PAICS

Summary

PAICS (phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase, HGNC:8587) is a protein-coding gene on chromosome 4q12, encoding Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (P22234). Bifunctional phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase catalyzing two reactions of the de novo purine biosynthetic pathway. It is a selective cancer dependency (DepMap: 47.4% of cell lines).

This gene encodes a bifunctional enzyme containing phosphoribosylaminoimidazole carboxylase activity in its N-terminal region and phosphoribosylaminoimidazole succinocarboxamide synthetase in its C-terminal region. It catalyzes steps 6 and 7 of purine biosynthesis. The gene is closely linked and divergently transcribed with a locus that encodes an enzyme in the same pathway, and transcription of the two genes is coordinately regulated. The human genome contains several pseudogenes of this gene. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10606 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PAICS deficiency (Limited, GenCC)
• Clinical variants (ClinVar): 48 total — 3 likely-pathogenic
• GTEx eGene: eQTL in 15 tissues, sQTL in 11 (q < 0.05)
• Phenotypes (HPO): 24
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 47.4% of screened cell lines
• Constraint (gnomAD): pLI 0.40 (intermediate), LOEUF 0.77 (unconstrained)
• MANE Select transcript: NM_001079524
• Interaction hub: 3,442 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8587
Approved symbol	PAICS
Name	phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	ADE2H1, AIRC
Ensembl gene	ENSG00000128050
Ensembl biotype	protein_coding
OMIM	172439
Entrez	10606

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 39 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000512576

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 4

ENST00000512576, ENST00000264221, ENST00000399688, ENST00000504188, ENST00000505164, ENST00000508554, ENST00000510584, ENST00000514888, ENST00000879753, ENST00000879754, ENST00000879755, ENST00000879756, ENST00000879757, ENST00000913768, ENST00000913769, ENST00000913770, ENST00000913771, ENST00000913772, ENST00000913773, ENST00000913774, ENST00000913775, ENST00000913776, ENST00000913777, ENST00000963017, ENST00000979509, ENST00001073443, ENST00001092891, ENST00001092892, ENST00001092893, ENST00001092894, ENST00001092895, ENST00001092896, ENST00001092897, ENST00001092898, ENST00001092899, ENST00001092900, ENST00001092901, ENST00001092902, ENST00001092903, ENST00001092904, ENST00001092905, ENST00001113280, ENST00001129334, ENST00001138620

RefSeq mRNA: 6 — MANE Select: NM_001079524 NM_001079524, NM_001079525, NM_001392010, NM_001392011, NM_001392012, NM_006452

CCDS: CCDS47060, CCDS47061

Canonical transcript exons

ENST00000512576 — 9 exons

Exon	Start	End
ENSE00000877958	56448418	56448597
ENSE00000877959	56448710	56448823
ENSE00000877960	56450619	56450702
ENSE00000877961	56451872	56452052
ENSE00000877962	56453603	56453761
ENSE00002057525	56436260	56436328
ENSE00003469518	56441663	56441860
ENSE00003523494	56446695	56446873
ENSE00004793187	56459372	56464578

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 97.9745 / max 2114.6077, expressed in 1817 samples.

Highest expression (Bgee): ventricular zone, embryo, ganglionic eminence, rectum, mucosa of sigmoid colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PAICS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 11 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 26 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells EBV-transformed lymphocytes	sqtl	5.9e-16	+0.97	4:56497875:C:T
Thyroid	eqtl	6.5e-16	-0.21	4:56439036:T:C
Cells Cultured fibroblasts	sqtl	5.9e-10	+0.65	4:56506527:GCAGGCCCT:G
Skin Sun Exposed Lower leg	sqtl	2.2e-06	-0.38	4:56459310:A:G
Testis	eqtl	1.8e-05	-0.10	4:56347692:G:A
Esophagus Mucosa	sqtl	3.4e-05	-0.41	4:56459310:A:G
Muscle Skeletal	sqtl	1.3e-04	-0.29	4:56436878:TC:T
Skin Not Sun Exposed Suprapubic	eqtl	4.9e-04	-0.12	4:56663731:A:C
Adrenal Gland	sqtl	8.5e-04	-0.59	4:56439036:T:C
Adipose Visceral Omentum	sqtl	9.1e-04	-0.38	4:56444758:T:C
Brain Amygdala	eqtl	1.0e-03	+0.70	4:56274556:A:T
Skin Sun Exposed Lower leg	eqtl	1.2e-03	-0.09	4:56460240:G:A
Brain Cerebellum	sqtl	1.2e-03	+0.59	4:56439036:T:C
Thyroid	sqtl	1.3e-03	-0.43	4:56331791:T:C
Brain Cortex	eqtl	2.9e-03	-0.29	4:56318766:G:C
Brain Cerebellum	eqtl	3.5e-03	+1.00	4:55507222:C:T
Cells Cultured fibroblasts	eqtl	7.8e-03	+0.04	4:57105753:A:G
Spleen	eqtl	1.1e-02	+0.41	4:57245468:A:G
Esophagus Mucosa	eqtl	1.1e-02	-0.21	4:55702962:G:T
Heart Left Ventricle	eqtl	1.1e-02	-0.34	4:57338713:G:A

