CPS1

Summary

CPS1 (carbamoyl-phosphate synthase 1, HGNC:2323) is a protein-coding gene on chromosome 2q34, encoding Carbamoyl-phosphate synthase [ammonia], mitochondrial (P31327). Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.

The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.

Source: NCBI Gene 1373 — RefSeq curated summary.

At a glance

• Gene–disease (curated): carbamoyl phosphate synthetase I deficiency disease (Definitive, ClinGen)
• Clinical variants (ClinVar): 2,276 total — 113 pathogenic, 247 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• MANE Select transcript: NM_001875

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2323
Approved symbol	CPS1
Name	carbamoyl-phosphate synthase 1
Location	2q34
Locus type	gene with protein product
Status	Approved
Aliases	GATD6
Ensembl gene	ENSG00000021826
Ensembl biotype	protein_coding
OMIM	608307
Entrez	1373

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 16 protein_coding, 4 retained_intron, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000233072, ENST00000430249, ENST00000451903, ENST00000467353, ENST00000470791, ENST00000479988, ENST00000497121, ENST00000497163, ENST00000645825, ENST00000671984, ENST00000673510, ENST00000673630, ENST00000673698, ENST00000673711, ENST00000674074, ENST00000881558, ENST00000881559, ENST00000881560, ENST00000881561, ENST00000881562, ENST00000881563, ENST00000881564, ENST00000921372, ENST00000921373, ENST00000965726

RefSeq mRNA: 4 — MANE Select: NM_001875 NM_001122633, NM_001369256, NM_001369257, NM_001875

CCDS: CCDS2393

Canonical transcript exons

ENST00000233072 — 38 exons

Exon	Start	End
ENSE00000411838	210582617	210582709
ENSE00000411839	210588058	210588147
ENSE00000411841	210590800	210590906
ENSE00000411842	210591831	210591969
ENSE00000411843	210592879	210592956
ENSE00000411847	210600555	210600712
ENSE00000411848	210602202	210602330
ENSE00000411849	210605102	210605246
ENSE00000411850	210606731	210606941
ENSE00000411852	210612117	210612293
ENSE00000411853	210616423	210616541
ENSE00000411858	210647863	210648057
ENSE00000411859	210648473	210648540
ENSE00000411861	210654025	210654102
ENSE00000411863	210658599	210658688
ENSE00000411866	210668186	210668284
ENSE00000411867	210674902	210674961
ENSE00000785357	210590106	210590234
ENSE00000785365	210599372	210599561
ENSE00000785370	210608361	210608559
ENSE00000785381	210650363	210650438
ENSE00000785385	210656525	210656632
ENSE00000785388	210663123	210663197
ENSE00001631521	210579714	210579770
ENSE00001677593	210576346	210576490
ENSE00001789225	210577421	210577510
ENSE00001851340	210556599	210556859
ENSE00002025675	210573298	210573407
ENSE00003510977	210637702	210637843
ENSE00003541625	210594508	210594606
ENSE00003544044	210639996	210640059
ENSE00003553760	210677007	210677136
ENSE00003563356	210660485	210660655
ENSE00003564748	210677887	210679107
ENSE00003626885	210595487	210595582
ENSE00003649177	210675728	210675840
ENSE00003679038	210639150	210639215
ENSE00003694550	210642484	210642665

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 99.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.8004 / max 2562.8467, expressed in 1046 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25026	13.9764	99
25015	3.3717	914
25014	0.4540	234
25013	0.4366	221
25016	0.3958	194
25033	0.0565	25
25031	0.0461	23
25038	0.0265	11
25017	0.0212	15
25025	0.0156	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	99.53	gold quality
right lobe of liver	UBERON:0001114	99.51	gold quality
jejunal mucosa	UBERON:0000399	99.42	gold quality
duodenum	UBERON:0002114	96.49	gold quality
buccal mucosa cell	CL:0002336	96.23	gold quality
ileal mucosa	UBERON:0000331	94.97	gold quality
secondary oocyte	CL:0000655	93.43	gold quality
oocyte	CL:0000023	91.46	gold quality
medial globus pallidus	UBERON:0002477	90.98	gold quality
small intestine	UBERON:0002108	89.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.52	gold quality
globus pallidus	UBERON:0001875	86.96	gold quality
jejunum	UBERON:0002115	85.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.78	gold quality
male germ cell	CL:0000015	83.97	silver quality
sperm	CL:0000019	83.96	silver quality
olfactory bulb	UBERON:0002264	82.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.93	gold quality
type B pancreatic cell	CL:0000169	81.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.00	gold quality
endothelial cell	CL:0000115	80.45	silver quality
spinal cord	UBERON:0002240	79.84	gold quality
substantia nigra	UBERON:0002038	79.33	gold quality
stromal cell of endometrium	CL:0002255	78.09	gold quality
inferior olivary complex	UBERON:0002127	77.57	gold quality
midbrain	UBERON:0001891	77.42	gold quality
right testis	UBERON:0004534	76.42	gold quality
testis	UBERON:0000473	76.19	gold quality
left testis	UBERON:0004533	75.94	gold quality
colonic epithelium	UBERON:0000397	75.74	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	1695.94
E-HCAD-9	yes	1257.70
E-GEOD-125970	yes	26.37
E-ANND-3	yes	11.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

