CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase [Homo sapiens (human)] - Gene

Summary

Official Symbol: CADprovided by HGNC
Official Full Name: carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotaseprovided by HGNC
Primary source: HGNC:HGNC:1424
See related: Ensembl:ENSG00000084774 MIM:114010; AllianceGenome:HGNC:1424
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: CDG1Z; DEE50; GATD4; EIEE50
Summary: 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. [provided by RefSeq, Apr 2015]
Expression: Ubiquitous expression in testis (RPKM 7.3), ovary (RPKM 6.7) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 2p23.3

Exon count:: 45

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (27217369..27243943)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (27259008..27285579)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (27440237..27466811)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Beyond genetics: Deciphering the impact of missense variants in CAD deficiency.
Title: Beyond genetics: Deciphering the impact of missense variants in CAD deficiency.
Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease.
Title: Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease.
New regulatory mechanism-based inhibitors of aspartate transcarbamoylase for potential anticancer drug development.
Title: New regulatory mechanism-based inhibitors of aspartate transcarbamoylase for potential anticancer drug development.
The Cellular Protein CAD is Recruited into Ebola Virus Inclusion Bodies by the Nucleoprotein NP to Facilitate Genome Replication and Transcription.
Title: The Cellular Protein CAD is Recruited into Ebola Virus Inclusion Bodies by the Nucleoprotein NP to Facilitate Genome Replication and Transcription.
Uridine treatment normalizes the congenital dyserythropoietic anemia type II-like hematological phenotype in a patient with homozygous mutation in the CAD gene.
Title: Uridine treatment normalizes the congenital dyserythropoietic anemia type II-like hematological phenotype in a patient with homozygous mutation in the CAD gene.
structural evidences indicated that post-translational carbamylated Lys was not required for Znalpha binding in PaDHPase and in huDHOase.
Title: Crystal structures of monometallic dihydropyrimidinase and the human dihydroorotase domain K1556A mutant reveal no lysine carbamylation within the active site.
The catalytic flexibile loop in the dihydrooratase domain possesses an absolutely conserved Phe-1563 residue required for catalytic activity.
Title: Characterization of the catalytic flexible loop in the dihydroorotase domain of the human multi-enzymatic protein CAD.
CAD dihydroorotase and aspartate transcarbamoylase domains self-assembles into dimers and trimers.
Title: Structural Insight into the Core of CAD, the Multifunctional Protein Leading De Novo Pyrimidine Biosynthesis.
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
Title: Tracking a CAD-ALK gene rearrangement in urine and blood of a colorectal cancer patient treated with an ALK inhibitor.
Charge neutralization in the active site of the catalytic trimer of aspartate transcarbamoylase promotes diverse structural changes.
Title: Charge neutralization in the active site of the catalytic trimer of aspartate transcarbamoylase promotes diverse structural changes.

Submit: New GeneRIF Correction See all GeneRIFs (26)

Phenotypes

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Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Developmental and epileptic encephalopathy, 50 MedGen: C4225320 OMIM: 616457 GeneReviews: Not available	Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Replication interactions

Interaction	Pubs
Knockdown of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) by siRNA inhibits the early stages of HIV-1 replication in 293T cells infected with VSV-G pseudotyped HIV-1	PubMed

Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	Tandem affinity purification and mass spectrometry analysis identify carbamoyl-phosphate synthetase 2 (CAD), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
Gag-Pol	gag-pol	Tandem affinity purification and mass spectrometry analysis identify carbamoyl-phosphate synthetase 2 (CAD), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
Nef	nef	Tandem affinity purification and mass spectrometry analysis identify carbamoyl-phosphate synthetase 2 (CAD), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
Pr55(Gag)	gag	Tandem affinity purification and mass spectrometry analysis identify carbamoyl-phosphate synthetase 2 (CAD), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells	PubMed
Vif	vif	HIV-1 Vif interacts with CAD; interaction predicted to be relevant to purine pyrimidine biosynthesis	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH70745 (e-PCR)
- UniSTS:67620