FANTOM5 promoters

showing 10 of 11 alternative TSS:

Promoter ID	TPM avg	Samples expressed
47728	77.6703	1790
47726	10.6728	1783
47724	3.3991	1265
47731	1.6361	733
47727	1.4561	983
47732	0.6973	387
47733	0.6445	347
47729	0.5870	328
47734	0.4632	224
47730	0.3788	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.45	gold quality
embryo	UBERON:0000922	97.65	gold quality
ganglionic eminence	UBERON:0004023	97.45	gold quality
rectum	UBERON:0001052	95.66	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.06	gold quality
lateral globus pallidus	UBERON:0002476	94.78	gold quality
islet of Langerhans	UBERON:0000006	94.62	gold quality
adrenal tissue	UBERON:0018303	94.39	gold quality
endometrium epithelium	UBERON:0004811	94.36	gold quality
cortical plate	UBERON:0005343	93.87	gold quality
endometrium	UBERON:0001295	93.79	gold quality
liver	UBERON:0002107	93.72	gold quality
colonic mucosa	UBERON:0000317	93.71	gold quality
vermiform appendix	UBERON:0001154	93.32	gold quality
stromal cell of endometrium	CL:0002255	92.90	gold quality
substantia nigra pars compacta	UBERON:0001965	92.77	gold quality
globus pallidus	UBERON:0001875	92.65	gold quality
caecum	UBERON:0001153	92.45	gold quality
medial globus pallidus	UBERON:0002477	92.44	gold quality
right lobe of liver	UBERON:0001114	92.43	gold quality
upper leg skin	UBERON:0004262	92.39	gold quality
adrenal gland	UBERON:0002369	92.35	gold quality
gingival epithelium	UBERON:0001949	92.34	gold quality
cranial nerve II	UBERON:0000941	92.33	gold quality
pigmented layer of retina	UBERON:0001782	92.30	gold quality
retina	UBERON:0000966	92.28	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.25	gold quality
left adrenal gland	UBERON:0001234	92.18	gold quality
right adrenal gland	UBERON:0001233	92.15	gold quality
smooth muscle tissue	UBERON:0001135	92.04	gold quality
left adrenal gland cortex	UBERON:0035825	91.92	gold quality
pons	UBERON:0000988	91.88	gold quality
tonsil	UBERON:0002372	91.80	gold quality
right adrenal gland cortex	UBERON:0035827	91.79	gold quality
gingiva	UBERON:0001828	91.78	gold quality
substantia nigra	UBERON:0002038	91.76	gold quality
adrenal cortex	UBERON:0001235	91.75	gold quality
cartilage tissue	UBERON:0002418	91.73	gold quality
midbrain	UBERON:0001891	91.66	gold quality
subthalamic nucleus	UBERON:0001906	91.66	gold quality
adult organism	UBERON:0007023	91.60	gold quality
superior vestibular nucleus	UBERON:0007227	91.60	gold quality
hypothalamus	UBERON:0001898	91.56	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.44	gold quality
spinal cord	UBERON:0002240	91.41	gold quality
esophagus mucosa	UBERON:0002469	91.36	gold quality
mucosa of transverse colon	UBERON:0004991	91.36	gold quality
nephron tubule	UBERON:0001231	91.29	gold quality
skin of hip	UBERON:0001554	91.06	gold quality
penis	UBERON:0000989	90.89	gold quality
pancreas	UBERON:0001264	90.87	gold quality
lymph node	UBERON:0000029	90.85	gold quality
gastrocnemius	UBERON:0001388	90.67	gold quality
placenta	UBERON:0001987	90.64	gold quality
skin of abdomen	UBERON:0001416	90.56	gold quality
zone of skin	UBERON:0000014	90.42	gold quality
oral cavity	UBERON:0000167	90.39	gold quality
entorhinal cortex	UBERON:0002728	90.39	gold quality
medulla oblongata	UBERON:0001896	90.38	gold quality
ventral tegmental area	UBERON:0002691	90.37	gold quality
ovary	UBERON:0000992	90.33	gold quality
choroid plexus epithelium	UBERON:0003911	90.32	gold quality
ectocervix	UBERON:0012249	90.25	gold quality
uterus	UBERON:0000995	90.24	gold quality
female reproductive system	UBERON:0000474	90.16	gold quality
