAG:G	donor_loss	1.0000
2:215312626:T:G	donor_loss	1.0000
2:215318151:TTTCA:T	acceptor_loss	1.0000
2:215318152:TTCA:T	acceptor_loss	1.0000
2:215318153:TCAGA:T	acceptor_loss	1.0000
2:215318154:CA:C	acceptor_loss	1.0000
2:215318155:A:AG	acceptor_gain	1.0000
2:215318155:A:C	acceptor_loss	1.0000
2:215318156:G:GA	acceptor_gain	1.0000
2:215318156:GA:G	acceptor_gain	1.0000
2:215318156:GAGA:G	acceptor_gain	1.0000
2:215318156:GAGAT:G	acceptor_gain	1.0000
2:215318230:GCTG:G	donor_gain	1.0000
2:215318234:G:GG	donor_gain	1.0000
2:215318235:T:A	donor_loss	1.0000
2:215319659:A:G	acceptor_gain	1.0000
2:215319727:ATAAG:A	donor_loss	1.0000
2:215319728:TAAGG:T	donor_loss	1.0000
2:215319729:AAGGT:A	donor_loss	1.0000
2:215319730:AG:A	donor_loss	1.0000
2:215319731:GG:G	donor_loss	1.0000
2:215319732:G:A	donor_loss	1.0000
2:215319733:T:A	donor_loss	1.0000
2:215325240:GA:G	acceptor_gain	1.0000
2:215326093:GA:G	donor_gain	1.0000
2:215326095:G:GG	donor_gain	1.0000

AlphaMissense

3859 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:215332489:A:G	K266E	1.000
2:215332490:A:T	K266I	1.000
2:215332491:A:C	K266N	1.000
2:215332491:A:T	K266N	1.000
2:215332498:A:C	S269R	1.000
2:215332500:C:A	S269R	1.000
2:215332500:C:G	S269R	1.000
2:215334939:T:C	F315L	1.000
2:215334941:T:A	F315L	1.000
2:215334941:T:G	F315L	1.000
2:215334943:G:A	G316D	1.000
2:215344844:C:A	N431K	1.000
2:215344844:C:G	N431K	1.000
2:215346800:C:G	C454W	1.000
2:215325253:C:G	C101W	0.999
2:215325324:A:T	D125V	0.999
2:215325325:C:A	D125E	0.999
2:215325325:C:G	D125E	0.999
2:215326018:A:C	K137N	0.999
2:215326018:A:T	K137N	0.999
2:215326916:G:A	G209E	0.999
2:215332400:G:A	G236E	0.999
2:215332418:A:C	D242A	0.999
2:215332418:A:T	D242V	0.999
2:215332492:C:G	H267D	0.999
2:215332493:A:G	H267R	0.999
2:215332494:T:A	H267Q	0.999
2:215332494:T:G	H267Q	0.999
2:215333455:G:C	R307T	0.999
2:215334924:G:C	D310H	0.999

dbSNP variants (sampled 300 via entrez): RS1000040088 (2:215339570 A>C,G), RS1000060627 (2:215366574 A>C), RS1000091641 (2:215321724 T>C), RS1000114319 (2:215313360 T>C), RS1000170447 (2:215317146 G>A), RS1000180424 (2:215364404 A>G), RS1000184770 (2:215359736 T>A), RS1000186580 (2:215360675 A>G), RS1000222793 (2:215317453 G>A,T), RS1000289246 (2:215347748 G>A,C), RS1000365749 (2:215354822 G>A,T), RS1000412001 (2:215366970 T>A), RS1000436626 (2:215316071 G>C), RS1000458425 (2:215332210 C>G,T), RS1000552584 (2:215333103 G>A,T)

Disease associations

OMIM: gene MIM:601731 | disease phenotypes: MIM:608688, MIM:184255, MIM:601894

GenCC curated gene-disease

Disease	Classification	Inheritance
AICA-ribosiduria	Definitive	Autosomal recessive

Mondo (5): AICA-ribosiduria (MONDO:0012099), spondylometaphyseal dysplasia, ‘corner fracture’ type (MONDO:0008479), glomerulopathy with fibronectin deposits 2 (MONDO:0011165), intellectual disability (MONDO:0001071), megacolon (MONDO:0001273)