106 targeting CPS1, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-3910	99.95	71.13	2227
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

Literature-anchored findings (GeneRIF, showing 40)

• The entire DNA sequence of the human CPS1 gene is presented, including all exon-intron boundaries. (PMID:12655559)
• CPSI T1405N genotype appears to be an important new factor in predicting susceptibility to pulmonry hypertension following surgical repair of congenital cardiac defects in children. (PMID:17188582)
• CPPS1 T1404N polymorphism may be associated with the risk of necrotizing enterocolitis in preterm infants. (PMID:17597649)
• Tight hydrogen binding mode is supported by the observation of reduced NAG affinity upon mutation of N-acetyl-L-glutamate-interacting residues of CPSI (PMID:19754428)
• Allelic imbalance may explain clinical variability in CPS1 deficiency in some families. (PMID:19793055)
• The differential expression of Hep Par 1(carbamoyl phosphate synthetase I) in dysplastic vs malignant tumors of the small intestine may be diagnostically useful in difficult cases. (PMID:19926579)
• CPS1, MUT, NOX4, and DPEP1 is associated with plasma homocysteine in healthy Women. (PMID:20031578)
• These data confirm a recent finding that CPS1 is a locus influencing homocysteine levels in women and suggest that genetic effects on Hcy may differ across developmental stages. (PMID:20154341)
• The present study in preterm infants did not confirm the earlier reported association between CPS1 genotype and L-arginine levels in term infants. (PMID:20520828)
• Data reported five of the CPS1 mutations (p.T471N, p.Q678P, p.P774L, p.R1453Q, and p.R1453W) in severe CPS1D patients. (PMID:20578160)
• structure-function analysis and pathogenicity-testing of mutations in CPS1 (PMID:20800523)
• This is the first large-scale report of CPS1 mutations spanning a wide variety of molecular defects highlighting important regions in this protein. (PMID:21120950)
• DNA methylation is a key mechanism of silencing CPS1 expression in human hepatocellular carcinoma cells. (PMID:21281797)
• Case Report: Late-onset carbamoyl phosphate synthetase 1 deficiency in an adult cured by liver transplantation. (PMID:21837743)
• Mutation analysis in these patients identified 17 genetic lesions, 9 of which were new confirming their “private” nature. (PMID:22173106)
• the human CPS unknown function domains are spatially located in a region that corresponds to the a/b subunits interface in Escherichia coli CPS. [Review] (PMID:22521883)
• Data show that carbamoyl phosphate synthetase 1, an enzyme involved in the urea cycle, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta, enzymes involved in DNA repair, were expressed at higher levels in Batten disease cells than in normal cells. (PMID:22692827)
• More HCC cells could be identified by the antibody cocktail for CPS1 and P-CK compared with a single antibody. (PMID:24763545)
• Findings support the disease-causing role of the mutations reported to affect the CPS1 deficiency, revealing a key role of the small CPS1 domain of unknown function (UFSD) for proper enzyme folding. (PMID:24813853)
• study examined patient characteristics, including genetic polymorphism, to identify risk factors associated with development of hyperammonemia during valproic acid-based therapy; found CPS1 4217C>A polymorphism may not be associated with development of hyperammonemia in Japanese population (PMID:24888247)
• CPS1 becomes readily detectable upon hepatocyte apoptotic and necrotic death. Its abundance and short serum half-life suggest that it may be a useful prognostic biomarker in acute liver injury. (PMID:24924744)
• Overexpression of CPS1 is associated with rectal cancers. (PMID:25099619)
• characterized the only currently known recurrent CPS1 mutation, p.Val1013del found in eleven unrelated patients of Turkish descent; mutation p.V1013del inactivates CPS1 but does not render the enzyme grossly unstable or insoluble (PMID:25410056)
• Mechanism for Switching On/Off the Urea Cycle (PMID:26059772)
• CPS1 and CPS1IT1 may be potential prognostic indicators for patients with intrahepatic cholangiocarcinoma. (PMID:26499888)
• Molecular structure of CPS1 has been deciphered. (PMID:26592762)
• These results suggest that glycine metabolism and/or the urea cycle represent potentially novel sex-specific mechanisms for the development of atherosclerosis. (PMID:26822151)
• CPS1 is involved in the urea cycle in weight maintenance. (PMID:26938218)
• These results may offer an increasing understand that CPS1 might have a function in differentiation. (PMID:27425868)
• Allele and genotype frequencies of the p.Thr1406Asn polymorphism did not differ between the infants with and without NEC, but the minor A-allele was less frequent in the group of 64 infants with the combined outcome NEC or death before 34 weeks of corrected gestational age than in the infants without this outcome. A significant negative association of the A-allele with the combined outcome NEC or death was found. (PMID:27833157)
• Hepatocyte Antigen Expression in Barrett Esophagus and Associated Neoplasia. (PMID:28187035)
• HNF3beta plays a vital role in regulation of CPS1 gene and could promote the metabolism of ammonia by regulating CPS1 expression. (PMID:28272778)
• CPS1 knockdown reduced cell growth, decreased levels of metabolites associated with nucleic acid biosynthesis. (PMID:28376202)
• CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells (PMID:28538732)
• In silico analysis potentially links CPS1 SNPs with major depression disorder. (PMID:29441491)
• To investigate the efficacy of gene therapy for CPS deficiency following knock-down of hepatic endogenous CPS1 expression, we injected these mice with a helper-dependent adenoviral vector (HDAd) expressing the large murine CPS1 cDNA under control of the phosphoenolpyruvate carboxykinase promoter (PMID:29801986)
• Serum CPS1 appears to be a promising marker for the identi fi cation of mitochondrial damage and the progress of liver pathologies in HCV infected patients, particularly in early stages of the disease. (PMID:30698308)
• ureagenesis can be improved in HepaRG cells by CPS1 overexpression, however, only in combination with DMF-culturing, suggesting that both the low CPS1 level and static-culturing, possibly due to insufficient mitochondria, are limiting urea cycle. (PMID:30802674)
• A liver-humanized mouse model of carbamoyl phosphate synthetase 1-deficiency. (PMID:30843237)
• Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion. (PMID:31386258)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cps1	ENSDARG00000020028
mus_musculus	Cps1	ENSMUSG00000025991
rattus_norvegicus	Cps1	ENSRNOG00000013704