parietal pleura	UBERON:0002400	90.16	gold quality
muscle of leg	UBERON:0001383	90.14	gold quality
skin of leg	UBERON:0001511	90.00	gold quality
amygdala	UBERON:0001876	89.91	gold quality
germinal epithelium of ovary	UBERON:0001304	89.87	gold quality
bone marrow	UBERON:0002371	89.83	gold quality
temporal lobe	UBERON:0001871	89.78	gold quality
body of pancreas	UBERON:0001150	89.72	gold quality
mammalian vulva	UBERON:0000997	89.70	gold quality
tibia	UBERON:0000979	89.69	gold quality
vagina	UBERON:0000996	89.63	gold quality
dorsal plus ventral thalamus	UBERON:0001897	89.60	gold quality
pericardium	UBERON:0002407	89.55	gold quality
right ovary	UBERON:0002118	89.52	gold quality
left ovary	UBERON:0002119	89.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.50	gold quality
prefrontal cortex	UBERON:0000451	89.48	gold quality
metanephros	UBERON:0000081	89.46	gold quality
renal medulla	UBERON:0000362	89.40	gold quality
kidney	UBERON:0002113	89.34	gold quality
cortex of kidney	UBERON:0001225	89.33	gold quality
inferior vagus X ganglion	UBERON:0005363	89.27	gold quality
squamous epithelium	UBERON:0006914	89.10	gold quality
postcentral gyrus	UBERON:0002581	89.07	gold quality
right uterine tube	UBERON:0001302	89.04	gold quality
inferior olivary complex	UBERON:0002127	89.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.00	gold quality
trabecular bone tissue	UBERON:0002483	88.98	gold quality
superior frontal gyrus	UBERON:0002661	88.89	gold quality
esophagus	UBERON:0001043	88.85	gold quality
duodenum	UBERON:0002114	88.85	gold quality
adult mammalian kidney	UBERON:0000082	88.82	gold quality
left uterine tube	UBERON:0001303	88.79	gold quality
endocervix	UBERON:0000458	88.72	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	136.62
E-HCAD-5	yes	37.95
E-MTAB-9067	yes	21.95
E-CURD-112	yes	20.11
E-CURD-122	yes	19.48
E-GEOD-93593	yes	15.56
E-MTAB-10042	yes	14.32
E-MTAB-6819	no	1629.72
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	102.5	high
Caudate putamen	tissue	101.4
Frontal cortex	tissue	100.4
Tonsil	tissue	60.4	high
Thymus	tissue	52.5
Rectum	tissue	51.4	high
Breast	tissue	51.0	high
Lymph node	tissue	47.8	high
Bone marrow	tissue	44.2	high
Placenta	tissue	43.2	high
Locus coeruleus	tissue	43.0
Colon	tissue	40.1	high
Kidney	tissue	39.8	high
Adrenal gland	tissue	38.0	high
Appendix	tissue	37.8	high
Parathyroid gland	tissue	37.2	high
Skin 1	tissue	35.5	high
Urinary bladder	tissue	35.0	high
Smooth muscle	tissue	33.4	medium
Fallopian tube	tissue	33.3	high
Choroid plexus	tissue	33.2
Postcentral gyrus	tissue	32.3
Esophagus	tissue	31.3	high
Thyroid gland	tissue	30.4	high
Ovary	tissue	30.3	medium
Duodenum	tissue	30.2	high
Prostate	tissue	29.1	high
Small intestine	tissue	29.0	high
Retina	tissue	28.1
Endometrium 1	tissue	27.7	high
Testis	tissue	27.6	high
Cervix	tissue	27.5	high
Nucleus accumbens	tissue	27.2
Spinal cord	tissue	26.6
Hippocampus	tissue	26.2	high
Salivary gland	tissue	24.9	medium
Seminal vesicle	tissue	24.3	high
Vagina	tissue	24.0	high
Adipose tissue	tissue	23.0	medium
Tongue	tissue	22.6
Corpus callosum	tissue	21.8
Skeletal muscle	tissue	21.2	low
Epididymis	tissue	20.9	high
Medulla oblongata	tissue	19.8
Pancreas	tissue	19.7	high
Substantia nigra	tissue	19.6
Stomach 1	tissue	19.5	high
Midbrain	tissue	19.5
Heart muscle	tissue	18.4	low
Hippocampal formation	tissue	18.4
Periaqueductal gray	tissue	17.7
Superior colliculi	tissue	17.6
Septum	tissue	17.3
Spleen	tissue	17.2	high
Hypothalamus	tissue	17.1
Thalamus	tissue	16.7
Gallbladder	tissue	16.7	high
Pituitary gland	tissue	16.6
Pons	tissue	16.6
Amygdala	tissue	16.3