Orphanet (4): AICA-ribosiduria (Orphanet:250977), Fibronectin glomerulopathy (Orphanet:84090), Spondylometaphyseal dysplasia, ‘corner fracture’ type (Orphanet:93315), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000063	Fused labia minora
HP:0000154	Wide mouth
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000565	Esotropia
HP:0000648	Optic atrophy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001684	Secundum atrial septal defect
HP:0001943	Hypoglycemia
HP:0002007	Frontal bossing
HP:0002187	Profound intellectual disability
HP:0002902	Hyponatremia
HP:0003577	Congenital onset
HP:0005487	Prominent metopic ridge
HP:0007875	Congenital blindness
HP:0008665	Clitoral hypertrophy
HP:0010781	Skin dimple
HP:0010864	Severe intellectual disability
HP:0011220	Prominent forehead
HP:0034565	Elevated urinary 5-amino-4-imidazolecarboxamide-riboside level
HP:6000752	Elevated erythrocyte AICA-ribotide concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002941_4	Airway imaging phenotypes	1.000000e-06
GCST009391_689	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007627	airway imaging measurement
EFO:0008529	kynurenine measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008531	Megacolon	C06.405.469.158.701
C563876	AICAR Transformylase Inosine Monophosphate Cyclohydrolase Deficiency (supp.)
C535793	Spondylometaphyseal dysplasia, ‘corner fracture’ type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2518 (SINGLE PROTEIN), CHEMBL3430882 (PROTEIN FAMILY), CHEMBL3885527 (PROTEIN FAMILY), CHEMBL3885528 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 527,786 (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
CHEMBL421	SULFASALAZINE	4	73,629

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10197559	Toxicity	3	methotrexate	Rheumatoid arthritis
rs16853826	Toxicity	3	methotrexate	Rheumatoid arthritis
rs2372536	Efficacy	4	methotrexate	Rheumatoid arthritis
rs4673993	Efficacy	2B	methotrexate	Rheumatoid arthritis

PharmGKB variants

12 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2177735	ATIC		0.00	0
rs2372536	ATIC	4	-6.75	1	methotrexate
rs3821353	ATIC		0.00	0
rs4673993	ATIC	2B	11.12	1	methotrexate
rs7563206	ATIC		0.00	0
rs10197559	ATIC	3	0.00	1	methotrexate
rs12995526	ATIC		0.00	0
rs16853826	ATIC	3	2.00	1	methotrexate
rs16853834	ATIC		0.00	0
rs17514110	ATIC		0.00	0
rs4673990	ATIC		0.00	0
rs4673991	ATIC		0.00	0

Binding affinities (BindingDB)

12 measured of 30 human assays (30 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
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
RY Analogue, 14	KI	685 nM
{4-[5-bromo-3-(sulfooxy)-1H-indol-2-yl]-13-chloro-3-thiatricyclo[7.4.0.0^{2,6}]trideca-1(9),2(6),4,7,10,12-hexaen-5-yl}oxidanesulfonic acid	IC50	1400 nM
5-chloro-2-{5-hydroxy-3-methyl-4-[(E)-2-[4-(4-methylphenoxysulfonyl)phenyl]diazen-1-yl]-1H-pyrazol-1-yl}benzene-1-sulfonic acid	IC50	3300 nM
2-[(E)-2-[5-hydroxy-3-methyl-1-(2-methyl-4-sulfophenyl)-1H-pyrazol-4-yl]diazen-1-yl]-4-sulfobenzoic acid	KI	7100 nM
4-{3-methyl-4-[(E)-2-[3-methyl-4-(phenylsulfamoyl)phenyl]diazen-1-yl]-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}benzene-1-sulfonic acid	IC50	11600 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
yellow 2G	IC50	20100 nM
4-chloro-2-[(E)-2-[5-hydroxy-3-methyl-1-(4-sulfophenyl)-1H-pyrazol-4-yl]diazen-1-yl]-6-sulfobenzoic acid	IC50	41600 nM
NSC-7524	IC50	231000 nM

