CAD

Summary

CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, HGNC:1424) is a protein-coding gene on chromosome 2p23.3, encoding Multifunctional protein CAD (P27708). Multifunctional protein that encodes the first 3 enzymatic activities of the de novo pyrimidine pathway: carbamoylphosphate synthetase (CPSase; EC 6.3.5.5), aspartate transcarbamylase (ATCase; EC 2.1.3.2) and dihydroorotase (DHOase; EC 3.5.2.3). It is a selective cancer dependency (DepMap: 38.2% of cell lines).

The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. This gene encodes a trifunctional protein which is associated with the enzymatic activities of the first 3 enzymes in the 6-step pathway of pyrimidine biosynthesis: carbamoylphosphate synthetase (CPS II), aspartate transcarbamoylase, and dihydroorotase. This protein is regulated by the mitogen-activated protein kinase (MAPK) cascade, which indicates a direct link between activation of the MAPK cascade and de novo biosynthesis of pyrimidine nucleotides. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 790 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 50 (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 2,376 total — 61 pathogenic, 35 likely-pathogenic (top 1% of genes corpus-wide)
• Regional missense constraint (gnomAD): 4 of 12 regions constrained (≈3% of expected missense variation)
• GTEx eGene: eQTL in 33 tissues, sQTL in 13 (q < 0.05)
• Phenotypes (HPO): 25
• Cancer dependency (DepMap): dependent in 38.2% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.41 (moderately constrained)
• MANE Select transcript: NM_004341
• Interaction hub: 1,990 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1424
Approved symbol	CAD
Name	carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	GATD4
Ensembl gene	ENSG00000084774
Ensembl biotype	protein_coding
OMIM	114010
Entrez	790

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000264705

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 3: 5, TSL 5: 4

ENST00000264705, ENST00000403525, ENST00000428460, ENST00000456311, ENST00000458503, ENST00000464159, ENST00000475695, ENST00000479002, ENST00000487239, ENST00000491461, ENST00000491891, ENST00000854433, ENST00000912693, ENST00001144914

RefSeq mRNA: 2 — MANE Select: NM_004341 NM_001306079, NM_004341

CCDS: CCDS1742, CCDS77396

Canonical transcript exons

ENST00000264705 — 44 exons

Exon	Start	End
ENSE00000732839	27217877	27218016
ENSE00000732842	27221218	27221347
ENSE00000732854	27222866	27223037
ENSE00000732858	27223563	27223748
ENSE00000732861	27223917	27224029
ENSE00000732870	27224745	27224876
ENSE00000732874	27225010	27225243
ENSE00000732878	27225705	27225926
ENSE00000732882	27226131	27226319
ENSE00000732885	27226525	27226649
ENSE00000732901	27233042	27233140
ENSE00000732910	27233626	27233808
ENSE00000732912	27234008	27234226
ENSE00000732914	27234518	27234685
ENSE00000733044	27238431	27238632
ENSE00000733057	27240265	27240361
ENSE00000733067	27241322	27241396
ENSE00000733070	27241911	27242123
ENSE00000733074	27242302	27242427
ENSE00000733078	27242620	27242775
ENSE00000733082	27242872	27242973
ENSE00000733087	27243198	27243292
ENSE00000809111	27217369	27217633
ENSE00000809117	27235536	27235640
ENSE00000809118	27236284	27236523
ENSE00000809121	27237379	27237545
ENSE00001035908	27222194	27222336
ENSE00001078281	27237718	27237882
ENSE00001078282	27236749	27236830
ENSE00001078283	27238056	27238187
ENSE00001078284	27222519	27222660
ENSE00001078287	27233312	27233536
ENSE00001078288	27224345	27224490
ENSE00001078290	27241058	27241227
ENSE00001078291	27232448	27232694
ENSE00001078293	27240911	27240955
ENSE00001078294	27239042	27239232
ENSE00001245850	27243416	27243943
ENSE00003499463	27226832	27226962
ENSE00003539197	27239331	27239471
ENSE00003567777	27231468	27231580
ENSE00003590301	27231980	27232224
ENSE00003646700	27239697	27239798
ENSE00003656422	27235245	27235427

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 90.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.3835 / max 477.6382, expressed in 1785 samples.

Highest expression (Bgee): body of uterus, stromal cell of endometrium, lobe of liver, primordial germ cell in gonad, ventricular zone.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CAD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 33 tissues and its splicing (sQTL) in 13 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 46 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Pancreas	eqtl	2.0e-24	+0.39	2:27177982:C:A
Skin Not Sun Exposed Suprapubic	sqtl	3.6e-15	-0.91	2:27239783:T:C
Thyroid	eqtl	7.7e-15	-0.22	2:27249128:A:G
Pituitary	eqtl	1.4e-08	-0.27	2:27187741:G:A
Skin Sun Exposed Lower leg	sqtl	3.4e-08	-0.61	2:27239783:T:C
Muscle Skeletal	eqtl	6.3e-08	-0.16	2:27251438:C:T
Whole Blood	eqtl	1.1e-07	+0.24	2:27205305:C:T
Heart Left Ventricle	eqtl	3.0e-07	-0.20	2:27319174:C:T
Testis	eqtl	3.3e-07	+0.16	2:27189395:A:G
Esophagus Mucosa	eqtl	5.6e-07	-0.10	2:27266683:A:G
Esophagus Muscularis	eqtl	1.9e-06	-0.15	2:27249159:A:G
Adipose Subcutaneous	sqtl	2.1e-06	-0.60	2:27229139:C:T
Nerve Tibial	sqtl	7.4e-06	-0.52	2:27239783:T:C
Esophagus Gastroesophageal Junction	eqtl	8.7e-06	-0.19	2:27266683:A:G
Skin Sun Exposed Lower leg	eqtl	1.0e-05	-0.13	2:27249128:A:G
Esophagus Muscularis	sqtl	1.1e-05	+1.47	2:27135163:G:A
Nerve Tibial	eqtl	2.1e-05	-0.11	2:27249128:A:G
Brain Nucleus accumbens basal ganglia	eqtl	2.5e-05	+0.42	2:27209774:C:A
Heart Atrial Appendage	eqtl	3.8e-05	-0.13	2:27266683:A:G
Artery Tibial	sqtl	4.9e-05	-1.49	2:27240642:T:C

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
19333	24.8228	1718
19334	7.5937	1525
19335	7.4323	1694
19336	2.1368	1136
19332	1.0878	652
19339	0.2047	105
19337	0.1055	42