Paralogs (2): OTC (ENSG00000036473), CAD (ENSG00000084774)

Protein

Protein identifiers

Carbamoyl-phosphate synthase [ammonia], mitochondrial — P31327 (reviewed: P31327)

Alternative names: Carbamoyl-phosphate synthetase I

All UniProt accessions (2): A0A669KBF2, P31327

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.

Subunit / interactions. Can form homooligomers (monomers as predominant form and dimers).

Subcellular location. Mitochondrion. Nucleus. Nucleolus. Cell membrane.

Tissue specificity. Primarily in the liver and small intestine.

Post-translational modifications. Undergoes proteolytic cleavage in the C-terminal region corresponding to the loss of approximately 12 AA residues from the C-terminus. Succinylated at Lys-287 and Lys-1291. Desuccinylated at Lys-1291 by SIRT5, leading to activation. Glutarylated. Glutarylation levels increase during fasting. Deglutarylated by SIRT5 at Lys-55, Lys-219, Lys-412, Lys-889, Lys-892, Lys-915, Lys-1360 and Lys-1486, leading to activation.

Disease relevance. Carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:237300] An autosomal recessive disorder of the urea cycle causing hyperammonemia. It can present as a devastating metabolic disease dominated by severe hyperammonemia in neonates or as a more insidious late-onset condition, generally manifesting as life-threatening hyperammonemic crises under catabolic situations. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and intellectual disability. The disease is caused by variants affecting the gene represented in this entry. CPS1 protein variants might influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation.

Activity regulation. Requires N-acetyl-L-glutamate (NAG) as an allosteric activator. Activated by glycerol in the absence of NAG, whereas in the presence of NAG it is inhibited by increasing concentrations of glycerol.

Domain organisation. The type-1 glutamine amidotransferase domain is defective.

Isoforms (3)

UniProt ID	Names	Canonical?
P31327-1	1	yes
P31327-2	2
P31327-3	3

RefSeq proteins (4): NP_001116105, NP_001356185, NP_001356186, NP_001866* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002474	CarbamoylP_synth_ssu_N	Domain
IPR005479	CPAse_ATP-bd	Domain
IPR005480	CPSase_lsu_oligo	Domain
IPR005483	CPSase_dom	Domain
IPR006274	CarbamoylP_synth_ssu	Family
IPR006275	CPSase_lsu	Family
IPR011607	MGS-like_dom	Domain
IPR011761	ATP-grasp	Domain
IPR013815	ATP_grasp_subdomain_1	Homologous_superfamily
IPR016185	PreATP-grasp_dom_sf	Homologous_superfamily
IPR017926	GATASE	Domain
IPR029062	Class_I_gatase-like	Homologous_superfamily
IPR035686	CPSase_GATase1	Domain
IPR036480	CarbP_synth_ssu_N_sf	Homologous_superfamily
IPR036897	CarbamoylP_synth_lsu_oligo_sf	Homologous_superfamily
IPR036914	MGS-like_dom_sf	Homologous_superfamily
IPR058047	CPSase_preATP-grasp	Domain