ChEMBL bioactivities

79 potent at pChembl≥5 of 115 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.11	IC50	0.078	nM	CHEMBL4177183
9.85	IC50	0.14	nM	CHEMBL4162649
8.40	EC50	4	nM	CHEMBL4100363
8.22	Ki	6	nM	CHEMBL1231520
8.12	EC50	7.6	nM	CHEMBL4063104
8.12	IC50	7.5	nM	CHEMBL4170578
8.11	IC50	7.8	nM	CHEMBL4081385
8.10	EC50	8	nM	CHEMBL4063104
8.10	EC50	7.9	nM	CHEMBL4081385
8.10	Ki	8	nM	CHEMBL4168306
8.00	EC50	10	nM	CHEMBL4083899
8.00	IC50	10	nM	METHOTREXATE
7.92	IC50	12	nM	CHEMBL4091668
7.89	IC50	13	nM	CHEMBL4076500
7.89	IC50	13	nM	CHEMBL4070790
7.85	IC50	14	nM	CHEMBL4074469
7.80	IC50	16	nM	CHEMBL4063104
7.77	EC50	17	nM	CHEMBL4099409
7.75	IC50	18	nM	CHEMBL4079085
7.75	EC50	18	nM	CHEMBL4079085
7.70	IC50	20	nM	CHEMBL4099409
7.70	Kd	20	nM	CHEMBL608337
7.68	EC50	21	nM	CHEMBL4076500
7.60	EC50	25	nM	CHEMBL4074469
7.58	IC50	26	nM	CHEMBL4101204
7.57	EC50	27	nM	CHEMBL4091668
7.51	EC50	31	nM	CHEMBL4070790
7.37	IC50	43	nM	CHEMBL4174018
7.21	EC50	62	nM	CHEMBL4075503
7.17	EC50	68	nM	CHEMBL4101204
7.16	IC50	70	nM	PEMETREXED
7.14	EC50	73	nM	CHEMBL4063104
7.14	Kd	72.97	nM	CHEMBL5653589
7.14	ED50	72.97	nM	CHEMBL5653589
7.04	IC50	92	nM	CHEMBL4163732
6.97	IC50	107	nM	CHEMBL4166099
6.90	IC50	125	nM	CHEMBL608337
6.89	Ki	130	nM	CHEMBL484860
6.82	Ki	150	nM	CHEMBL484861
6.81	Ki	154	nM	CHEMBL375938
6.64	Ki	230	nM	CHEMBL485481
6.45	EC50	356	nM	CHEMBL4063104
6.40	Ki	400	nM	FAICAR
6.25	EC50	567	nM	CHEMBL4092503
6.22	IC50	608	nM	CHEMBL4092503
6.22	IC50	600	nM	CHEMBL375938
6.16	IC50	700	nM	CHEMBL13659
6.14	IC50	723	nM	CHEMBL4084757
6.06	Ki	880	nM	METHOTREXATE
6.06	Ki	880	nM	PEMETREXED