PMC139788P1 (e-PCR)
- UniSTS:270895

G54144 (e-PCR)
- UniSTS:109381

SGC30858 (e-PCR)
- UniSTS:55118

WI-14618 (e-PCR)
- UniSTS:83552

PMC207647P2 (e-PCR)
- UniSTS:271974

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	ISS Inferred from Sequence or Structural Similarity more info
enables aspartate binding	ISS Inferred from Sequence or Structural Similarity more info
enables aspartate carbamoyltransferase activity	IBA Inferred from Biological aspect of Ancestor more info
enables aspartate carbamoyltransferase activity	ISS Inferred from Sequence or Structural Similarity more info
enables carbamoyl-phosphate synthase (ammonia) activity	IEA Inferred from Electronic Annotation more info
contributes_to carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity	IBA Inferred from Biological aspect of Ancestor more info
enables carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity	ISS Inferred from Sequence or Structural Similarity more info
enables dihydroorotase activity	IBA Inferred from Biological aspect of Ancestor more info
enables dihydroorotase activity	IDA Inferred from Direct Assay more info	PubMed
enables dihydroorotase activity	ISS Inferred from Sequence or Structural Similarity more info
enables enzyme binding	IPI Inferred from Physical Interaction more info	PubMed
enables glutaminase activity	IEA Inferred from Electronic Annotation more info
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables identical protein binding	ISS Inferred from Sequence or Structural Similarity more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein kinase activity	ISS Inferred from Sequence or Structural Similarity more info
enables zinc ion binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in 'de novo' UMP biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
involved_in 'de novo' UMP biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in 'de novo' pyrimidine nucleobase biosynthetic process	IBA Inferred from Biological aspect of Ancestor more info
involved_in 'de novo' pyrimidine nucleobase biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
involved_in 'de novo' pyrimidine nucleobase biosynthetic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in UDP biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
involved_in UTP biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in animal organ regeneration	IEA Inferred from Electronic Annotation more info
involved_in cellular response to epidermal growth factor stimulus	IEA Inferred from Electronic Annotation more info
involved_in citrulline biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in female pregnancy	IEA Inferred from Electronic Annotation more info
involved_in glutamine metabolic process	IBA Inferred from Biological aspect of Ancestor more info
involved_in glutamine metabolic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in heart development	IEA Inferred from Electronic Annotation more info
involved_in lactation	IEA Inferred from Electronic Annotation more info
involved_in liver development	IEA Inferred from Electronic Annotation more info
involved_in peptidyl-threonine phosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein autophosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in response to amine	IEA Inferred from Electronic Annotation more info
involved_in response to caffeine	IEA Inferred from Electronic Annotation more info
involved_in response to cortisol	IEA Inferred from Electronic Annotation more info
involved_in response to insulin	IEA Inferred from Electronic Annotation more info
involved_in response to starvation	IEA Inferred from Electronic Annotation more info
involved_in response to testosterone	IEA Inferred from Electronic Annotation more info
involved_in xenobiotic metabolic process	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
located_in cell projection	ISS Inferred from Sequence or Structural Similarity more info
is_active_in cytoplasm	IBA Inferred from Biological aspect of Ancestor more info
is_active_in cytosol	IBA Inferred from Biological aspect of Ancestor more info
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
located_in extracellular exosome	HDA more info	PubMed
located_in membrane	HDA more info	PubMed
located_in neuronal cell body	ISS Inferred from Sequence or Structural Similarity more info
located_in nuclear matrix	IDA Inferred from Direct Assay more info	PubMed
located_in nucleus	IDA Inferred from Direct Assay more info	PubMed
part_of protein-containing complex	IEA Inferred from Electronic Annotation more info
located_in terminal bouton	ISS Inferred from Sequence or Structural Similarity more info

General protein information

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Preferred Names: multifunctional protein CAD

Names: CAD trifunctional protein; carbamoyl phosphate synthetase 2-aspartate transcarbamylase-dihydroorotase

NP_001293008.1

EC 2.1.3.2

EC 3.5.1.2

EC 3.5.2.3

EC 6.3.4.16

EC 6.3.5.5

NP_004332.2

EC 2.1.3.2

EC 3.5.1.2

EC 3.5.2.3

EC 6.3.4.16

EC 6.3.5.5

XP_006712164.1

EC 2.1.3.2

EC 3.5.1.2

EC 3.5.2.3

EC 6.3.4.16

EC 6.3.5.5

XP_047301759.1

EC 2.1.3.2

EC 3.5.1.2

EC 3.5.2.3

EC 6.3.4.16

EC 6.3.5.5

XP_054199815.1

EC 2.1.3.2

EC 3.5.1.2

EC 3.5.2.3

EC 6.3.4.16

EC 6.3.5.5

XP_054199816.1

EC 2.1.3.2

EC 3.5.1.2

EC 3.5.2.3

EC 6.3.4.16

EC 6.3.5.5

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_046394.1 RefSeqGene

Range

4980..31554

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001306079.2 → NP_001293008.1 multifunctional protein CAD isoform 2

See identical proteins and their annotated locations for NP_001293008.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an alternate in-frame exon in the 5' coding region compared to variant 1. It encodes isoform 2 which is shorter than isoform 1.

Source sequence(s)

AC013403, AC013413, AK226105, BC065510, BG766243, BQ447516

Consensus CDS

CCDS77396.1

UniProtKB/TrEMBL

F8VPD4, Q53SY7

Related

ENSP00000384510.1, ENST00000403525.5

Conserved Domains (4) summary

PRK00856
Location:1857 → 2161

pyrB; aspartate carbamoyltransferase catalytic subunit

PRK12564
Location:1 → 355

PRK12564; carbamoyl-phosphate synthase small subunit

cd01316
Location:1397 → 1743

CAD_DHOase; The eukaryotic CAD protein is a trifunctional enzyme of carbamoylphosphate synthetase-aspartate transcarbamoylase-dihydroorotase, which catalyzes the first three steps of de novo pyrimidine nucleotide biosynthesis. Dihydroorotase (DHOase) catalyzes the ...