Pfam: PF00117, PF00988, PF02142, PF02786, PF02787, PF25596

Enzyme classification (BRENDA):

• EC 6.3.4.16 — carbamoyl-phosphate synthase (ammonia) (BRENDA: 25 organisms, 46 substrates, 41 inhibitors, 77 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0372–4.12	26
NH4+	0.35–15.6	15
HCO3-	2.44–242	13
NH3	0.038–0.86	8
HYDROGENCARBONATE	7.1–12.4	4
CO2	2.3–7.2	2
N-ACETYLGLUTAMATE	0.29–0.44	2
AMMONIA	0.39	1

Catalyzed reactions (Rhea), 1 shown:

• hydrogencarbonate + NH4(+) + 2 ATP = carbamoyl phosphate + 2 ADP + phosphate + 2 H(+) (RHEA:18029)

UniProt features (469 total): sequence variant 154, modified residue 153, strand 69, helix 55, sequence conflict 12, turn 8, binding site 6, domain 4, glycosylation site 3, splice variant 2, transit peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6UEL	X-RAY DIFFRACTION	1.9
2YVQ	X-RAY DIFFRACTION	1.98
4UTV	X-RAY DIFFRACTION	2.4
5DOT	X-RAY DIFFRACTION	2.4
5DOU	X-RAY DIFFRACTION	2.6
6W2J	X-RAY DIFFRACTION	2.62
4UUA	X-RAY DIFFRACTION	2.8
4UTR	X-RAY DIFFRACTION	2.9
4UU8	X-RAY DIFFRACTION	2.9
4UUB	X-RAY DIFFRACTION	2.9
4UU7	X-RAY DIFFRACTION	3
4UTX	X-RAY DIFFRACTION	3.1
5OJO	X-RAY DIFFRACTION	3.1
4UTZ	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31327-F1	93.80	0.88

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 (6): 1437; 1440; 1449; 1391; 1394; 1410

Post-translational modifications (153): 856, 869, 875, 875, 875, 889, 889, 889, 892, 892, 892, 896, 898, 905, 908, 908, 915, 915, 915, 919 …

Glycosylation sites (3): 537, 1331, 1332

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-70635	Urea cycle
R-HSA-9955542	CPS1 variants cause CPS1 deficiency

MSigDB gene sets: 304 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_RESPONSE_TO_ZINC_ION, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_RESPONSE_TO_FOOD, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (34): urea cycle (GO:0000050), ‘de novo’ pyrimidine nucleobase biosynthetic process (GO:0006207), L-glutamine metabolic process (GO:0006541), midgut development (GO:0007494), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), response to zinc ion (GO:0010043), response to amine (GO:0014075), L-citrulline biosynthetic process (GO:0019240), triglyceride catabolic process (GO:0019433), response to food (GO:0032094), response to lipopolysaccharide (GO:0032496), vasodilation (GO:0042311), response to starvation (GO:0042594), response to amino acid (GO:0043200), cellular response to fibroblast growth factor stimulus (GO:0044344), nitric oxide metabolic process (GO:0046209), homocysteine metabolic process (GO:0050667), monoatomic anion homeostasis (GO:0055081), response to growth hormone (GO:0060416), hepatocyte differentiation (GO:0070365), carbamoyl phosphate biosynthetic process (GO:0070409), cellular response to ammonium ion (GO:0071242), cellular response to cAMP (GO:0071320), cellular response to glucagon stimulus (GO:0071377), cellular response to oleic acid (GO:0071400), response to dexamethasone (GO:0071548), response to alcohol (GO:0097305), liver development (GO:0001889), response to glucagon (GO:0033762), response to oleic acid (GO:0034201), response to steroid hormone (GO:0048545), response to glucocorticoid (GO:0051384), response to cAMP (GO:0051591)