PubChem BioAssay actives

88 with measured affinity, of 353 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
(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
5-(5-ethyl-5-methyl-6-oxo-1,4-dihydropyridin-3-yl)-N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)thiophene-2-sulfonamide	1467848: Inhibition of AICARFT in human NCI-H460 cells assessed as increase in ZMP levels using low folate media after 16 hrs by LC-MS method	ec50	0.0040	uM
5-(5,5-dimethyl-6-oxo-1,4-dihydropyridin-3-yl)-N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0050	uM
N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)-5-(6-oxo-1H-pyridin-3-yl)thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0050	uM
(2S)-2-[[4-[(2-amino-4-oxo-3H-quinazolin-6-yl)sulfamoyl]benzoyl]amino]pentanedioic acid	1467902: Inhibition of human AICARFT	ki	0.0060	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
N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide	1467861: Inhibition of AICARFT in human MDA-MB-231 cells assessed as increase in ZMP levels using low folate media after 16 hrs by LC-MS method	ec50	0.0076	uM
5-[(3S,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl]-N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0078	uM
(2S)-2-[[4-[(2-amino-4-oxo-3H-quinazolin-6-yl)sulfonylamino]benzoyl]amino]pentanedioic acid	1501140: Inhibition of recombinant human AICARFTase using AICAR as substrate incubated at 37 degC for 30 mins measured after overnight incubation at 4 degC	ki	0.0080	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
5-[(4R)-3,3-difluoro-4-hydroxypyrrolidin-1-yl]-N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0120	uM
N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)-5-(4-hydroxypiperidin-1-yl)thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0130	uM
5-[(4S)-3,3-difluoro-4-hydroxypyrrolidin-1-yl]-N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0130	uM
N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)-5-[(3S)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0140	uM
5-[(3R,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl]-N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)thiophene-2-sulfonamide	1467848: Inhibition of AICARFT in human NCI-H460 cells assessed as increase in ZMP levels using low folate media after 16 hrs by LC-MS method	ec50	0.0170	uM
N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)-5-[(3S)-3-hydroxypiperidin-1-yl]thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0180	uM
(2S)-2-[[4-[(2-amino-4-oxo-4a,8a-dihydro-3H-pyrido[3,2-d]pyrimidin-6-yl)methyl-[(E)-3-[5-carbamoyl-3-[(3R,4S,5R)-3,4-dihydroxy-5-(phosphonooxymethyl)oxolan-2-yl]imidazol-4-yl]prop-2-enoyl]amino]benzoyl]amino]pentanedioic acid	31300: Binding affinity towards AICAR formyltransferase	kd	0.0200	uM
N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)-5-[(3R)-3-hydroxypiperidin-1-yl]thiophene-2-sulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.0260	uM
(2S)-2-[5-[[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)acetyl]amino]pentanoylamino]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	0.0430	uM
Pemetrexed	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	0.0700	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147903: Binding affinity to human ATIC incubated for 45 mins by Kinobead based pull down assay	kd	0.0730	uM
(2S)-2-[3-[[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)acetyl]amino]propanoylamino]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	0.0920	uM
(2S)-2-[4-[[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)acetyl]amino]butanoylamino]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	0.1070	uM
2,2-dioxo-1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4-one	1798215: IMPCH Activity Assay from Article 10.1074/jbc.m607293200: “Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.”	ki	0.1300	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-(2,2,4-trioxo-1H-imidazo[4,5-c][1,2,6]thiadiazin-7-yl)oxolan-2-yl]methyl dihydrogen phosphate	1798215: IMPCH Activity Assay from Article 10.1074/jbc.m607293200: “Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.”	ki	0.1500	uM
5-[(5-sulfamoylnaphthalen-2-yl)diazenyl]naphthalene-1-sulfonic acid	282344: Inhibition of human AICAR Tfase	ki	0.1540	uM
7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,2-dioxo-1H-imidazo[4,5-c][1,2,6]thiadiazin-4-one	1798215: IMPCH Activity Assay from Article 10.1074/jbc.m607293200: “Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.”	ki	0.2300	uM
[(2R,3S,4R,5R)-5-(4-carbamoyl-5-formamidoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate	360482: Inhibition of IMPCH activity of human wild-type ATIC	ki	0.4000	uM
4-cyano-N-(1-oxo-2H-isoquinolin-7-yl)benzenesulfonamide	1467848: Inhibition of AICARFT in human NCI-H460 cells assessed as increase in ZMP levels using low folate media after 16 hrs by LC-MS method	ec50	0.5670	uM
(2S)-2-acetamido-5-(diaminomethylideneamino)-N-[(2S)-1-(ethylamino)-3-(4-nitrophenyl)-1-oxopropan-2-yl]pentanamide	1799760: Enzyme Inhibition Assay from Article 10.1002/cbic.201200279: “Targeting Tumour Proliferation with a Small-Molecule Inhibitor of AICAR Transformylase Homodimerization.”	ki	0.6850	uM