Top tissues by expression

showing 100 of 282 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of uterus	UBERON:0009853	90.89	gold quality
stromal cell of endometrium	CL:0002255	90.68	gold quality
right lobe of liver	UBERON:0001114	90.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.46	gold quality
ventricular zone	UBERON:0003053	90.32	gold quality
right testis	UBERON:0004534	90.18	gold quality
right uterine tube	UBERON:0001302	90.15	gold quality
left testis	UBERON:0004533	90.08	gold quality
right ovary	UBERON:0002118	90.06	gold quality
mucosa of transverse colon	UBERON:0004991	90.03	gold quality
lower esophagus mucosa	UBERON:0035834	89.98	gold quality
right lobe of thyroid gland	UBERON:0001119	89.84	gold quality
left ovary	UBERON:0002119	89.78	gold quality
ectocervix	UBERON:0012249	89.51	gold quality
left uterine tube	UBERON:0001303	89.26	gold quality
adenohypophysis	UBERON:0002196	89.23	gold quality
apex of heart	UBERON:0002098	88.93	gold quality
tibial nerve	UBERON:0001323	88.85	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.85	gold quality
metanephros cortex	UBERON:0010533	88.82	gold quality
pituitary gland	UBERON:0000007	88.70	gold quality
endocervix	UBERON:0000458	88.64	gold quality
endothelial cell	CL:0000115	88.57	silver quality
left lobe of thyroid gland	UBERON:0001120	88.19	gold quality
cerebellar hemisphere	UBERON:0002245	87.90	gold quality
cerebellar cortex	UBERON:0002129	87.73	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.70	gold quality
body of pancreas	UBERON:0001150	87.65	gold quality
testis	UBERON:0000473	87.34	gold quality
skin of leg	UBERON:0001511	87.23	gold quality
thyroid gland	UBERON:0002046	86.91	gold quality
skin of abdomen	UBERON:0001416	86.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.89	gold quality
lower esophagus	UBERON:0013473	86.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.83	gold quality
esophagus mucosa	UBERON:0002469	86.82	gold quality
ganglionic eminence	UBERON:0004023	86.76	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.61	gold quality
esophagus	UBERON:0001043	86.52	gold quality
right frontal lobe	UBERON:0002810	86.48	gold quality
spleen	UBERON:0002106	86.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.30	gold quality
right coronary artery	UBERON:0001625	86.24	gold quality
transverse colon	UBERON:0001157	86.09	gold quality
ascending aorta	UBERON:0001496	86.09	gold quality
right adrenal gland	UBERON:0001233	86.08	gold quality
embryo	UBERON:0000922	86.05	gold quality
left coronary artery	UBERON:0001626	85.92	gold quality
thoracic aorta	UBERON:0001515	85.91	gold quality
granulocyte	CL:0000094	85.80	gold quality
ovary	UBERON:0000992	85.80	gold quality
upper lobe of left lung	UBERON:0008952	85.78	gold quality
body of stomach	UBERON:0001161	85.56	gold quality
omental fat pad	UBERON:0010414	85.53	gold quality
endometrium epithelium	UBERON:0004811	85.47	silver quality
peritoneum	UBERON:0002358	85.45	gold quality
minor salivary gland	UBERON:0001830	85.40	gold quality
left adrenal gland cortex	UBERON:0035825	85.35	gold quality
left adrenal gland	UBERON:0001234	85.27	gold quality
cerebellum	UBERON:0002037	85.22	gold quality
right adrenal gland cortex	UBERON:0035827	85.18	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.91	gold quality
aorta	UBERON:0000947	84.80	gold quality
zone of skin	UBERON:0000014	84.69	gold quality
sigmoid colon	UBERON:0001159	84.61	gold quality
cortical plate	UBERON:0005343	84.56	gold quality
upper lobe of lung	UBERON:0008948	84.48	gold quality
coronary artery	UBERON:0001621	84.43	gold quality
mucosa of stomach	UBERON:0001199	84.40	gold quality
popliteal artery	UBERON:0002250	84.28	gold quality
tibial artery	UBERON:0007610	84.27	gold quality
vagina	UBERON:0000996	84.26	gold quality
vermiform appendix	UBERON:0001154	84.08	gold quality
pancreas	UBERON:0001264	84.04	gold quality
small intestine	UBERON:0002108	83.87	gold quality
smooth muscle tissue	UBERON:0001135	83.73	gold quality
rectum	UBERON:0001052	83.71	gold quality
colon	UBERON:0001155	83.61	gold quality
stomach	UBERON:0000945	83.55	gold quality
subcutaneous adipose tissue	UBERON:0002190	83.52	gold quality
adrenal gland	UBERON:0002369	83.51	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.30	gold quality
descending thoracic aorta	UBERON:0002345	83.28	gold quality
mouth mucosa	UBERON:0003729	83.23	gold quality
adrenal cortex	UBERON:0001235	83.21	gold quality
intestine	UBERON:0000160	82.99	gold quality
right atrium auricular region	UBERON:0006631	82.86	gold quality
large intestine	UBERON:0000059	82.77	gold quality
lymph node	UBERON:0000029	82.69	gold quality
right lung	UBERON:0002167	82.55	gold quality
gastrocnemius	UBERON:0001388	82.39	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.20	gold quality
gall bladder	UBERON:0002110	82.12	gold quality
muscle of leg	UBERON:0001383	82.02	gold quality
saliva-secreting gland	UBERON:0001044	81.93	gold quality
cingulate cortex	UBERON:0003027	81.85	gold quality
anterior cingulate cortex	UBERON:0009835	81.67	gold quality
nucleus accumbens	UBERON:0001882	81.64	gold quality
caudate nucleus	UBERON:0001873	81.53	gold quality
tibia	UBERON:0000979	81.49	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.35

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pituitary gland	tissue	19.1
Skin 1	tissue	17.7	medium
Vagina	tissue	15.6	not detected
Nucleus accumbens	tissue	14.7
Choroid plexus	tissue	14.7
Lymph node	tissue	14.0	high
Locus coeruleus	tissue	13.9
Hippocampus	tissue	13.7	low
Appendix	tissue	11.7	high
Ovary	tissue	11.3	medium
Smooth muscle	tissue	11.1	not detected
Thymus	tissue	10.8
Endometrium 1	tissue	10.5	high
Postcentral gyrus	tissue	10.5
Fallopian tube	tissue	10.1	high
Tonsil	tissue	9.8	high
Spleen	tissue	9.6	high
Testis	tissue	9.3	high
Epididymis	tissue	9.3	medium
Skeletal muscle	tissue	9.0	not detected
Esophagus	tissue	8.8	medium
Pancreas	tissue	8.7	medium
Bone marrow	tissue	8.5	high
Seminal vesicle	tissue	8.3	low
Adipose tissue	tissue	8.0	medium
Duodenum	tissue	8.0	medium
Spinal cord	tissue	8.0
Colon	tissue	7.9	medium
Salivary gland	tissue	7.6	low
Thyroid gland	tissue	7.4	low
Rectum	tissue	7.3	high
Small intestine	tissue	7.3	medium
Stomach 1	tissue	7.2	medium
Gallbladder	tissue	7.2	low
Medulla oblongata	tissue	7.1
Urinary bladder	tissue	7.0	medium
Placenta	tissue	7.0	high
Corpus callosum	tissue	7.0
Cervix	tissue	6.7	medium
Breast	tissue	6.7	high
Lung	tissue	6.7	not detected
Prostate	tissue	6.7	low
Midbrain	tissue	6.6
Substantia nigra	tissue	6.6
Superior colliculi	tissue	6.3
Pons	tissue	6.1
Thalamus	tissue	6.1
Hypothalamus	tissue	6.1
Adrenal gland	tissue	6.0	medium
Parathyroid gland	tissue	5.5	not detected
Tongue	tissue	5.5
Frontal cortex	tissue	5.4
Periaqueductal gray	tissue	5.4
Heart muscle	tissue	5.2	not detected
Liver	tissue	4.9	low
Caudate putamen	tissue	4.9
Retina	tissue	4.7
Septum	tissue	4.7
Ventral forebrain	tissue	4.6
Hippocampal formation	tissue	4.2

Brain sub-regions (HPA Brain Atlas): detected in 404; highest nTPM — Flocculonodular lobe (35.4), Cerebellar cortex (34.6), Area striata (26.8), Hippocampus, CA3 (26.6), Frontal eye field (26.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, ESR1, HDAC2, HIF1A, MYC, SMARCA4, SP1, TBXT, TEF, USF1

miRNA regulators (miRDB)