GO Molecular Function (16): carbamoyl-phosphate synthase (ammonia) activity (GO:0004087), carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity (GO:0004088), endopeptidase activity (GO:0004175), calcium ion binding (GO:0005509), ATP binding (GO:0005524), phospholipid binding (GO:0005543), glutamate binding (GO:0016595), potassium ion binding (GO:0030955), small molecule binding (GO:0036094), protein-containing complex binding (GO:0044877), metal ion binding (GO:0046872), modified amino acid binding (GO:0072341), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (13): nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), plasma membrane (GO:0005886), protein-containing complex (GO:0032991), mitochondrial nucleoid (GO:0042645), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), nucleus (GO:0005634), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Diseases of the urea cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
binding	4
response to chemical	3
response to nutrient levels	2
intracellular membraneless organelle	2
cytoplasm	2
intracellular membrane-bounded organelle	2
mitochondrion	2
sperm flagellum	2
biosynthetic process	1
urea metabolic process	1
pyrimidine nucleobase biosynthetic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
digestive tract development	1
response to metal ion	1
response to nitrogen compound	1
amino acid biosynthetic process	1
non-proteinogenic amino acid biosynthetic process	1
triglyceride metabolic process	1
acylglycerol catabolic process	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
blood vessel diameter maintenance	1
response to stress	1
response to acid chemical	1
cellular response to growth factor stimulus	1
response to fibroblast growth factor	1
reactive nitrogen species metabolic process	1
sulfur amino acid metabolic process	1
non-proteinogenic amino acid metabolic process	1
monoatomic ion homeostasis	1
response to peptide hormone	1
ligase activity, forming carbon-nitrogen bonds	1
carbon-nitrogen ligase activity, with glutamine as amido-N-donor	1
peptidase activity	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

2510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPS1	ASS1	P00966	926
CPS1	NAGS	Q8N159	830
CPS1	OTC	P00480	782
CPS1	AIMP1	Q12904	754
CPS1	ASL	P04424	749
CPS1	FOXL1	Q12952	720
CPS1	FOXF1	Q12946	719
CPS1	FOXC2	Q99958	648
CPS1	SIRT5	Q9NXA8	636
CPS1	ARG1	P05089	586
CPS1	BMPR2	Q13873	542
CPS1	GLUL	P15104	540
CPS1	OAT	P04181	511
CPS1	ARG2	P78540	499
CPS1	GLUD1	P00367	484

IntAct

127 interactions, top by confidence:

A	B	Type	Score
LMO1	ZBTB43	psi-mi:“MI:0914”(association)	0.830
YWHAZ	HSPB1	psi-mi:“MI:0914”(association)	0.680
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
CPS1	YWHAZ	psi-mi:“MI:0915”(physical association)	0.560
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
OTC	RTL8C	psi-mi:“MI:0914”(association)	0.530
DEFB121	COL6A2	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
ARHGEF26	CPS1	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
RPUSD3	HSPD1	psi-mi:“MI:0914”(association)	0.530
NDUFS7	NDUFV2	psi-mi:“MI:0914”(association)	0.530
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
Sirt5	CPS1	psi-mi:“MI:0915”(physical association)	0.400
Cdk1		psi-mi:“MI:0915”(physical association)	0.400
Csnk1e		psi-mi:“MI:0915”(physical association)	0.400
ARAF	CPS1	psi-mi:“MI:0915”(physical association)	0.370
RAF1	CPS1	psi-mi:“MI:0915”(physical association)	0.370
Tubg1	BDP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (193): CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), HNRNPH1 (Co-fractionation), HSPA4 (Co-fractionation), HSPA8 (Co-fractionation), HSPH1 (Co-fractionation), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), CPS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A061AYY2, A0A061B0Q2, A0A1E3P8S6, A0A1E3P8S8, A0A1E4S2N7, A0A1E4S2P1, A0A1E5RIW9, A0A1E5RUL9, A6ZN18, A7TJS7, A7TQJ9, B5RUN4, B9WLN5, G8JVR4, K0KPV8, K0KSN3, O13897, O14081, O43007, O44476, O74727, O74802, P07756, P09440, P31327, P32048, P32580, P32843, P35183, P38295, P40012, P46580, P53208, P53219, P75311, Q01163, Q02891, Q12385, Q54M29, Q54NS1

Diamond homologs: A1CA18, A1CZ92, A2R9B9, A4G0Y3, A4SXM1, A4YI77, B2RQC6, B2URJ0, B4S5S1, B8GNX4, O27079, O28995, O60060, O66727, O93937, P05990, P07258, P07259, P07756, P08955, P0DA12, P0DA13, P14845, P20054, P22572, P27708, P31327, P36838, P58894, P63729, P63733, P63734, P63735, P77885, P87183, Q09794, Q0U5H7, Q18990, Q1DUF5, Q2H132

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CPS1	“up-regulates quantity”	“carbamoyl phosphate(2-)”	“chemical modification”
CPS1	“up-regulates activity”	“Pyrimidine biosynthesis”
CPS1	“down-regulates quantity”	glutamine	“chemical modification”
SIRT5	“up-regulates activity”	CPS1	“post translational modification”
STK11	“down-regulates quantity”	CPS1	“transcriptional regulation”
AMPK	“down-regulates quantity”	CPS1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	6	45.4×	2e-06
mitochondrial electron transport, NADH to ubiquinone	5	13.7×	9e-03
mitochondrial translation	7	9.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2276 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	113
Likely pathogenic	247
Uncertain significance	508
Likely benign	1063
Benign	122