(2S)-2-[[4-[3-(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)propylamino]benzoyl]amino]pentanedioic acid	31288: Hexaglutamyl homologue inhibition activity against the AICAR formyltransferase was determined against MOLT-4	ic50	0.7000	uM
4-cyano-N-(6-fluoro-1-oxo-2H-isoquinolin-7-yl)benzenesulfonamide	1467847: Inhibition of human full length N-terminal His-tagged AICARFT expressed in Escherichia coli BL21 (DE3) using ZMP/10-formyltetrahydrofolate as substrate assessed as decrease in IMP levels after 1 hr by mass spectrometric method	ic50	0.7230	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-3-fluorothiophene-2-carbonyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	0.9300	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-3-carbonyl]amino]pentanedioic acid	1709484: Inhibition of human full length N-terminal His-tagged ATIC expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in THF formation using 10-CHOTHF as substrate by spectrophotometric method	ki	1.0700	uM
[5-bromo-2-(9-chloro-3-sulfooxybenzo[g][1]benzothiol-2-yl)-1H-indol-3-yl] hydrogen sulfate	1798214: AICAR Tfase Inhibition Assay from Article 10.1074/jbc.M406801200: “Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening.”	ic50	1.4000	uM
(2S)-2-acetamido-5-(diaminomethylideneamino)-N-[(2S)-1-(ethylamino)-3-(4-nitrophenyl)-1-oxopropan-2-yl]-N-methylpentanamide	1799760: Enzyme Inhibition Assay from Article 10.1002/cbic.201200279: “Targeting Tumour Proliferation with a Small-Molecule Inhibitor of AICAR Transformylase Homodimerization.”	ki	2.5000	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]benzoyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	2.8200	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	2.9900	uM
3-iodo-N-[2-[[2-[(4-methoxyphenyl)methylamino]-2-oxoethyl]-[2-oxo-2-(2-phenylethylamino)ethyl]amino]-2-oxoethyl]benzamide	238193: Inhibition constant against AICAR formyltransferase	ki	3.1000	uM
5-chloro-2-[5-methyl-4-[[4-(4-methylphenoxy)sulfonylphenyl]diazenyl]-3-oxo-1H-pyrazol-2-yl]benzenesulfonic acid	1798214: AICAR Tfase Inhibition Assay from Article 10.1074/jbc.M406801200: “Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening.”	ic50	3.3000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147903: Binding affinity to human ATIC incubated for 45 mins by Kinobead based pull down assay	kd	3.3886	uM
(2S)-2-[[4-[4-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	3.7200	uM
4-[(5-aminonaphthalen-2-yl)sulfonylamino]benzoic acid	282344: Inhibition of human AICAR Tfase	ic50	4.1000	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propoxy]benzoyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	4.3800	uM
(2S)-2-[[4-[5-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]-2-fluorobenzoyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	4.7100	uM
(2S)-2-[[4-[3-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)propylsulfanyl]benzoyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	4.8100	uM
(2S)-2-[[5-[4-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl]amino]pentanedioic acid	1709484: Inhibition of human full length N-terminal His-tagged ATIC expressed in Chinese Hamster MTXRII-OuaR2-4 R2 cells assessed as reduction in THF formation using 10-CHOTHF as substrate by spectrophotometric method	ki	5.1500	uM
(2S)-2-[[4-[2-(2-amino-4-oxo-3H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]benzoyl]amino]pentanedioic acid	2011534: Binding affinity to N-terminal 6His-tagged full length human ATIC expressed in Escherichia coli Rosetta (DE3) pLysS assessed as inhibition constant by spectrophotometric analysis	ki	5.7400	uM
2-[[4-[(2-amino-4-oxo-3H-pyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]amino]pentanedioic acid	31281: Inhibitory activity against AICAR formyltransferase of Lactobacillus casei	ic50	6.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	4
Methotrexate	affects response to substance, decreases expression	4
chloropicrin	increases expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
salinomycin	decreases expression	1
methotrexate polyglutamate	affects abundance, affects cotreatment	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	increases secretion, affects cotreatment	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dinitrochlorobenzene	affects binding	1
Doxorubicin	decreases expression	1
Furaldehyde	affects localization, increases expression, decreases expression, affects cotreatment	1

ChEMBL screening assays

95 unique, capped per target: 95 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000393	Binding	Inhibition of human recombinant AICAR transformylase	Asymmetric synthesis of inhibitors of glycinamide ribonucleotide transformylase. — J Med Chem

Clinical trials (associated diseases)

200 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)
NCT06845501	Not specified	RECRUITING	Purine Supplementation in Patients With AICA-Ribosiduria
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