CAD protein - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot P27708 (PYR1_HUMAN)

Last modified November 25, 2008. Version 103. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    CAD protein
Including the following 3 domains:
    1- Recommended name:
            Glutamine-dependent carbamoyl-phosphate synthase
              EC=6.3.5.5
    2- Recommended name:
            Aspartate carbamoyltransferase
              EC=2.1.3.2
    3- Recommended name:
            Dihydroorotase
              EC=3.5.2.3

Gene names

Name:

CAD

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	2225 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase).
Catalytic activity	2 ATP + L-glutamine + HCO(3)(-) + H(2)O = 2 ADP + phosphate + L-glutamate + carbamoyl phosphate. Carbamoyl phosphate + L-aspartate = phosphate + N-carbamoyl-L-aspartate. (S)-dihydroorotate + H(2)O = N-carbamoyl-L-aspartate.
Cofactor	Binds 1 zinc ion per subunit (for dihydroorotase activity) Potential.
Enzyme regulation	Allosterically regulated and controlled by phosphorylation. 5-phosphoribose 1-diphosphate is an activator while UMP is an inhibitor of the CPSase reaction.
Pathway	Pyrimidine metabolism; UMP biosynthesis via de novo pathway; UMP from HCO(3)(-): step 1/6. Pyrimidine metabolism; UMP biosynthesis via de novo pathway; UMP from HCO(3)(-): step 2/6. Pyrimidine metabolism; UMP biosynthesis via de novo pathway; UMP from HCO(3)(-): step 3/6.
Subunit structure	Homohexamer.
Subcellular location	Cytoplasm.
Miscellaneous	GATase (glutamine amidotransferase) and CPSase (carbamoyl phosphate synthase) form together the glutamine-dependent CPSase (GD-CPSase) (EC 6.3.5.5).
Sequence similarities	In the central section; belongs to the DHOase family. Contains 2 ATP-grasp domains. Contains 1 glutamine amidotransferase type-1 domain.

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Ontologies

Keywords
Biological process	Pyrimidine biosynthesis
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Domain	Repeat
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Ligase Transferase
PTM	Acetylation Phosphoprotein
Technical term	Allosteric enzyme Direct protein sequencing Multifunctional enzyme
Gene Ontology (GO)
Biological process	'de novo' pyrimidine base biosynthetic process Inferred from electronic annotation. Source: InterPro glutamine metabolic process Inferred from electronic annotation. Source: InterPro pyrimidine nucleotide biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Ref.1 Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro amino acid binding Inferred from electronic annotation. Source: InterPro aspartate carbamoyltransferase activity Inferred from electronic annotation. Source: InterPro carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity Ref.1 Traceable author statement. Source: ProtInc dihydroorotase activity Ref.1 Inferred from electronic annotation. Source: EC zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

Removed

Chain

2 – 2225

2224

CAD protein

PRO_0000199506

Regions

Domain

177 – 363

187

Glutamine amidotransferase type-1

Domain

519 – 711

193

ATP-grasp 1

Domain

1052 – 1243

192

ATP-grasp 2

Region

2 – 365

364

GATase (Glutamine amidotransferase)

Region

366 – 394

Linker

Region

395 – 1455

1061

CPSase (Carbamoyl-phosphate synthase)

Region

395 – 933

539

CPSase A

Region

934 – 1455

522

CPSase B

Region

1456 – 1788

333

DHOase (dihydroorotase)

Region

1789 – 1917

129

Linker

Region

1918 – 2225

308

ATCase (Aspartate transcarbamylase)

Sites

Active site

252

For GATase activity By similarity

Active site

336

For GATase activity By similarity

Active site

338

For GATase activity By similarity

Metal binding

1471

Zinc Potential

Metal binding

1473

Zinc Potential

Amino acid modifications

Modified residue

N-acetylalanine

Modified residue

1423

Phosphoserine

Modified residue

1823

Phosphoserine

Modified residue

1859

Phosphoserine

Natural variations

Natural variant

177

R → Q in a colorectal cancer sample; somatic mutation.

VAR_035897

Natural variant

735

Y → C in a colorectal cancer sample; somatic mutation.