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Inferior colliculus (50.7), Cerebellar nuclei (47.1), Mammillary body (46.1), Periaquaductal grey, dorsal (45.0), Posterior thalamic nucleus (44.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

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

showing 30 of 101 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488

Functional genomics

gnomAD constraint: pLI 0.397, LOEUF 0.772, missense Z 0.429 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000512576 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
4:56,436,313–56,448,547	168 / 199.3	0.84	no
4:56,448,548–56,453,695	131 / 205.5	0.64	no
4:56,453,696–56,459,535	95 / 89.3	1.06	no
DepMap (CRISPR cell-line fitness): dependent in 47.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): HCC1806 (-1.832), KMS-11 (-1.795), SNU-C5 (-1.757), SU-DHL-5 (-1.728), SU-DHL-1 (-1.725), PC-14 (-1.683), U-937 (-1.658), KATO III (-1.654), KCL-22 (-1.632), NCI-H211 (-1.607), PF-382 (-1.599), SU-DHL-10 (-1.598), Reh (-1.597), DEL (-1.55), Ki-JK (-1.545).

Literature-anchored findings (GeneRIF, showing 11)

• purine biosynthetic pathway enzymes PPAT and PAICS, as well as pyruvate kinase activity are increased in lung cancer (PMID:26140362)
• we show that PAICS, which catalyzes a critical step in purine biosynthetic pathway, is overexpressed and plays a role in BLCA cell proliferation, colony formation, and 3D spheroid invasion, suggesting a role in oncogenesis. (PMID:30121007)
• PAICS is hypomethylated in the lung adenocarcinoma tissues.PAICS is highly expressed in the lung adenocarcinoma tissues. (PMID:30641222)
• Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy. (PMID:31624245)
• Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target. (PMID:32571877)
• PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2. (PMID:32632107)
• PAICS is related to glioma grade and can promote glioma growth and migration. (PMID:34173716)
• Regulating COX10-AS1 / miR-142-5p / PAICS axis inhibits the proliferation of non-small cell lung cancer. (PMID:34323174)
• Evidence Supporting Substrate Channeling between Domains of Human PAICS: A Time-Course Analysis of (13)C-Bicarbonate Incorporation. (PMID:35285625)
• Multienzyme interactions of the de novo purine biosynthetic protein PAICS facilitate purinosome formation and metabolic channeling. (PMID:35331738)
• PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly. (PMID:37848033)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	paics	ENSDARG00000033539
mus_musculus	Paics	ENSMUSG00000029247
rattus_norvegicus	Paics	ENSRNOG00000002101
drosophila_melanogaster	Paics	FBGN0020513
caenorhabditis_elegans		WBGENE00015116

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1914304) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
preweaning lethality, complete penetrance	1
prenatal lethality prior to heart atrial septation	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
Chloroflexus aurantiacus J-10-fl	A9WK38	100.0%	Diamond
Chloroflexus aurantiacus Y-400-fl	B9LC05	100.0%	Diamond
Cryptococcus deneoformans JEC21	P0CQ36	99.1%	Diamond
Cryptococcus deneoformans B-3501A	P0CQ37	99.1%	Diamond
Pongo abelii	Q5RB59	98.4%	Diamond
Cryptococcus neoformans H99	P0C017	98.1%	Diamond
Roseiflexus sp. RS-1	A5UWC5	91.1%	Diamond
Roseiflexus castenholzii DSM 13941	A7NKB4	91.1%	Diamond
Chloroflexus aggregans DSM 9485	B8GCM2	86.6%	Diamond
Gallus gallus	P38024	86.0%	Diamond
Mycobacterium leprae TN	P46702	81.5%	Diamond
Schwanniomyces occidentalis	P50504	80.9%	Diamond
Pyrococcus horikoshii OT3	O58058	76.5%	Diamond
Pyrococcus abyssi GE5	Q9UY68	76.5%	Diamond
Dictyostelium discoideum	Q54QE4	74.0%	Diamond
Thermotoga maritima MSB8	Q9WYS7	73.8%	Diamond
Aquifex aeolicus VF5	O67239	72.7%	Diamond
Corynebacterium ammoniagenes	Q44679	68.8%	Diamond
Pseudomonas aeruginosa PAO1	P72157	67.3%	Diamond
Herpetosiphon aurantiacus DSM 785	A9B302	61.0%	Diamond
Methanocaldococcus jannaschii DSM 2661	Q58033	57.6%	Diamond
Methanobrevibacter smithii	P22348	56.5%	Diamond
Archaeoglobus fulgidus DSM 4304	O28997	51.0%	Diamond
Treponema denticola ATCC 35405	Q73PV9	51.0%	Diamond
Methanothermobacter thermautotrophicus str. Delta H	P41654	48.7%	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
AASDH	protein-coding	132949
PPAT	protein-coding	5471
CRACD	protein-coding	57482
SPMAP2L	protein-coding	100506564
HOPX-AS1	ncRNA	124900708
ARL9	protein-coding	132946
SRP72	protein-coding	6731
HOPX	protein-coding	84525