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

17 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-18A-5P	99.29	71.05	806
HSA-MIR-18B-5P	99.29	71.05	806
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-4735-3P	99.14	69.85	777
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-222-5P	98.75	69.17	1242
HSA-MIR-595	98.25	67.44	699
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-943	97.81	64.42	694
HSA-MIR-4313	97.18	63.15	420
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-11400	94.03	67.12	81

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.409, missense Z 5.78 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264705 splits into 12 regions with different missense tolerance; 4 are missense-constrained (≈3% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:27,217,552–27,223,027	314 / 339.4	0.93	no
2:27,223,028–27,223,595	4 / 18.4	0.22	yes (p 7.8e-04)
2:27,223,596–27,224,421	129 / 143.3	0.90	no
2:27,224,422–27,224,483	5 / 24.1	0.21	yes (p 9.8e-05)
2:27,224,484–27,225,824	174 / 215.8	0.81	no
2:27,225,825–27,225,869	2 / 16.6	0.12	yes (p 3.3e-04)
2:27,225,870–27,233,351	385 / 535.1	0.72	no
2:27,233,352–27,236,830	306 / 607.9	0.50	no
2:27,237,379–27,240,298	478 / 515.0	0.93	no
2:27,240,299–27,242,367	203 / 284.5	0.71	no
2:27,242,368–27,242,646	11 / 39.4	0.28	yes (p 6.1e-06)
2:27,242,647–27,243,515	170 / 212.1	0.80	no
DepMap (CRISPR cell-line fitness): dependent in 38.2% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): RKO (-2.547), SU-DHL-10 (-2.157), Evsa-T (-2.059), AU565 (-2.054), COLO 205 (-2.019), OCI-LY-19 (-1.927), JHH-6 (-1.83), Panc 04.03 (-1.759), A-375 (-1.758), 639-V (-1.744), SU-DHL-8 (-1.657), PACADD-165 (-1.625), HCC-461 (-1.617), SU-DHL-1 (-1.595), WPE1-NA22 (-1.568).

Literature-anchored findings (GeneRIF, showing 23)

• the cad gene is regulated by a nonclassical ERalpha/Sp1-mediated pathway. (PMID:12746293)
• Data show that PRMT5 can be found in association with hSWI/SNF complexes and is involved in regulating the expression of carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase. (PMID:14559996)
• the nuclear import of CAD appears to promote optimal cell growth (PMID:15890648)
• cad gene expression is repressed by hypoxia-inducible factor-1alpha, which represents a functional link between hypoxia and cell-cycle arrest. (PMID:16155188)
• hCPS_DeltaA was not able to fully assume the catalytically competent conformation, with specific activity of CP formation decreased 700-fold. (PMID:18679823)
• findings show that in prostate tumor cells, CAD fosters androgen receptor translocation into the nucleus and stimulates its transcriptional activity; in radical prostatectomy specimens, CAD expression was not correlated with proliferation markers, but a higher CAD mRNA level was associated with local tumor extension and cancer relapse (PMID:21982950)
• preliminary X-ray diffraction analysis of the dihydroorotase domain of human CAD (PMID:23143245)
• The results obtained indicate that mLST8 bridges between CAD and mTOR, and plays a role in the signaling mechanism where CAD is regulated in the mTOR pathway through the association with mLST8 (PMID:23594158)
• Recombinant aspartate carbamoyltransferase domain from the CAD enzyme complex forms homotrimers in solution. (PMID:24316846)
• These results establish CAD as a downstream effector of Rheb and suggest a possible role of Rheb in regulating de novo pyrimidine nucleotide synthesis (PMID:25422319)
• Changes in glycosylation in caused by mutations in CAD. (PMID:25678555)
• Previous study found three metal ions in huDHOase active site; in the present study, the putative third metal binding site in type II enzymes, such as StDHOase and ScDHOase, was created and identified. (PMID:26446564)
• This study showed that CAD deficiency co-occurrence of anaemia, anisopoikilocytosis, global developmental delay, and seizures. (PMID:28007989)
• Detection of the CAD-ALK gene fusion in urine tr-DNA anticipated radiological confirmation of disease progression. Analysis of plasma ctDNA identified ALK kinase mutations that emerged during treatment with the ALK inhibitor entrectinib (PMID:28368455)
• CAD dihydroorotase and aspartate transcarbamoylase domains self-assembles into dimers and trimers. (PMID:28552578)
• Charge neutralization in the active site of the catalytic trimer of aspartate transcarbamoylase promotes diverse structural changes. (PMID:28833948)
• structural evidences indicated that post-translational carbamylated Lys was not required for Znalpha binding in PaDHPase and in huDHOase. (PMID:30268498)
• The catalytic flexibile loop in the dihydrooratase domain possesses an absolutely conserved Phe-1563 residue required for catalytic activity. (PMID:30315107)
• New regulatory mechanism-based inhibitors of aspartate transcarbamoylase for potential anticancer drug development. (PMID:31967710)
• The Cellular Protein CAD is Recruited into Ebola Virus Inclusion Bodies by the Nucleoprotein NP to Facilitate Genome Replication and Transcription. (PMID:32370067)
• Uridine treatment normalizes the congenital dyserythropoietic anemia type II-like hematological phenotype in a patient with homozygous mutation in the CAD gene. (PMID:32720728)
• Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease. (PMID:34288185)
• Beyond genetics: Deciphering the impact of missense variants in CAD deficiency. (PMID:37540500)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cad	ENSDARG00000041895
mus_musculus	Cad	ENSMUSG00000013629
rattus_norvegicus	Cad	ENSRNOG00000026474
drosophila_melanogaster	r	FBGN0003189
caenorhabditis_elegans		WBGENE00004259