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1001895	NM_001875.5(CPS1):c.1141_1149del (p.Thr381_Gly383del)	Pathogenic
1068809	NM_001875.5(CPS1):c.2051C>G (p.Ser684Ter)	Pathogenic
1069202	NM_001875.5(CPS1):c.1432C>T (p.Gln478Ter)	Pathogenic
1070017	NC_000002.11:g.(?211421433)(211421593_?)del	Pathogenic
1070018	NC_000002.11:g.(?211441050)(211542729_?)del	Pathogenic
1071808	NM_001875.5(CPS1):c.2171_2175del (p.Ala724fs)	Pathogenic
1072514	NM_001875.5(CPS1):c.2470_2482del (p.Thr824fs)	Pathogenic
1076647	NM_001875.5(CPS1):c.3520C>T (p.Arg1174Ter)	Pathogenic
1076733	NM_001875.5(CPS1):c.1112del (p.Phe371fs)	Pathogenic
1076846	NM_001875.5(CPS1):c.3763G>T (p.Glu1255Ter)	Pathogenic
1172776	NM_001875.5(CPS1):c.1164+2T>C	Pathogenic
1192241	NM_001875.5(CPS1):c.2798del (p.Arg932_Leu933insTer)	Pathogenic
1321400	NM_001875.5(CPS1):c.1770T>G (p.Tyr590Ter)	Pathogenic
1381784	NM_001875.5(CPS1):c.3666+1G>T	Pathogenic
1408700	NM_001875.5(CPS1):c.1509del (p.Gly503_Leu504insTer)	Pathogenic
1435669	NM_001875.5(CPS1):c.2408dup (p.Thr804fs)	Pathogenic
1444282	NC_000002.12:g.210577425_210577431del	Pathogenic
1452254	NM_001875.5(CPS1):c.3307C>T (p.Gln1103Ter)	Pathogenic
1453334	NM_001875.5(CPS1):c.4159A>T (p.Lys1387Ter)	Pathogenic
1454065	NM_001875.5(CPS1):c.3935dup (p.Met1312fs)	Pathogenic
1455500	NM_001875.5(CPS1):c.1468C>T (p.Gln490Ter)	Pathogenic
1455517	NC_000002.11:g.(?211512577)(211513274_?)del	Pathogenic
1455929	NM_001875.5(CPS1):c.2876_2877del (p.Tyr959fs)	Pathogenic
1457203	NM_001875.5(CPS1):c.3216del (p.Val1073fs)	Pathogenic
1458288	NM_001875.5(CPS1):c.2446del (p.Cys816fs)	Pathogenic
1486720	NM_001875.5(CPS1):c.3266G>T (p.Arg1089Leu)	Pathogenic
1685668	NM_001875.5(CPS1):c.345_351del (p.Gly116fs)	Pathogenic
1685669	NM_001875.5(CPS1):c.4275-2A>C	Pathogenic
1935741	NM_001875.5(CPS1):c.2477del (p.Arg826fs)	Pathogenic
1940644	NM_001875.5(CPS1):c.1221_1222del (p.Val409fs)	Pathogenic

SpliceAI

4246 predictions. Top by Δscore:

Variant	Effect	Δscore
2:210556855:TCAAG:T	donor_loss	1.0000
2:210556856:CAAG:C	donor_loss	1.0000
2:210556858:AGGT:A	donor_loss	1.0000
2:210556859:GGTAA:G	donor_loss	1.0000
2:210556860:GTA:G	donor_loss	1.0000
2:210573406:GG:G	donor_gain	1.0000
2:210573407:GG:G	donor_gain	1.0000
2:210576335:T:G	acceptor_gain	1.0000
2:210576341:CCCA:C	acceptor_loss	1.0000
2:210576343:CAG:C	acceptor_loss	1.0000
2:210576344:A:C	acceptor_loss	1.0000
2:210576486:TCAAG:T	donor_loss	1.0000
2:210576487:CAAG:C	donor_loss	1.0000
2:210576488:AAG:A	donor_loss	1.0000
2:210576489:AG:A	donor_loss	1.0000
2:210576490:GG:G	donor_loss	1.0000
2:210576491:G:C	donor_loss	1.0000
2:210576491:G:T	donor_gain	1.0000
2:210576492:T:A	donor_loss	1.0000
2:210577419:AG:A	acceptor_gain	1.0000
2:210577420:GG:G	acceptor_gain	1.0000
2:210577508:AAGGT:A	donor_loss	1.0000
2:210577511:GTAA:G	donor_loss	1.0000
2:210577512:T:A	donor_loss	1.0000
2:210579708:TTATA:T	acceptor_loss	1.0000
2:210579709:TATAG:T	acceptor_loss	1.0000
2:210579711:TAG:T	acceptor_loss	1.0000
2:210579712:A:T	acceptor_loss	1.0000
2:210579764:GGA:G	donor_gain	1.0000
2:210579765:GA:G	donor_gain	1.0000