Protein

Protein identifiers

Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase — P22234 (reviewed: P22234)

All UniProt accessions (3): D6RF62, E9PBS1, P22234

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase catalyzing two reactions of the de novo purine biosynthetic pathway.

Subunit / interactions. Homooctamer.

Disease relevance. Phosphoribosylaminoimidazole carboxylase deficiency (PAICSD) [MIM:619859] An autosomal recessive inborn error of purine metabolism, clinically characterized by multiple congenital anomalies and early neonatal death. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Purine metabolism; IMP biosynthesis via de novo pathway; 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate: step 1/2. Purine metabolism; IMP biosynthesis via de novo pathway; 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate from 5-amino-1-(5-phospho-D-ribosyl)imidazole (carboxylase route): step 1/1.

Similarity. In the N-terminal section; belongs to the SAICAR synthetase family. In the C-terminal section; belongs to the AIR carboxylase family. Class II subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P22234-1	1	yes
P22234-2	2

RefSeq proteins (6): NP_001072992, NP_001072993, NP_001378939, NP_001378940, NP_001378941, NP_006443 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000031	PurE_dom	Domain
IPR018236	SAICAR_synthetase_CS	Conserved_site
IPR028923	SAICAR_synt/ADE2_N	Domain
IPR033626	PurE_classII	Domain
IPR050089

Pfam: PF00731, PF01259

Enzyme classification (BRENDA)

• EC 4.1.1.21 — phosphoribosylaminoimidazole carboxylase (BRENDA: 16 organisms, 12 substrates, 11 inhibitors, 5 Km, 4 kcat entries)
• EC 6.3.2.6 — phosphoribosylaminoimidazolesuccinocarboxamide synthase (BRENDA: 23 organisms, 27 substrates, 38 inhibitors, 4 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-CARBOXY-5-AMINOIMIDAZOLE RIBONUCLEOTIDE	0.0038–0.009	2
1-(5-PHOSPHORIBOSYL)-5-AMINOIMIDAZOLE	0.076	1
5-AMINOIMIDAZOLE RIBONUCLEOTIDE	0.06	1
CO2	13	1
1-(5’-PHOSPHORIBOSYL)-5-AMINO-4-CARBOXYIMIDAZOLE	1.3	1
ASP	0.036	1
MGATP2-	0.04	1

Catalyzed reactions (Rhea)

• 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate + H(+) = 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole + CO2 (RHEA:10792)
• 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate + L-aspartate + ATP = (2S)-2-[5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamido]succinate + ADP + phosphate + 2 H(+) (RHEA:22628)

UniProt features (64 total): helix 18, strand 17, modified residue 8, turn 6, mutagenesis site 4, region of interest 3, sequence variant 2, sequence conflict 2, initiator methionine 1, chain 1, splice variant 1, binding site 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
6YB8	Human octameric PAICS in complex with CAIR and SAICAR	X-RAY DIFFRACTION	2.36
6YB9	Human octameric PAICS in complex with SAICAR, AMP-PNP, and magnesium	X-RAY DIFFRACTION	2.41
2H31	Crystal structure of human PAICS, a bifunctional carboxylase and synthetase in purine …	X-RAY DIFFRACTION	2.8
7ALE	Crystal structure of human PAICS in complex with inhibitor 69	X-RAY DIFFRACTION	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22234-F1	95.96	0.95

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Lyases, Ligase, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

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.

Ligand- & substrate-binding residues (1)

Position	Role
332	CO2

Post-translational modifications (8)

Type	Positions
Phosphoserine	107, 274, 27
Phosphothreonine	238
N6-acetyllysine	247, 36
N-acetylalanine	2
Phosphotyrosine	22

Mutagenesis-validated functional residues (4)

Position	Phenotype
303	loss of phosphoribosylaminoimidazole carboxylase activity.
332	loss of phosphoribosylaminoimidazole carboxylase activity.
334	loss of phosphoribosylaminoimidazole carboxylase activity.
400	no effect on phosphoribosylaminoimidazole carboxylase activity.