VAR_035898

Experimental info

Sequence conflict

505

P → T in BAA11423. Ref.1

Sequence conflict

535

A → G in BAA11423. Ref.1

Sequence conflict

560

L → V in BAA11423. Ref.1

Sequence conflict

1103

T → A in BAA11423. Ref.1

Sequence conflict

1513

A → G in BAA11423. Ref.1

Sequence conflict

1676

N → D in BAA11423. Ref.1

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Sequences

Sequence

Length

Mass (Da)

Tools

P27708-1 [UniParc].

Last modified July 19, 2004. Version 3.
Checksum: 2AB8E8413E825A8F
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FASTA

2,225

242,984

        10         20         30         40         50         60 
MAALVLEDGS VLRGQPFGAA VSTAGEVVFQ TGMVGYPEAL TDPSYKAQIL VLTYPLIGNY 

        70         80         90        100        110        120 
GIPPDEMDEF GLCKWFESSG IHVAALVVGE CCPTPSHWSA TRTLHEWLQQ HGIPGLQGVD 

       130        140        150        160        170        180 
TRELTKKLRE QGSLLGKLVQ NGTEPSSLPF LDPNARPLVP EVSIKTPRVF NTGGAPRILA 

       190        200        210        220        230        240 
LDCGLKYNQI RCLCQRGAEV TVVPWDHALD SQEYEGLFLS NGPGDPASYP SVVSTLSRVL 

       250        260        270        280        290        300 
SEPNPRPVFG ICLGHQLLAL AIGAKTYKMR YGNRGHNQPC LLVGSGRCFL TSQNHGFAVE 

       310        320        330        340        350        360 
TDSLPADWAP LFTNANDGSN EGIVHNSLPF FSVQFHPEHQ AGPSDMELLF DIFLETVKEA 

       370        380        390        400        410        420 
TAGNPGGQTV RERLTERLCP PGIPTPGSGL PPPRKVLILG SGGLSIGQAG EFDYSGSQAI 

       430        440        450        460        470        480 
KALKEENIQT LLINPNIATV QTSQGLADKV YFLPITPHYV TQVIRNERPD GVLLTFGGQT 

       490        500        510        520        530        540 
ALNCGVELTK AGVLARYGVR VLGTPVETIE LTEDRRAFAA RMAEIGEHVA PSEAANSLEQ 

       550        560        570        580        590        600 
AQAAAERLGY PVLVRAAFAL GGLGSGFASN REELSALVAP AFAHTSQVLV DKSLKGWKEI 

       610        620        630        640        650        660 
EYEVVRDAYG NCVTVCNMEN LDPLGIHTGE SIVVAPSQTL NDREYQLLRQ TAIKVTQHLG 

       670        680        690        700        710        720 
IVGECNVQYA LNPESEQYYI IEVNARLSRS SALASKATGY PLAYVAAKLA LGIPLPELRN 

       730        740        750        760        770        780 
SVTGGTAAFE PSVDYCVVKI PRWDLSKFLR VSTKIGSCMK SVGEVMGIGR SFEEAFQKAL 

       790        800        810        820        830        840 
RMVDENCVGF DHTVKPVSDM ELETPTDKRI FVVAAALWAG YSVDRLYELT RIDRWFLHRM 

       850        860        870        880        890        900 
KRIIAHAQLL EQHRGQPLPP DLLQQAKCLG FSDKQIALAV LSTELAVRKL RQELGICPAV 

       910        920        930        940        950        960 
KQIDTVAAEW PAQTNYLYLT YWGTTHDLTF RTPHVLVLGS GVYRIGSSVE FDWCAVGCIQ 

       970        980        990       1000       1010       1020 
QLRKMGYKTI MVNYNPETVS TDYDMCDRLY FDEISFEVVM DIYELENPEG VILSMGGQLP 

      1030       1040       1050       1060       1070       1080 
NNMAMALHRQ QCRVLGTSPE AIDSAENRFK FSRLLDTIGI SQPQWRELSD LESARQFCQT 

      1090       1100       1110       1120       1130       1140 
VGYPCVVRPS YVLSGAAMNV AYTDGDLERF LSSAAAVSKE HPVVISKFIQ EAKEIDVDAV 

      1150       1160       1170       1180       1190       1200 
ASDGVVAAIA ISEHVENAGV HSGDATLVTP PQDITAKTLE RIKAIVHAVG QELQVTGPFN 

      1210       1220       1230       1240       1250       1260 
LQLIAKDDQL KVIECNVRVS RSFPFVSKTL GVDLVALATR VIMGEEVEPV GLMTGSGVVG 