AlphaMissense

9874 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:210595544:T:C	F441L	1.000
2:210595546:T:A	F441L	1.000
2:210595546:T:G	F441L	1.000
2:210595547:G:C	D442H	1.000
2:210595548:A:T	D442V	1.000
2:210599407:C:A	N465K	1.000
2:210599407:C:G	N465K	1.000
2:210600645:G:T	R547M	1.000
2:210602254:G:C	R587P	1.000
2:210605178:G:C	R638P	1.000
2:210605209:T:G	C648W	1.000
2:210606736:T:C	S663P	1.000
2:210606840:C:G	C697W	1.000
2:210606843:C:A	N698K	1.000
2:210606843:C:G	N698K	1.000
2:210606890:A:T	E714V	1.000
2:210606897:T:A	N716K	1.000
2:210606897:T:G	N716K	1.000
2:210606902:G:C	R718T	1.000
2:210606908:C:T	S720F	1.000
2:210606913:A:C	S722R	1.000
2:210606915:C:A	S722R	1.000
2:210606915:C:G	S722R	1.000
2:210606920:C:A	A724D	1.000
2:210606923:T:C	L725P	1.000
2:210606932:A:T	K728I	1.000
2:210606933:A:C	K728N	1.000
2:210606933:A:T	K728N	1.000
2:210606935:C:A	A729D	1.000
2:210606941:G:A	G731D	1.000

dbSNP variants (sampled 300 via entrez): RS1000005028 (2:210494548 A>G,T), RS1000052913 (2:210599651 G>A,T), RS1000082407 (2:210513498 T>C), RS1000101170 (2:210669236 A>G), RS1000109096 (2:210644869 A>T), RS1000115981 (2:210661070 C>T), RS1000119100 (2:210528578 C>G,T), RS1000177577 (2:210605211 A>T), RS1000180677 (2:210476736 C>G,T), RS1000189250 (2:210658844 A>G), RS1000201211 (2:210562922 G>A), RS1000208499 (2:210476959 C>G,T), RS1000218755 (2:210571510 A>G), RS1000233086 (2:210519069 G>T), RS1000255390 (2:210475842 A>G)

Disease associations

OMIM: gene MIM:608307 | disease phenotypes: MIM:237300, MIM:615371

GenCC curated gene-disease

Disease	Classification	Inheritance
carbamoyl phosphate synthetase I deficiency disease	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
carbamoyl phosphate synthetase I deficiency disease	Definitive	AR

Mondo (4): carbamoyl phosphate synthetase I deficiency disease (MONDO:0009376), pulmonary hypertension, neonatal, susceptibility to (MONDO:0014151), hereditary breast ovarian cancer syndrome (MONDO:0003582), intellectual disability (MONDO:0001071)

Orphanet (3): Carbamoyl-phosphate synthetase 1 deficiency (Orphanet:147), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001297	Stroke
HP:0001508	Failure to thrive
HP:0001950	Respiratory alkalosis
HP:0001951	Episodic ammonia intoxication
HP:0001987	Hyperammonemia
HP:0002013	Vomiting
HP:0002038	Protein avoidance
HP:0002093	Respiratory insufficiency
HP:0002181	Cerebral edema
HP:0003355	Aminoaciduria
HP:0003572	Low plasma citrulline
HP:0003623	Neonatal onset
HP:0005961	Hypoargininemia

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020165	Carbamoyl-Phosphate Synthase I Deficiency Disease	C10.228.140.163.100.937.249; C16.320.565.100.940.249; C16.320.565.189.937.249; C18.452.132.100.937.249; C18.452.648.100.940.249; C18.452.648.189.937.249; C18.452.660.097
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2362990 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1047891	CPS1		0.00	0