Paralogs (2): CPS1 (ENSG00000021826), OTC (ENSG00000036473)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1916969) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
limb grasping	1
decreased white fat cell size	1
decreased prepulse inhibition	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	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
Clostridium botulinum A str. Hall	A5I6X1	100.0%	Diamond
Clostridium kluyveri DSM 555	A5N2L8	100.0%	Diamond
Clostridium botulinum A str. ATCC 19397	A7FYJ2	100.0%	Diamond
Leptospira biflexa serovar Patoc strain ‘Patoc 1 (Ames)’	B0SEH6	100.0%	Diamond
Leptospira biflexa serovar Patoc strain ‘Patoc 1 (Paris)’	B0SMK5	100.0%	Diamond
Clostridium kluyveri NBRC 12016	B9E695	100.0%	Diamond
Clostridium botulinum A2 str. Kyoto	C1FLB6	100.0%	Diamond
Saccharolobus islandicus L.S.2.15	C3MQE3	100.0%	Diamond
Saccharolobus islandicus M.14.25	C3MW21	100.0%	Diamond
Saccharolobus islandicus M.16.27	C3N664	100.0%	Diamond
Saccharolobus islandicus Y.G.57.14	C3NEM0	100.0%	Diamond
Leptospira borgpetersenii serovar Hardjo-bovis str. JB197	Q04UL7	100.0%	Diamond
Leptospira borgpetersenii serovar Hardjo-bovis str. L550	Q04YW0	100.0%	Diamond
Saccharolobus islandicus M.16.4	C4KHM7	99.9%	Diamond
Saccharolobus islandicus Y.N.15.51	C3NH23	99.8%	Diamond
Clostridium botulinum F str. Langeland	A7GII2	99.7%	Diamond
Leptospira interrogans serovar Copenhageni str. Fiocruz L1-130	Q72NJ5	99.7%	Diamond
Leptospira interrogans serovar Lai str. 56601	Q8F812	99.7%	Diamond
Clostridium botulinum B1 str. Okra	B1INE7	99.3%	Diamond
Clostridium botulinum Ba4 str. 657	C3KU87	99.3%	Diamond
Clostridium perfringens ATCC 13124	Q0TRA8	99.3%	Diamond
Clostridium perfringens str. 13	Q8XL59	99.3%	Diamond
Clostridium botulinum A3 str. Loch Maree	B1L1E7	99.0%	Diamond
Clostridium perfringens SM101	Q0STN4	99.0%	Diamond
Aspergillus fischeri NRRL 181	A1CZ92	98.7%	Diamond
Aspergillus fumigatus Af293	Q4WU09	98.7%	Diamond
Mesocricetus auratus	P08955	98.3%	Diamond
Lathyrus oleraceus	Q43064	96.4%	Diamond
Methanosarcina mazei Go1	Q8Q0U4	96.2%	Diamond
Aspergillus niger CBS 513.88	A2R9B9	94.9%	Diamond
Aspergillus oryzae RIB40	Q2U913	94.9%	Diamond
Aspergillus clavatus NRRL 1	A1CA18	94.2%	Diamond
Saccharolobus solfataricus P2	Q59969	92.9%	Diamond
Aspergillus nidulans FGSC A4	Q5BB37	92.4%	Diamond
Neurospora crassa OR74A	P22572	87.7%	Diamond
Chaetomium globosum CBS 148.51	Q2H132	87.3%	Diamond
Pyrococcus horikoshii OT3	O57740	84.3%	Diamond
Arabidopsis thaliana	P49077	84.2%	Diamond
Pyrococcus abyssi GE5	Q9UXV6	84.1%	Diamond
Sulfolobus acidocaldarius DSM 639	Q4J8E8	82.3%	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
TCF23	protein-coding	150921
PRR30	protein-coding	339779
ATRAID	protein-coding	51374
SLC5A6	protein-coding	8884
DNAJC5G	protein-coding	285126
TRIM54	protein-coding	57159
UCN	protein-coding	7349
SLC30A3	protein-coding	7781
MPV17	protein-coding	4358
PREB	protein-coding	10113
ABHD1	protein-coding	84696
GTF3C2-AS1	ncRNA	100505624
GTF3C2	protein-coding	2976

Protein

Protein identifiers

Multifunctional protein CAD — P27708 (reviewed: P27708)

Alternative names: Carbamoyl phosphate synthetase 2-aspartate transcarbamylase-dihydroorotase

All UniProt accessions (5): P27708, F8VPD4, H7BZB3, H7C2E4, H7C3Z5

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional protein that encodes the first 3 enzymatic activities of the de novo pyrimidine pathway: carbamoylphosphate synthetase (CPSase; EC 6.3.5.5), aspartate transcarbamylase (ATCase; EC 2.1.3.2) and dihydroorotase (DHOase; EC 3.5.2.3). The CPSase-function is accomplished in 2 steps, by a glutamine-dependent amidotransferase activity (GATase) that binds and cleaves glutamine to produce ammonia, followed by an ammonium-dependent carbamoyl phosphate synthetase, which reacts with the ammonia, hydrogencarbonate and ATP to form carbamoyl phosphate. The endogenously produced carbamoyl phosphate is sequestered and channeled to the ATCase active site. ATCase then catalyzes the formation of carbamoyl-L-aspartate from L-aspartate and carbamoyl phosphate. In the last step, DHOase catalyzes the cyclization of carbamoyl aspartate to dihydroorotate.

Subunit / interactions. Homohexamer. Interacts with CIPC.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Activated by MAP kinase (Erk1/2) phosphorylation just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. Phosphorylation at Ser-1859 by RPS6KB1 downstream of MTOR promotes oligomerization and stimulates dihydroorotase activity. Phosphorylation at Ser-1406 reduces sensitivity to feedback inhibition by UTP.

Disease relevance. Developmental and epileptic encephalopathy 50 (DEE50) [MIM:616457] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE50 is an autosomal recessive, progressive disease with onset in infancy and favorable response to treatment with oral uridine. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosterically regulated and controlled by phosphorylation. 5-phosphoribose 1-diphosphate (PRPP) is an activator while UMP and UTP are inhibitors of the CPSase reaction.

Cofactor. Binds 3 Zn(2+) ions per subunit (for dihydroorotase activity). Binds 4 magnesium or manganese ions per subunit.

Induction. Transcriptionally repressed following hypoxia by HIF1A.

Pathway. Pyrimidine metabolism; UMP biosynthesis via de novo pathway; (S)-dihydroorotate from bicarbonate: step 1/3. Pyrimidine metabolism; UMP biosynthesis via de novo pathway; (S)-dihydroorotate from bicarbonate: step 2/3. Pyrimidine metabolism; UMP biosynthesis via de novo pathway; (S)-dihydroorotate from bicarbonate: step 3/3.

Miscellaneous. GATase (glutamine amidotransferase) and CPSase (carbamoyl phosphate synthase) form together the glutamine-dependent CPSase (GD-CPSase) (EC 6.3.5.5).

Similarity. In the N-terminal section; belongs to the CarA family. In the 2nd section; belongs to the CarB family. In the 3rd section; belongs to the metallo-dependent hydrolases superfamily. DHOase family. CAD subfamily. In the C-terminal section; belongs to the aspartate/ornithine carbamoyltransferase superfamily. ATCase family.

RefSeq proteins (2): NP_001293008, NP_004332* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002082	Asp_carbamoyltransf	Family
IPR002195	Dihydroorotase_CS	Conserved_site
IPR002474	CarbamoylP_synth_ssu_N	Domain
IPR005479	CPAse_ATP-bd	Domain
IPR005480	CPSase_lsu_oligo	Domain
IPR005483	CPSase_dom	Domain
IPR006130	Asp/Orn_carbamoylTrfase	Family
IPR006131	Asp_carbamoyltransf_Asp/Orn-bd	Domain
IPR006132	Asp/Orn_carbamoyltranf_P-bd	Domain
IPR006274	CarbamoylP_synth_ssu	Family
IPR006275	CPSase_lsu	Family
IPR006680	Amidohydro-rel	Domain
IPR011059	Metal-dep_hydrolase_composite	Homologous_superfamily
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
IPR032466	Metal_Hydrolase	Homologous_superfamily
IPR035686	CPSase_GATase1	Domain
IPR036480	CarbP_synth_ssu_N_sf	Homologous_superfamily
IPR036897	CarbamoylP_synth_lsu_oligo_sf	Homologous_superfamily
IPR036901	Asp/Orn_carbamoylTrfase_sf	Homologous_superfamily
IPR036914	MGS-like_dom_sf	Homologous_superfamily
IPR058047	CPSase_preATP-grasp	Domain

Pfam: PF00117, PF00185, PF00988, PF01979, PF02142, PF02729, PF02786, PF02787, PF25596

Enzyme classification (BRENDA)