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: 414 (showing top): GNF2_CKS1B, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, HORIUCHI_WTAP_TARGETS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, BASSO_B_LYMPHOCYTE_NETWORK, MODULE_56, MATTIOLI_MGUS_VS_PCL, 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, MODULE_16, USF_C

GO Biological Process (6): GMP biosynthetic process (GO:0006177), ‘de novo’ IMP biosynthetic process (GO:0006189), purine nucleobase biosynthetic process (GO:0009113), ‘de novo’ AMP biosynthetic process (GO:0044208), ‘de novo’ XMP biosynthetic process (GO:0097294), purine nucleotide biosynthetic process (GO:0006164)

GO Molecular Function (11): phosphoribosylaminoimidazole carboxylase activity (GO:0004638), phosphoribosylaminoimidazolesuccinocarboxamide synthase activity (GO:0004639), ATP binding (GO:0005524), identical protein binding (GO:0042802), cadherin binding (GO:0045296), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), lyase activity (GO:0016829), carboxy-lyase activity (GO:0016831), ligase activity (GO:0016874)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), 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

28 GO namespaces:

Category	Terms
cellular anatomical structure	3
purine-containing compound biosynthetic process	2
catalytic activity	2
purine ribonucleotide biosynthetic process	1
purine ribonucleoside monophosphate biosynthetic process	1
GMP metabolic process	1
IMP biosynthetic process	1
purine nucleobase metabolic process	1
nucleobase biosynthetic process	1
AMP biosynthetic process	1
XMP biosynthetic process	1
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
carboxy-lyase activity	1
acid-amino acid ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein binding	1
cell adhesion molecule binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
carbon-carbon lyase activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 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
purine nucleobase biosynthetic process	BP	direct assay
cytoplasm	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
cadherin binding	MF	high-throughput assay
identical protein binding	MF	physical interaction
phosphoribosylaminoimidazole carboxylase activity	MF	direct assay
phosphoribosylaminoimidazolesuccinocarboxamide synthase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,442 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAICS	PPAT	Q06203	985
PAICS	CHD7	Q9P2D1	920
PAICS	GART	P22102	877
PAICS	HPRT1	P00492	813
PAICS	MYB	P10242	791
PAICS	LGALS4	P56470	772
PAICS	ATIC	P31939	767
PAICS	ADSL	P30566	766
PAICS	CDH17	Q12864	760
PAICS	TRPC4	Q9UBN4	737
PAICS	LGALS2	P05162	719
PAICS	PFAS	O15067	711
PAICS	RAD52	P43351	683
PAICS	PRDM16	Q9HAZ2	679
PAICS	LGALS7B	P47929	655

IntAct

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

showing 30 of 36 partners by confidence:

Partner	Interaction type	MIscore	Records
L3MBTL2	physical association	0.720	6
FXR2	physical association	0.710	4
LNX1	physical association	0.670	4
NUDT18	physical association	0.620	3
CDC37	physical association	0.560	3
FAA2	physical association	0.560	3
PIAS2	physical association	0.560	3
PILRA	physical association	0.560	3
RAD54L2	physical association	0.560	3
RNF4	physical association	0.560	3
SRP1	physical association	0.560	3
UBE2I	physical association	0.560	3
ZMYM2	physical association	0.560	3
E6	physical association	0.490	3
NIF3L1	physical association	0.490	2
CEP76	physical association	0.370	1
FXR1	physical association	0.370	1
PRKAG1	physical association	0.370	1
SMARCD1	physical association	0.370	1
TERF1	physical association	0.370	1
CCNA1	physical association	0.000	1
CHD3	physical association	0.000	1
DGKE	physical association	0.000	1
EIF1B	physical association	0.000	1
EIF6	physical association	0.000	1
EPB41	physical association	0.000	1
FTSJ1	physical association	0.000	1
GNAS	physical association	0.000	1
HLA-B	physical association	0.000	1
LCOR	physical association	0.000	1

BioGRID (426 interactions; top human partners by supporting records): ASB11 (Proximity Label-MS; 4 records), FXR2 (Two-hybrid; 4 records), UBAP2 (Proximity Label-MS; 4 records), PARK2 (Affinity Capture-MS; 3 records), ACTR2 (Affinity Capture-MS; 2 records), CALD1 (Co-fractionation; 2 records), CUL3 (Affinity Capture-MS; 2 records), EPB41 (Affinity Capture-MS; 2 records), GART (Co-fractionation; 2 records), HSPA1A (Affinity Capture-MS; 2 records), HUWE1 (Affinity Capture-MS; 2 records), KCNA3 (Proximity Label-MS; 2 records), L3MBTL2 (Two-hybrid; 2 records), LNX1 (Two-hybrid; 2 records), MAP1LC3B (Proximity Label-MS; 2 records)

SIGNOR signaling

5 signaling interactions:

A	Effect	B	Mechanism
PAICS	“down-regulates quantity”	5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium	“chemical modification”
PAICS	“up-regulates quantity”	5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	“chemical modification”
PAICS	“down-regulates quantity”	L-aspartate(1-)	“chemical modification”
PAICS	“up-regulates quantity”	SAICAR(4-)	“chemical modification”
PAICS	“down-regulates quantity”	5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	“chemical modification”

Disease & clinical

Genetic variants

Variant evidence for PAICS: 48 ClinVar records (3 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	28
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (3)

Showing all 3 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
1686821	NM_001079524.2(PAICS):c.158A>G (p.Lys53Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
4850860	NM_001079524.2(PAICS):c.843_844del (p.Cys281_Glu282delinsTer)	Likely pathogenic	criteria provided, single submitter	1
3242227	NM_001079524.2(PAICS):c.535T>C (p.Ser179Pro)	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PAICS’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; 29 predictions of 757):

Position(s)	Effect	Δscore	Sites
4:56441661–56441662	acceptor_loss	1.0000	3
4:56446693–56446694	acceptor_loss	1.0000	3
4:56448416–56448417	acceptor_loss	1.0000	6
4:56448824–56448825	donor_loss	1.0000	5
4:56451850	acceptor_gain	1.0000
4:56451934	acceptor_gain	1.0000
4:56452041	donor_gain	1.0000
4:56436329–56436330	donor_loss	0.9900	5
4:56441660	acceptor_gain	0.9900
4:56441661–56441662	acceptor_loss	0.9900	3

AlphaMissense

1,274 missense substitutions predicted likely pathogenic (of 2,790 scored), across 307 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
M93	9	0.926	0.992
D212	8	0.998	0.999
D189	8	0.997	0.999
D227	8	0.995	0.999
D210	8	0.993	0.997
D137	8	0.991	0.997
D207	8	0.991	0.996
D277	8	0.983	0.991
D133	8	0.979	0.993
H303	8	0.978	0.996
D361	8	0.974	0.990
F121	8	0.962	0.996
S332	8	0.961	0.998
F173	8	0.948	0.996
F65	8	0.916	0.981
F86	8	0.866	0.973
N248	8	0.831	0.951
F325	8	0.823	0.989
W217	7	0.995	0.999
E97	7	0.992	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.57e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	1.7e-05
Lung Adenocarcinoma (TCGA)	unfavorable	5.52e-05
Lung Adenocarcinoma (validation)	unfavorable	0.000241
Rectum Adenocarcinoma (TCGA)	favorable	0.000273

Disease associations

OMIM: gene MIM:172439 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
PAICS deficiency	Limited	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Fetal anomalies	green
Hypotonic infant	amber
Leukodystrophy, childhood onset	amber
Likely inborn error of metabolism	amber
Paediatric disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (1): PAICS deficiency (MONDO:0859003)

HPO phenotypes

24 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000452	Choanal stenosis
HP:0000453	Choanal atresia
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000921	Missing ribs
HP:0001561	Polyhydramnios
HP:0001762	Talipes equinovarus
HP:0002032	Esophageal atresia
HP:0002575	Tracheoesophageal fistula
HP:0003196	Short nose
HP:0003811	Neonatal death
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0004502	Bilateral choanal atresia
HP:0005280	Depressed nasal bridge
HP:0008439	Lumbar hemivertebrae
HP:0008689	Bilateral cryptorchidism
HP:0008743	Coronal hypospadias
HP:0011461	Fetal onset
HP:0012368	Flat face

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5922 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,542 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3301622	GILTERITINIB	4	2,542