ChEMBL bioactivities

25 potent at pChembl≥5 of 32 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.18	IC50	66	nM	CHEMBL4649653
6.89	IC50	130	nM	CHEMBL4649844
6.77	IC50	170	nM	CHEMBL4638888
6.73	Kd	187.7	nM	CHEMBL5653589
6.73	ED50	187.7	nM	CHEMBL5653589
6.62	IC50	240	nM	CHEMBL4649653
6.44	IC50	360	nM	CHEMBL4636473
6.44	IC50	360	nM	CHEMBL4634845
6.42	IC50	380	nM	CHEMBL4644019
6.27	IC50	540	nM	CHEMBL4634332
6.00	IC50	1000	nM	CHEMBL4638888
5.89	IC50	1300	nM	CHEMBL4648689
5.85	IC50	1400	nM	CHEMBL4639378
5.82	IC50	1500	nM	CHEMBL4649609
5.66	IC50	2200	nM	CHEMBL4647643
5.58	IC50	2600	nM	CHEMBL4649456
5.31	IC50	4900	nM	CHEMBL4641727
5.29	IC50	5100	nM	CHEMBL4632591
5.28	IC50	5200	nM	CHEMBL4634479
5.20	IC50	6300	nM	CHEMBL4642964
5.19	IC50	6500	nM	CHEMBL4635675
5.19	IC50	6400	nM	CHEMBL4648273
5.16	IC50	6900	nM	CHEMBL4637265
5.11	IC50	7800	nM	CHEMBL4647565
5.11	IC50	7700	nM	CHEMBL4644645

PubChem BioAssay actives

24 with measured affinity, of 39 total; 22 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
[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(1H-indol-6-yl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	0.0660	uM
(4-ethoxy-2-fluorophenyl)-[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	0.1300	uM
[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-methyl-1H-indol-6-yl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	0.1700	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148134: Binding affinity to human CPS1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1877	uM
(2-fluoro-4-methoxyphenyl)-[(3R,5R)-4-(2-fluoro-4-methylbenzoyl)-3,5-dimethylpiperazin-1-yl]methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	0.3600	uM
[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	0.3600	uM
[(3R,5R)-4-(4-ethoxy-2-fluorobenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	0.3800	uM
[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(3-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	0.5400	uM
[(3R,5R)-4-(2,4-difluorobenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	1.3000	uM
(2-fluoro-4-methoxyphenyl)-[(3R,5R)-4-(2-fluoro-4-propan-2-yloxybenzoyl)-3,5-dimethylpiperazin-1-yl]methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	1.4000	uM
1-N-benzyl-1-N-methyl-4-N-(4-methyl-1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	1.5000	uM
[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methylphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	2.2000	uM
(2,4-difluorophenyl)-[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	2.6000	uM
3H-benzimidazol-5-yl-[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	4.9000	uM
[(3R,5R)-4-(2-fluoro-5-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	5.1000	uM
[4-(2-fluoro-4-methoxybenzoyl)-3-methylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	5.2000	uM
[4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	6.3000	uM
2,3-dihydro-1H-indol-6-yl-[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	6.4000	uM
[(3S,5S)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	6.5000	uM
[(3R,5S)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	6.9000	uM
[(3R,5R)-4-(2-fluoro-4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl]-(1-methyl-2,3-dihydroindol-6-yl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	7.7000	uM
[4-(2-fluoro-4-methoxybenzoyl)piperazin-1-yl]-(2-fluoro-4-methoxyphenyl)methanone	1658694: Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	ic50	7.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects response to substance, affects expression, decreases expression, decreases methylation, increases expression	6
Benzo(a)pyrene	decreases expression	5
perfluorooctanoic acid	increases expression, decreases expression	4
perfluorooctane sulfonic acid	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases methylation	3
arsenite	affects binding, decreases reaction, increases abundance, increases expression, increases reaction (+1 more)	2
sodium arsenite	affects expression, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
bisphenol A	decreases methylation	1
diisononyl phthalate	affects cotreatment, decreases expression	1
sulforaphane	decreases expression	1
zinc chloride	increases expression	1
lead nitrate	affects cotreatment, decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
ochratoxin A	increases expression	1
butylbenzyl phthalate	affects cotreatment, decreases expression	1
cupric chloride	decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
brequinar	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4619220	Binding	Allosteric inhibition of His-tagged CPS1 (unknown origin) expressed in baculovirus infected Sf21 insect cells assessed as reduction in ADP level preincubated for 20 mins followed by ATP addition measured after 60 mins by ADP-Glo assay	Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1. — ACS Med Chem Lett

Cellosaurus cell lines

5 cell lines: 3 transformed cell line, 1 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_AY82	GM23684	Transformed cell line	Female
CVCL_AY91	GM23882	Transformed cell line	Female
CVCL_AZ24	GM24354	Transformed cell line	Female
CVCL_B1P5	Abcam HeLa CPS1 KO	Cancer cell line	Female
CVCL_C9JL	SDQLCHi061-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
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
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
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
NCT00718627	PHASE2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
NCT00475904	PHASE2	COMPLETED	A Comparison of EpiCept™ NP-1 Topical Cream vs. Oral Gabapentin in Postherpetic Neuralgia (PHN)
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
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
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
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)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4