• EC 2.1.3.2 — aspartate carbamoyltransferase (BRENDA: 52 organisms, 33 substrates, 217 inhibitors, 81 Km, 10 kcat entries)
• EC 3.5.2.3 — dihydroorotase (BRENDA: 34 organisms, 29 substrates, 74 inhibitors, 68 Km, 27 kcat entries)
• EC 6.3.5.5 — carbamoyl-phosphate synthase (glutamine-hydrolysing) (BRENDA: 45 organisms, 73 substrates, 72 inhibitors, 194 Km, 142 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.004–8.36	84
CARBAMOYL PHOSPHATE	0.004–88	33
L-ASPARTATE	0.009–44.7	33
L-GLN	0.0119–22	29
L-GLUTAMINE	0.04–18.87	25
HCO3-	0.64–32.5	16
L-DIHYDROOROTATE	0.004–0.45	15
NH4+	9.8–160	14
N-CARBAMOYL-L-ASPARTATE	0.0281–24	12
ADP	0.022–0.53	11
(S)-DIHYDROOROTATE	0.02–0.6024	9
N-(AMINOCARBONYL)-L-ASPARTIC ACID	0.285–6	7
CARBAMOYL ASPARTATE	0.51–15	6
L-CARBAMOYLASPARTATE	0.015–2.2	6
DIHYDROOROTATE	0.063–3.03	5

Catalyzed reactions (Rhea)

• L-glutamine + H2O = L-glutamate + NH4(+) (RHEA:15889)
• hydrogencarbonate + NH4(+) + 2 ATP = carbamoyl phosphate + 2 ADP + phosphate + 2 H(+) (RHEA:18029)
• hydrogencarbonate + L-glutamine + 2 ATP + H2O = carbamoyl phosphate + L-glutamate + 2 ADP + phosphate + 2 H(+) (RHEA:18633)
• carbamoyl phosphate + L-aspartate = N-carbamoyl-L-aspartate + phosphate + H(+) (RHEA:20013)
• (S)-dihydroorotate + H2O = N-carbamoyl-L-aspartate + H(+) (RHEA:24296)

UniProt features (205 total): binding site 70, helix 42, strand 26, mutagenesis site 15, modified residue 12, region of interest 9, turn 8, sequence conflict 6, sequence variant 5, active site 4, domain 4, compositionally biased region 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

showing 30 of 57 structures by resolution:

PDB	Title	Method	Resolution (Å)
9FS2	Mutant S1538A of the dihydroorotase domain of human CAD protein bound to substrate	X-RAY DIFFRACTION	1.12
6HFQ	Human dihydroorotase mutant F1563T co-crystallized with carbamoyl aspartate at pH 7.5	X-RAY DIFFRACTION	1.15
9FS3	Mutant S1538A of the dihydroorotase domain of human CAD protein in apo form	X-RAY DIFFRACTION	1.18
6HFP	Human dihydroorotase mutant F1563T co-crystallized with carbamoyl aspartate at pH 7.0	X-RAY DIFFRACTION	1.2
6HFJ	Human dihydroorotase mutant F1563A co-crystallized with carbamoyl aspartate at pH 7.5	X-RAY DIFFRACTION	1.2
9FS1	Mutant S1538L of the dihydroorotase domain of human CAD protein bound to carbamoyl …	X-RAY DIFFRACTION	1.21
4C6F	Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 6.5	X-RAY DIFFRACTION	1.26
4C6E	Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 5.5	X-RAY DIFFRACTION	1.26
8PBM	Mutant R1789Q of the dihydroorotase domain of human CAD protein bound to the substrate …	X-RAY DIFFRACTION	1.28
4C6D	Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 6.0	X-RAY DIFFRACTION	1.3
4C6J	Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 7.5	X-RAY DIFFRACTION	1.3
6HFR	Human dihydroorotase mutant F1563Y co-crystallized with carbamoyl aspartate at pH 7.0	X-RAY DIFFRACTION	1.3
6HFS	Human dihydroorotase mutant F1563Y co-crystallized with carbamoyl aspartate at pH 6.5	X-RAY DIFFRACTION	1.35
4C6I	Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 7.0	X-RAY DIFFRACTION	1.35
6HFL	Human dihydroorotase mutant F1563L co-crystallized with carbamoyl aspartate at pH 7.0	X-RAY DIFFRACTION	1.35
6HFU	Human dihydroorotase mutant F1563Y co-crystallized with carbamoyl aspartate at pH 7.5	X-RAY DIFFRACTION	1.4
8PBT	Mutant K1482M of the dihydroorotase domain of human CAD protein bound to the substrate …	X-RAY DIFFRACTION	1.43
6HFH	Human dihydroorotase mutant F1563A co-crystallized with carbamoyl aspartate at pH 7.0	X-RAY DIFFRACTION	1.45
6HFN	Human dihydroorotase mutant F1563L co-crystallized with carbamoyl aspartate at pH 7.5	X-RAY DIFFRACTION	1.45
4C6C	Crystal structure of the dihydroorotase domain of human CAD in apo- form obtained …	X-RAY DIFFRACTION	1.45
6HFK	Human dihydroorotase mutant F1563L co-crystallized with carbamoyl aspartate at pH 6.5	X-RAY DIFFRACTION	1.46
6HFI	Human dihydroorotase mutant F1563A apo structure	X-RAY DIFFRACTION	1.46
8PBG	Mutant K1556T of the dihydroorotase domain of human CAD protein bound to the inhibitor …	X-RAY DIFFRACTION	1.46
4C6K	Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 8.0	X-RAY DIFFRACTION	1.48
6HFE	Human dihydroorotase mutant F1563T apo structure	X-RAY DIFFRACTION	1.48
8PBI	Mutant R1617Q of the dihydroorotase domain of human CAD protein bound to the inhibitor …	X-RAY DIFFRACTION	1.5
6HFF	Human dihydroorotase mutant F1563Y apo structure	X-RAY DIFFRACTION	1.51
4C6P	Crystal structure of the dihydroorotase domain of human CAD C1613S mutant in apo-form at …	X-RAY DIFFRACTION	1.52
8PBP	Mutant R1785C of the dihydroorotase domain of human CAD protein bound to the substrate …	X-RAY DIFFRACTION	1.54
8PBQ	Mutant R1810Q of the dihydroorotase domain of human CAD protein bound to the substrates	X-RAY DIFFRACTION	1.54

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27708-F1	87.25	0.62

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Hydrolases, Ligase, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Mutational cancer driver genes, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of glycan/glycoprotein metabolism, Epilepsy

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4)

Position	Role
252	nucleophile; for gatase activity
336	for gatase activity
338	for gatase activity
1686	for dhoase activity

Ligand- & substrate-binding residues (70)

Position	Role
44	L-glutamine
222	L-glutamine
224	L-glutamine
253	L-glutamine
256	L-glutamine
294	L-glutamine
296	L-glutamine
297	L-glutamine
515	ATP
555	ATP
561	ATP
562	ATP
592	ATP
599	ATP
625	ATP
626	ATP
627	ATP
668	ATP
668	Mg(2+)
668	Mn(2+)
682	ATP
682	Mg(2+)
682	Mn(2+)
684	Mg(2+)
684	Mn(2+)
1088	ATP
1127	ATP
1129	ATP
1134	ATP
1159	ATP
1160	ATP
1161	ATP
1162	ATP
1202	ATP
1202	Mg(2+)
1202	Mn(2+)
1214	ATP
1214	Mg(2+)
1214	Mn(2+)
1216	Mg(2+)
1216	Mn(2+)
1471	Zn(2+)
1473	Zn(2+)
1475	(S)-dihydroorotate
1505	(S)-dihydroorotate
1556	Zn(2+)
1590	Zn(2+)
1613	Zn(2+)
1614	Zn(2+)
1637	Zn(2+)
1661	(S)-dihydroorotate
1686	Zn(2+)
1690	(S)-dihydroorotate
1702	(S)-dihydroorotate

…and 10 more — see UniProt.