      1270       1280       1290       1300       1310       1320 
VKVPQFSFSR LAGADVVLGV EMTSTGEVAG FGESRCEAYL KAMLSTGFKI PKKNILLTIG 

      1330       1340       1350       1360       1370       1380 
SYKNKSELLP TVRLLESLGY SLYASLGTAD FYTEHGVKVT AVDWHFEEAV DGECPPQRSI 

      1390       1400       1410       1420       1430       1440 
LEQLAEKNFE LVINLSMRGA GGRRLSSFVT KGYRTRRLAA DFSVPLIIDI KCTKLFVEAL 

      1450       1460       1470       1480       1490       1500 
GQIGPAPPLK VHVDCMTSQK LVRLPGLIDV HVHLREPGGT HKEDFASGTA AALAGGITMV 

      1510       1520       1530       1540       1550       1560 
CAMPNTRPPI IDAPALALAQ KLAEAGARCD FALFLGASSE NAGTLGTVAG SAAGLKLYLN 

      1570       1580       1590       1600       1610       1620 
ETFSELRLDS VVQWMEHFET WPSHLPIVAH AEQQTVAAVL MVAQLTQRSV HICHVARKEE 

      1630       1640       1650       1660       1670       1680 
ILLIKAAKAR GLPVTCEVAP HHLFLSHDDL ERLGPGKGEV RPELGSRQDV EALWENMAVI 

      1690       1700       1710       1720       1730       1740 
DCFASDHAPH TLEEKCGSRP PPGFPGLETM LPLLLTAVSE GRLSLDDLLQ RLHHNPRRIF 

      1750       1760       1770       1780       1790       1800 
HLPPQEDTYV EVDLEHEWTI PSHMPFSKAH WTPFEGQKVK GTVRRVVLRG EVAYIDGQVL 

      1810       1820       1830       1840       1850       1860 
VPPGYGQDVR KWPQGAVPQL PPSAPATSEM TTTPERPRRG IPGLPDGRFH LPPRIHRASD 

      1870       1880       1890       1900       1910       1920 
PGLPAEEPKE KSSRKVAEPE LMGTPDGTCY PPPPVPRQAS PQNLGTPGLL HPQTSPLLHS 

      1930       1940       1950       1960       1970       1980 
LVGQHILSVQ QFTKDQMSHL FNVAHTLRMM VQKERSLDIL KGKVMASMFY EVSTRTSSSF 

      1990       2000       2010       2020       2030       2040 
AAAMARLGGA VLSFSEATSS VQKGESLADS VQTMSCYADV VVLRHPQPGA VELAAKHCRR 

      2050       2060       2070       2080       2090       2100 
PVINAGDGVG EHPTQALLDI FTIREELGTV NGMTITMVGD LKHGRTVHSL ACLLTQYRVS 

      2110       2120       2130       2140       2150       2160 
LRYVAPPSLR MPPTVRAFVA SRGTKQEEFE SIEEALPDTD VLYMTRIQKE RFGSTQEYEA 

      2170       2180       2190       2200       2210       2220 
CFGQFILTPH IMTRAKKKMV VMHPMPRVNE ISVEVDSDPR AAYFRQAENG MYIRMALLAT 


VLGRF

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a human cDNA encoding a trifunctional enzyme of carbamoyl-phosphate synthetase-aspartate transcarbamoylase-dihydroorotase in de Novo pyrimidine synthesis." Iwahana H., Fujimura M., Ii S., Kondo M., Moritani M., Takahashi Y., Yamaoka T., Yoshimoto K., Itakura M. Biochem. Biophys. Res. Commun. 219:249-255(1996) [PubMed: 8619816] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal lung fibroblast.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Eye.
[3]	Bienvenut W.V., Dhillon A.S., Matallanas D., Murray L., Brunton V.G., Cooper W.N., Boldt K., von Kriegsheim A.F., Kolch W., Frame M.C. Submitted (FEB-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-13; 157-165; 169-177; 359-371; 501-516; 548-555; 599-606; 697-719; 761-778; 843-854; 932-944; 1034-1048; 1067-1075; 1110-1127; 1229-1240; 1263-1270; 1313-1323; 1326-1333; 1658-1667; 1723-1731; 1840-1848; 1976-1986; 2025-2036; 2103-2110; 2179-2187 AND 2215-2225, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Colon adenocarcinoma and Hepatoma.
[4]	"Organization and nucleotide sequence of the 3' end of the human CAD gene." Davidson J.N., Rao G.N., Niswander L., Andreano C., Tamer C., Chen K.C. DNA Cell Biol. 9:667-676(1990) [PubMed: 1979741] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1752-2225.
[5]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1823 AND SER-1859, MASS SPECTROMETRY. Tissue: Epithelium.
[6]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, MASS SPECTROMETRY. Tissue: Epithelium.
[7]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1423, MASS SPECTROMETRY.
[8]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLN-177 AND CYS-735.
+	Additional computationally mapped references.