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

29 measured of 46 human assays (47 total across all organisms); most potent 29 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1-methylazetidin-3-yl)methyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-chlorophenyl]piperazine-1-carboxylate	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-(cyclopropylamino)ethyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-bromophenyl]piperazine-1-carboxylate	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-(dimethylamino)ethyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-bromophenyl]piperazine-1-carboxylate	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
3-(dimethylamino)propyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-bromophenyl]piperazine-1-carboxylate	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-(methylamino)ethyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-bromophenyl]piperazine-1-carboxylate	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
(1-methylazetidin-3-yl) 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-bromophenyl]piperazine-1-carboxylate	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
N-[2-bromo-6-[4-[(1-methylazetidin-3-yl)methyl]-3-oxopiperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-bromo-6-[4-[2-(dimethylamino)ethyl]-3-oxopiperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-(methylamino)ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-(dimethylamino)ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-(4-methylpiperazin-1-yl)ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-[2-(dimethylamino)ethylamino]ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-(propan-2-ylamino)ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-[(1-methylpiperidin-4-yl)amino]ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-(ethylamino)ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-(propylamino)ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[3-(dimethylamino)propylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[3-(methylamino)propylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-(4-piperidin-4-ylsulfonylpiperazin-1-yl)phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-(1-methylpiperidin-4-yl)sulfonylpiperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	17.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
3-(dimethylamino)propyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-chlorophenyl]piperazine-1-carboxylate	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-(methylamino)ethyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-chlorophenyl]piperazine-1-carboxylate	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
pyrrolidin-3-yl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-chlorophenyl]piperazine-1-carboxylate	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-(dimethylamino)ethyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-chlorophenyl]piperazine-1-carboxylate	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
(1-methylazetidin-3-yl) 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-chlorophenyl]piperazine-1-carboxylate	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-(cyclopropylamino)ethyl 4-[3-[(2-amino-1,3-oxazole-4-carbonyl)amino]-4-chlorophenyl]piperazine-1-carboxylate	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[5-[4-(2-aminoethylsulfonyl)piperazin-1-yl]-2-chlorophenyl]-1,3-oxazole-4-carboxamide	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
2-amino-N-[2-chloro-5-[4-[2-(cyclopropylamino)ethylsulfonyl]piperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide	IC50	62.5 nM	US-10961233: Oxazole derivatives for use in the treatment of cancer
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

43 potent at pChembl≥5 of 43 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	IC50	10	nM	CHEMBL4439335
8.00	IC50	10	nM	CHEMBL4586958
8.00	IC50	10	nM	CHEMBL4445327
8.00	IC50	10	nM	CHEMBL4516567
8.00	IC50	10	nM	CHEMBL4514185
8.00	IC50	10	nM	CHEMBL4551539
8.00	IC50	10	nM	CHEMBL4575613
8.00	IC50	10	nM	CHEMBL4466413
8.00	IC50	10	nM	CHEMBL4536252
8.00	IC50	10	nM	CHEMBL4442163
8.00	IC50	10	nM	CHEMBL4474352
8.00	IC50	10	nM	CHEMBL4468822
8.00	IC50	10	nM	CHEMBL4438093
8.00	IC50	10	nM	CHEMBL4459387
8.00	IC50	10	nM	CHEMBL4578668
8.00	IC50	10	nM	CHEMBL4455550
8.00	IC50	10	nM	CHEMBL4565482
8.00	IC50	10	nM	CHEMBL4546611
8.00	IC50	10	nM	CHEMBL4518584
8.00	IC50	10	nM	CHEMBL4593253
8.00	IC50	10	nM	CHEMBL4446674
7.69	Kd	20.52	nM	CHEMBL3752910
7.69	ED50	20.52	nM	CHEMBL3752910
7.60	IC50	25	nM	CHEMBL4451506
7.60	IC50	25	nM	CHEMBL4470155
7.60	IC50	25	nM	CHEMBL4462176
7.60	IC50	25	nM	CHEMBL4444329
7.60	IC50	25	nM	CHEMBL4445038
7.60	IC50	25	nM	CHEMBL4585820
7.60	IC50	25	nM	CHEMBL4516092
7.60	IC50	25	nM	CHEMBL4446513
7.60	IC50	25	nM	CHEMBL4454750
7.60	IC50	25	nM	CHEMBL4473997
7.60	IC50	25	nM	CHEMBL4476811
7.60	IC50	25	nM	CHEMBL4466767
7.60	IC50	25	nM	CHEMBL4538041
7.60	IC50	25	nM	CHEMBL4590239
7.60	IC50	25	nM	CHEMBL4458444
7.60	IC50	25	nM	CHEMBL4570990
7.60	IC50	25	nM	CHEMBL4578225
7.26	Kd	54.77	nM	CHEMBL5653589
7.26	ED50	54.77	nM	CHEMBL5653589
5.26	Kd	5481	nM	GILTERITINIB

PubChem BioAssay actives

3 with measured affinity, of 250 total; 3 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148931: Binding affinity to human PAICS incubated for 45 mins by Kinobead based pull down assay	kd	0.0205	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148931: Binding affinity to human PAICS incubated for 45 mins by Kinobead based pull down assay	kd	0.0548	uM
Gilteritinib	1425098: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	5.4810	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment	4
Tretinoin	decreases expression	4
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	2
bisphenol S	increases expression	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Estradiol	increases expression	2
Nickel	decreases expression, increases expression	2
Ozone	increases abundance, affects cotreatment, increases oxidation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression	1
ochratoxin A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
hydroquinone	decreases expression	1
quinoline	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991811	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — *Science*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1PJ	Abcam K-562 PAICS KO	Cancer cell line	Female
CVCL_D2L5	Abcam Raji PAICS KO	Cancer cell line	Male
CVCL_WQ20	Abcam Jurkat PAICS KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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