Post-translational modifications (12)

Type	Positions
Phosphothreonine	1884, 456
Phosphoserine	1900, 1938, 1038, 1406, 1859, 1873
N-acetylalanine	2
N6-acetyllysine	747, 1411
N6-carboxylysine	1556

Mutagenesis-validated functional residues (15)

Position	Phenotype
1471	no zinc-binding and no catalytic activity.
1471	abolishes dihydroorotase activity.
1473	no zinc-binding and no catalytic activity.
1512	no change in catalytic activity.
1562	abolishes dihydroorotase activity.
1563	abolishes dihydroorotase activity.
1590	abolishes dihydroorotase activity.
1590	no catalytic activity.
1613	reduces dihydroorotase activity.
1614	abolishes dihydroorotase activity.
1637	abolishes dihydroorotase activity.
1642	11.5% of wild-type catalytic activity.
1686	abolishes dihydroorotase activity.
1690	3% of wild-type catalytic activity.
1873	abolishes pma-induced thr-456 phosphorylation.

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-500753	Pyrimidine biosynthesis	curated
R-HSA-1430728	Metabolism	—
R-HSA-15869	Metabolism of nucleotides	—
R-HSA-8956320	Nucleotide biosynthesis	—

MSigDB gene sets: 404 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MATTIOLI_MGUS_VS_PCL, CAIRO_PML_TARGETS_BOUND_BY_MYC_UP, MORF_CDK2, GOBP_PYRIMIDINE_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_REGENERATION, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (27): liver development (GO:0001889), ‘de novo’ pyrimidine nucleobase biosynthetic process (GO:0006207), UDP biosynthetic process (GO:0006225), UTP biosynthetic process (GO:0006228), L-glutamine metabolic process (GO:0006541), xenobiotic metabolic process (GO:0006805), heart development (GO:0007507), female pregnancy (GO:0007565), lactation (GO:0007595), response to amine (GO:0014075), L-citrulline biosynthetic process (GO:0019240), response to caffeine (GO:0031000), animal organ regeneration (GO:0031100), response to insulin (GO:0032868), response to testosterone (GO:0033574), response to starvation (GO:0042594), ‘de novo’ UMP biosynthetic process (GO:0044205), response to cortisol (GO:0051414), cellular response to epidermal growth factor stimulus (GO:0071364), pyrimidine nucleotide biosynthetic process (GO:0006221), amino acid metabolic process (GO:0006520), L-glutamine catabolic process (GO:0006543), phosphate-containing compound metabolic process (GO:0006796), pyrimidine nucleoside biosynthetic process (GO:0046134), nucleobase-containing small molecule metabolic process (GO:0055086), cellular response to xenobiotic stimulus (GO:0071466), pyrimidine-containing compound biosynthetic process (GO:0072528)

GO Molecular Function (22): aspartate carbamoyltransferase activity (GO:0004070), carbamoyl-phosphate synthase (ammonia) activity (GO:0004087), carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity (GO:0004088), dihydroorotase activity (GO:0004151), glutaminase activity (GO:0004359), protein kinase activity (GO:0004672), ATP binding (GO:0005524), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), identical protein binding (GO:0042802), aspartate binding (GO:0070335), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), amino acid binding (GO:0016597), transferase activity (GO:0016740), carboxyl- or carbamoyltransferase activity (GO:0016743), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds (GO:0016810), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides (GO:0016812), ligase activity (GO:0016874), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear matrix (GO:0016363), protein-containing complex (GO:0032991), cell projection (GO:0042995), neuronal cell body (GO:0043025), terminal bouton (GO:0043195), 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

showing 60 of 72 GO namespaces:

Category	Terms
cellular anatomical structure	5
pyrimidine ribonucleotide biosynthetic process	2
animal organ development	2
response to ketone	2
protein binding	2
binding	2
catalytic activity	2
gland development	1
hepaticobiliary system development	1
pyrimidine nucleobase biosynthetic process	1
pyrimidine ribonucleoside diphosphate biosynthetic process	1
UDP metabolic process	1
nucleoside triphosphate biosynthetic process	1
pyrimidine ribonucleoside triphosphate biosynthetic process	1
UTP metabolic process	1
proteinogenic amino acid metabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
circulatory system development	1
multi-organism reproductive process	1
multi-multicellular organism process	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
response to nitrogen compound	1
amino acid biosynthetic process	1
non-proteinogenic amino acid biosynthetic process	1
response to purine-containing compound	1
response to alkaloid	1
regeneration	1
response to peptide hormone	1
response to lipid	1
response to stress	1
response to nutrient levels	1
UMP biosynthetic process	1
response to glucocorticoid	1
response to alcohol	1
response to epidermal growth factor	1
cellular response to growth factor stimulus	1
pyrimidine nucleotide metabolic process	1
nucleotide biosynthetic process	1
pyrimidine-containing compound biosynthetic process	1
carboxyl- or carbamoyltransferase activity	1
ligase activity, forming carbon-nitrogen bonds	1
carbon-nitrogen ligase activity, with glutamine as amido-N-donor	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
transition metal ion binding	1
amino acid binding	1
carboxylic acid binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
transferase activity, transferring one-carbon groups	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 59 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
‘de novo’ UMP biosynthetic process	BP	direct assay
‘de novo’ pyrimidine nucleobase biosynthetic process	BP	direct assay
UDP biosynthetic process	BP	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
nuclear matrix	CC	direct assay
nucleus	CC	direct assay
dihydroorotase activity	MF	direct assay
enzyme binding	MF	physical interaction
identical protein binding	MF	physical interaction
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,990 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAD	DHODH	Q02127	937
CAD	UMPS	P11172	776
CAD	ACKR4	Q9NPB9	630
CAD	PPAT	Q06203	624
CAD	RPS6KB1	P23443	618
CAD	ASS1	P00966	594
CAD	CTPS1	P17812	582
CAD	GLS	O94925	549
CAD	DTYMK	P23919	549
CAD	PFAS	O15067	535
CAD	GMPS	P49915	510
CAD	GART	P22102	486
CAD	UPP2	O95045	483
CAD	ASL	P04424	475
CAD	CMPK1	P30085	474

IntAct

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

22 partners by confidence:

Partner	Interaction type	MIscore	Records
YWHAZ	physical association	0.560	1
CNTROB	physical association	0.400	2
CDC37	physical association	0.400	1
MRTO4	association	0.350	1
TBX19	association	0.350	1
TBXT	association	0.350	1
NFKB2	physical association	0.000	2
IKBKG	physical association	0.000	1
MAP3K1	physical association	0.000	1
MAP3K14	physical association	0.000	1
MAP3K3	physical association	0.000	1
MAP3K7	physical association	0.000	1
NFKBIE	physical association	0.000	1
RELA	physical association	0.000	1
RELB	physical association	0.000	1
RIPK1	physical association	0.000	1
RIPK3	physical association	0.000	1
TAB2	physical association	0.000	1
TNFRSF1A	physical association	0.000	1
TNFRSF1B	physical association	0.000	1
TRADD	physical association	0.000	1
TRAF2	physical association	0.000	1

BioGRID (558 interactions; top human partners by supporting records): ILK (Affinity Capture-MS; 4 records), CCNF (Proximity Label-MS; 3 records), HSPA8 (Co-fractionation; 3 records), PARK2 (Affinity Capture-MS; 3 records), PSMC2 (Co-fractionation; 3 records), TP53 (Affinity Capture-MS; 3 records), YAP1 (Affinity Capture-MS; 3 records), ATP1A1 (Co-fractionation; 2 records), BAP1 (Affinity Capture-MS; 2 records), BRD4 (Affinity Capture-MS; 2 records), C9orf72 (Affinity Capture-MS; 2 records), CUL3 (Affinity Capture-MS; 2 records), CYLD (Affinity Capture-MS; 2 records), DNAJC7 (Affinity Capture-MS; 2 records), ESR1 (Affinity Capture-MS; 2 records)