TIGR01369
Location:391 → 1377

CPSaseII_lrg; carbamoyl-phosphate synthase, large subunit
NM_004341.5 → NP_004332.2 multifunctional protein CAD isoform 1

See identical proteins and their annotated locations for NP_004332.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).

Source sequence(s)

AC013403, AC013413, BC065510, BM927624, BQ447516, BU541191, BU558264, D78586

Consensus CDS

CCDS1742.1

UniProtKB/Swiss-Prot

D6W552, P27708, Q6P0Q0, Q96CK3

UniProtKB/TrEMBL

Q53SY7

Related

ENSP00000264705.3, ENST00000264705.9

Conserved Domains (13) summary

cd01744
Location:178 → 354

GATase1_CPSase; Small chain of the glutamine-dependent form of carbamoyl phosphate synthase, CPSase II

PRK09060
Location:1429 → 1810

PRK09060; dihydroorotase; Validated

PRK00856
Location:1920 → 2224

pyrB; aspartate carbamoyltransferase catalytic subunit; Provisional

PRK12564
Location:1 → 355

PRK12564; carbamoyl phosphate synthase small subunit; Reviewed

cd01316
Location:1460 → 1806

CAD_DHOase; The eukaryotic CAD protein is a trifunctional enzyme of carbamoylphosphate synthetase-aspartate transcarbamoylase-dihydroorotase, which catalyzes the first three steps of de novo pyrimidine nucleotide biosynthesis. Dihydroorotase (DHOase) catalyzes the ...

cd01423
Location:1313 → 1438

MGS_CPS_I_III; Methylglyoxal synthase-like domain found in pyr1 and URA1-like carbamoyl phosphate synthetases (CPS), including ammonia-dependent CPS Type I, and glutamine-dependent CPS Type III. These are multidomain proteins, in which MGS is the C-terminal domain.

TIGR01369
Location:391 → 1440

CPSaseII_lrg; carbamoyl-phosphate synthase, large subunit

pfam00185
Location:2072 → 2221

OTCace; Aspartate/ornithine carbamoyltransferase, Asp/Orn binding domain

pfam00988
Location:2 → 138

CPSase_sm_chain; Carbamoyl-phosphate synthase small chain, CPSase domain

pfam02729
Location:1925 → 2065

OTCace_N; Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain

pfam02786
Location:514 → 716

CPSase_L_D2; Carbamoyl-phosphate synthase L chain, ATP binding domain

pfam02787
Location:801 → 921

CPSase_L_D3; Carbamoyl-phosphate synthetase large chain, oligomerization domain

cl17255
Location:1048 → 1245

ATP-grasp_4; ATP-grasp domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000002.12 Reference GRCh38.p14 Primary Assembly

Range

27217369..27243943

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_047445803.1 → XP_047301759.1 multifunctional protein CAD isoform X1
XM_006712101.4 → XP_006712164.1 multifunctional protein CAD isoform X2

UniProtKB/TrEMBL

Q53SY7

Conserved Domains (12) summary

cd01744
Location:178 → 354

GATase1_CPSase; Small chain of the glutamine-dependent form of carbamoyl phosphate synthase, CPSase II

PRK09060
Location:1366 → 1747

PRK09060; dihydroorotase; Validated

PRK00856
Location:1874 → 2178

pyrB; aspartate carbamoyltransferase catalytic subunit; Provisional

PRK12564
Location:1 → 355

PRK12564; carbamoyl phosphate synthase small subunit; Reviewed

cd01316
Location:1397 → 1743

CAD_DHOase; The eukaryotic CAD protein is a trifunctional enzyme of carbamoylphosphate synthetase-aspartate transcarbamoylase-dihydroorotase, which catalyzes the first three steps of de novo pyrimidine nucleotide biosynthesis. Dihydroorotase (DHOase) catalyzes the ...

cd01423
Location:1250 → 1375

MGS_CPS_I_III; Methylglyoxal synthase-like domain found in pyr1 and URA1-like carbamoyl phosphate synthetases (CPS), including ammonia-dependent CPS Type I, and glutamine-dependent CPS Type III. These are multidomain proteins, in which MGS is the C-terminal domain.

TIGR01369
Location:391 → 1377

CPSaseII_lrg; carbamoyl-phosphate synthase, large subunit

pfam00185
Location:2026 → 2175

OTCace; Aspartate/ornithine carbamoyltransferase, Asp/Orn binding domain

pfam00988
Location:2 → 138

CPSase_sm_chain; Carbamoyl-phosphate synthase small chain, CPSase domain

pfam02729
Location:1879 → 2019

OTCace_N; Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain

pfam02787
Location:738 → 858

CPSase_L_D3; Carbamoyl-phosphate synthetase large chain, oligomerization domain

cl17255
Location:514 → 653

ATP-grasp_4; ATP-grasp domain