SIGNOR signaling

25 signaling interactions:

A	Effect	B	Mechanism
MAPK1	up-regulates	CAD	phosphorylation
MAPK3	up-regulates	CAD	phosphorylation
PRKACA	down-regulates	CAD	phosphorylation
RPS6KB1	up-regulates	CAD	phosphorylation
CAD	“up-regulates quantity”	“carbamoyl phosphate(2-)”	“chemical modification”
CAD	“up-regulates activity”	“Pyrimidine biosynthesis”
RPS6K	“up-regulates activity”	CAD	phosphorylation
CAD	“down-regulates quantity”	glutamine	“chemical modification”
CAD	“down-regulates quantity”	“L-glutamine zwitterion”	“chemical modification”
CAD	“down-regulates quantity”	hydrogencarbonate	“chemical modification”
CAD	“up-regulates quantity”	(S)-dihydroorotate	“chemical modification”
CAD	“up-regulates quantity”	L-glutamate(1-)	“chemical modification”
CAD	“down-regulates quantity”	L-aspartate(1-)	“chemical modification”
CAD	“up-regulates quantity”	N-carbamoyl-L-aspartate(2-)	“chemical modification”
CAD	“down-regulates quantity”	N-carbamoyl-L-aspartate(2-)	“chemical modification”
RPS6KB1	“up-regulates activity”	CAD	phosphorylation
CAD	“down-regulates quantity”	“carbamoyl phosphate(2-)”	“chemical modification”
Gbeta	up-regulates	CAD	phosphorylation
PRKACA	unknown	CAD	phosphorylation
PRKACA	“down-regulates activity”	CAD	phosphorylation
CAD	“up-regulates activity”	CAD	phosphorylation
PPP1CA	“down-regulates activity”	CAD	dephosphorylation
PP1	“down-regulates activity”	CAD	dephosphorylation
ERK1/2	“up-regulates activity”	CAD	phosphorylation
PKA	“down-regulates activity”	CAD	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RIP-mediated NFkB activation via ZBP1	5	176.8×	4e-09
TNF signaling	7	155.8×	2e-12
TNFR1-induced NF-kappa-B signaling pathway	7	123.8×	6e-12
RIPK1-mediated regulated necrosis	5	120.2×	2e-08
TRAF6 mediated NF-kB activation	5	120.2×	2e-08
Regulation of necroptotic cell death	5	115.6×	2e-08
TAK1-dependent IKK and NF-kappa-B activation	5	79.1×	1e-07
Fc epsilon receptor (FCERI) signaling	5	71.5×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	7	280.9×	2e-14
canonical NF-kappaB signal transduction	9	157.0×	3e-16
tumor necrosis factor-mediated signaling pathway	6	94.4×	2e-09
negative regulation of canonical NF-kappaB signal transduction	5	40.9×	4e-06
cellular response to tumor necrosis factor	5	39.0×	5e-06
positive regulation of canonical NF-kappaB signal transduction	9	31.1×	4e-10
inflammatory response	8	14.4×	2e-06

Disease & clinical

Genetic variants

Variant evidence for CAD: 2,376 ClinVar records (96 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

2,376 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	61
Likely pathogenic	35
Uncertain significance	746
Likely benign	1387
Benign	62

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 96 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
374829	NM_004341.5(CAD):c.98T>G (p.Met33Arg)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
374831	NM_004341.5(CAD):c.5365C>T (p.Arg1789Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
430523	NM_004341.5(CAD):c.5296_5308del (p.Phe1766fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
801658	NM_004341.5(CAD):c.571C>T (p.Arg191Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
817700	NM_004341.5(CAD):c.1070_1071del (p.Val357fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
977206	NM_004341.5(CAD):c.4810C>T (p.Gln1604Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
203465	NM_004341.5(CAD):c.1843-1G>A	Pathogenic	criteria provided, single submitter	2
426813	NM_004341.5(CAD):c.2617_2620del (p.Asp873fs)	Pathogenic	criteria provided, single submitter	1
930757	NM_004341.5(CAD):c.5545_5546del (p.Phe1849fs)	Pathogenic	criteria provided, single submitter	1
1351531	NM_004341.5(CAD):c.135C>A (p.Tyr45Ter)	Pathogenic	criteria provided, single submitter	1
1363933	NM_004341.5(CAD):c.5420dup (p.Asp1808fs)	Pathogenic	criteria provided, single submitter	1
1439500	NM_004341.5(CAD):c.3088C>T (p.Gln1030Ter)	Pathogenic	criteria provided, single submitter	1
1446574	NM_004341.5(CAD):c.1172del (p.Pro391fs)	Pathogenic	criteria provided, single submitter	1
1453934	NM_004341.5(CAD):c.473del (p.Leu158fs)	Pathogenic	criteria provided, single submitter	1
1454035	NM_004341.5(CAD):c.4246C>T (p.Arg1416Ter)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CAD’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; 33 predictions of 3,210):

Position(s)	Effect	Δscore	Sites
2:27222661–27222662	donor_loss	1.0000	4
2:27224030–27224031	donor_loss	1.0000	4
2:27224342	acceptor_gain	1.0000
2:27224491–27224492	donor_loss	1.0000	5
2:27224743–27224744	acceptor_loss	1.0000	6
2:27224877–27224878	donor_loss	1.0000	5
2:27225003	acceptor_gain	1.0000
2:27225008–27225009	acceptor_loss	1.0000	5
2:27225201	donor_gain	1.0000
2:27225224	donor_gain	1.0000

AlphaMissense

6,100 missense substitutions predicted likely pathogenic (of 14,390 scored), across 1,427 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
M1282	9	0.980	0.998
M1098	9	0.947	0.995
M759	9	0.938	0.996
M618	9	0.920	0.991
M782	9	0.899	0.984
M1503	9	0.865	0.976
M766	9	0.862	0.989
D413	8	0.998	0.999
D952	8	0.998	1.000
H1154	8	0.998	0.999
D982	8	0.993	0.998
D1138	8	0.993	0.997
D1164	8	0.993	0.999
F951	8	0.992	1.000
H1161	8	0.990	0.998
S1973	8	0.988	1.000
S948	8	0.987	1.000
F412	8	0.985	1.000
N620	8	0.985	0.998
D873	8	0.985	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

6 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.51e-11
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	5.72e-09
Liver Hepatocellular Carcinoma (validation)	unfavorable	8.85e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000121
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000348
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000981

Disease associations

OMIM: gene MIM:114010 | disease phenotypes: MIM:616457

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
developmental and epileptic encephalopathy, 50	Definitive	Autosomal recessive	5

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 50	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (9 panels, 9 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

9 panels:

Panel	Rating
Ataxia and cerebellar anomalies - childhood onset	green
DDG2P	green
Early onset or syndromic epilepsy	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (2): developmental and epileptic encephalopathy, 50 (MONDO:0014647), infantile epileptic-dyskinetic encephalopathy (MONDO:0018226)

Orphanet (2): CAD-CDG (Orphanet:448010), Infantile epileptic-dyskinetic encephalopathy (Orphanet:364063)

HPO phenotypes

25 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001903	Anemia
HP:0001927	Acanthocytosis
HP:0001947	Renal tubular acidosis
HP:0001981	Schistocytosis
HP:0001987	Hyperammonemia
HP:0002014	Diarrhea
HP:0002015	Dysphagia
HP:0002133	Status epilepticus
HP:0002136	Broad-based gait
HP:0002283	Global brain atrophy
HP:0002376	Developmental regression
HP:0002465	Poor speech
HP:0003218	Oroticaciduria
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0003819	Death in childhood
HP:0004823	Anisopoikilocytosis
HP:0011463	Childhood onset
HP:0012345	Abnormal glycosylation
HP:0200134	Epileptic encephalopathy

GWAS associations

1 associations:

Study	Trait	p-value
GCST010244_66	Triglyceride levels	7e-32

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C567924	Infantile Epileptic-Dyskinetic Encephalopathy *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3093 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

6 measured of 6 human assays (7 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
6-Mercaptomethyl-2-oxo-2,3,4,5-tetrahydro-pyrimidine-4-carboxylic acid	KI	140 nM
6-Mercaptomethyl-2-oxo-hexahydro-pyrimidine-4-carboxylic acid	KI	140 nM
CHEMBL5653589	KD	1440 nM
(2R,4S)-4-Mercapto-4,6-dioxo-4lambda*5*-[1,4]azaphosphinane-2-carboxylic acid	KI	2900 nM
4-Hydroxy-4,6-dioxo-4lambda*5*-[1,4]azaphosphinane-2-carboxylic acid	KI	4000 nM
Ethyl-3-borono-2-(carbamylamino)propionate	KI	5070 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.58	Kd	2.645	nM	CHEMBL3752910
8.58	ED50	2.645	nM	CHEMBL3752910
8.35	Kd	4.477	nM	CHEMBL5653589
8.35	ED50	4.477	nM	CHEMBL5653589
6.85	Ki	140	nM	CHEMBL29908
6.85	Ki	140	nM	CHEMBL170214
5.54	Ki	2900	nM	CHEMBL141678
5.51	Ki	3100	nM	CHEMBL343069
5.40	Ki	4000	nM	CHEMBL336479
5.29	Ki	5070	nM	CHEMBL168878

PubChem BioAssay actives

8 with measured affinity, of 21 total; 7 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	2147979: Binding affinity to human CAD incubated for 45 mins by Kinobead based pull down assay	kd	0.0026	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147979: Binding affinity to human CAD incubated for 45 mins by Kinobead based pull down assay	kd	0.0045	uM
(4S,6R)-2-oxo-6-(sulfanylmethyl)-1,3-diazinane-4-carboxylic acid	55730: Compound ability to inhibit the catalytic activity of hamster Dihydroorotase (DHOase) expressed in Escherichia coli.	ki	0.1400	uM
2-oxo-4-(sulfanylmethyl)-5,6-dihydro-1H-pyrimidine-6-carboxylic acid	55732: Inhibitory activity against Dihydroorotase (DHO) at pH 7.4 and 8.5	ki	0.1400	uM
(2R)-4-hydroxy-6-oxo-4-sulfanylidene-1,4lambda5-azaphosphinane-2-carboxylic acid	55730: Compound ability to inhibit the catalytic activity of hamster Dihydroorotase (DHOase) expressed in Escherichia coli.	ki	2.9000	uM
4-hydroxy-4,6-dioxo-1,4lambda5-azaphosphinane-2-carboxylic acid	55730: Compound ability to inhibit the catalytic activity of hamster Dihydroorotase (DHOase) expressed in Escherichia coli.	ki	4.0000	uM
[2-(carbamoylamino)-3-ethoxy-3-oxopropyl]boronic acid	55731: Inhibitory activity against Dihydroorotase (DHO) at pH 6.0	ki	5.0700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression, affects expression	5
Estradiol	increases reaction, decreases phosphorylation, increases expression, affects binding, decreases reaction	4
bisphenol A	decreases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	increases expression, increases mutagenesis	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	decreases expression, increases expression, affects cotreatment, affects localization	1
decabromobiphenyl ether	increases expression	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	increases expression	1
manganese chloride	decreases expression, increases abundance	1
ochratoxin A	increases expression	1
potassium chromate(VI)	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	decreases expression	1

ChEMBL screening assays

17 unique, capped per target: 16 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118734	Binding	Binding affinity to CAD in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *Bioorg Med Chem*
CHEMBL4619225	ADMET	Inhibition of CAD (unknown origin) CSP2 activity expressed in Escherichia coli BL21 (DE3) 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: 4 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C4S7	BCHNEi001-A	Induced pluripotent stem cell	Male
CVCL_D9Z5	Ubigene HeLa CAD KO	Cancer cell line	Female
CVCL_XM42	HAP1 CAD (-)	Cancer cell line	Male
CVCL_ZD03	Mel 04.01	Cancer cell line	Male
CVCL_ZD06	Mel 12.07	Cancer cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT01574313	Phase 4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	Phase 4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	Phase 4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00004637	Phase 4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	Phase 4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	Phase 4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	Phase 4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	Phase 4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	Phase 4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	Phase 4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	Phase 4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	Phase 4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	Phase 4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	Phase 4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	Phase 4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	Phase 4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	Phase 4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	Phase 4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	Phase 4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	Phase 4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	Phase 4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	Phase 4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	Phase 4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	Phase 4	COMPLETED	RNS® System LTT Study
NCT00610532	Phase 4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	Phase 4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	Phase 4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	Phase 4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	Phase 4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	Phase 4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	Phase 4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	Phase 4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	Phase 4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	Phase 4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	Phase 4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	Phase 4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	Phase 4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	Phase 4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	Phase 4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	Phase 4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	Phase 4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	Phase 4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	Phase 4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy
NCT01309074	Phase 4	WITHDRAWN	Does Pregabalin Improve Symptoms of Anxiety in Patients With Epilepsy? A Comparison With Sertraline
NCT01318408	Phase 4	COMPLETED	Levetiracetam: The Anti-Convulsant of Choice for Elderly Patients With Dementia
NCT01498822	Phase 4	COMPLETED	Levetiracetam Versus Oxcarbazepine as Monotherapy to Evaluate Efficacy and Safety in Subjects With Newly or Recently Diagnosed Partial Epilepsy
NCT01546688	Phase 4	TERMINATED	A Study to Evaluate the Safety and Tolerability and Explore the Efficacy of Zonisamide as add-on Therapy in Elderly Patients With Refractory Partial Seizures
NCT01607346	Phase 4	TERMINATED	An Open Label Study to Evaluate the Effects of Ezogabine/Retigabine Added to Existing Anti-epileptic Drug(s) on Urinary Voiding Function in Subjects With Partial Onset Seizures
NCT01627860	Phase 4	COMPLETED	First Add-on vs. Mono-therapy Study of Topiramate in Neuro-Surgical Patients
NCT01689649	Phase 4	COMPLETED	A Study to Assess Tolerability and Efficacy of Topiramate Monotherapy in Recently Diagnosed Patients With Epilepsy
NCT01713777	Phase 4	COMPLETED	Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design
NCT01733394	Phase 4	COMPLETED	Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Single-Dose 6-Period Replicate Design (EQUIGEN Single-Dose Study)
NCT01804322	Phase 4	COMPLETED	Standardized Educational Plan for Epilepsy Patients With Comorbidities
NCT01932502	Phase 4	UNKNOWN	Evaluation of Onfi Conversion Therapy Replacing Clonazepam in Patients With Medically Refractory Epilepsy
NCT01995825	Phase 4	COMPLETED	Lamotrigine Bioequivalence
NCT02100644	Phase 4	COMPLETED	Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study

Predicted chemistry — Sugi Predict

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