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Web resources

Wikipedia

Aspartate carbamoyltransferase entry

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Cross-references

Sequence databases
	D78586 mRNA. Translation: BAA11423.1. BC065510 mRNA. Translation: AAH65510.1. M38561 Genomic DNA. Translation: AAA51907.1.
PIR	A36240.
RefSeq	NP_004332.2.
UniGene	Hs.377010
3D structure databases
HSSP	HSSP built from PDB template 3CSU based on UniProtKB P00479.
ModBase	Search...
Protein-protein interaction databases
IntAct	P27708.
Protein family/group databases
MEROPS	C26.952. M38.972.
PTM databases
PhosphoSite	P27708.
Proteomic databases
PeptideAtlas	P27708.
Genome annotation databases
Ensembl	ENSG00000084774. Homo sapiens. [Contig view]
GeneID	790.
KEGG	hsa:790.
Organism-specific databases
H-InvDB	HIX0001913.
HGNC	HGNC:1424. CAD.
HPA	CAB007781.
MIM	114010. gene.
PharmGKB	PA26023.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOGENOM	P27708.
HOVERGEN	P27708.
Enzyme and pathway databases
BioCyc	MetaCyc:MON-11353.
Reactome	REACT_1698. Nucleotide metabolism.
Gene expression databases
ArrayExpress	P27708.
CleanEx	HS_CAD.
GermOnline	ENSG00000084774. Homo sapiens.
Family and domain databases
InterPro	IPR006680. Amidohydro_1. IPR006220. Anth_synthII. IPR006130. Asp/Orn_carbamoyltranf. IPR006132. Asp/Orn_carbamoyltranf_P_bd. IPR006131. Asp_carbamoyltransf_Asp/Orn_bd. IPR002082. Aspartate_carbamoyltransf_euk. IPR011761. ATP-grasp. IPR013816. ATP_grasp_subdomain_2. IPR001317. CarbamoylP_synth_GATase. IPR005483. CarbamoylP_synth_lsu. IPR005479. CarbamoylP_synth_lsu_ATP-bd. IPR006275. CarbamoylP_synth_lsu_Gln-dep. IPR005481. CarbamoylP_synth_lsu_N. IPR005480. CarbamoylP_synth_lsu_oligo. IPR006274. CarbamoylP_synth_ssu. IPR002474. CarbamoylP_synth_ssu_N. IPR004722. DHOmult. IPR002195. Dihydroorotase_CS. IPR011702. GATASE. IPR012998. GATase_1_AS. IPR000991. GATase_class1_C. IPR011607. MGS. IPR013817. Pre-ATP_grasp. [Graphical view]
Gene3D	G3DSA:3.30.470.20. ATP_grasp_subdomain_2. 2 hits. G3DSA:3.40.50.20. Pre-ATP_grasp. 2 hits.
Pfam	PF01979. Amidohydro_1. 1 hit. PF00289. CPSase_L_chain. 2 hits. PF02786. CPSase_L_D2. 2 hits. PF02787. CPSase_L_D3. 1 hit. PF00988. CPSase_sm_chain. 1 hit. PF00117. GATase. 1 hit. PF02142. MGS. 1 hit. PF00185. OTCace. 1 hit. PF02729. OTCace_N. 1 hit. [Graphical view]
PRINTS	PR00097. ANTSNTHASEII. PR00100. AOTCASE. PR00101. ATCASE. PR00098. CPSASE. PR00099. CPSGATASE. PR00096. GATASE.
TIGRFAMs	TIGR00670. asp_carb_tr. 1 hit. TIGR01369. CPSaseII_lrg. 1 hit. TIGR01368. CPSaseIIsmall. 1 hit. TIGR00857. pyrC_multi. 1 hit.
PROSITE	PS50975. ATP_GRASP. 2 hits. PS00097. CARBAMOYLTRANSFERASE. 1 hit. PS00866. CPSASE_1. 2 hits. PS00867. CPSASE_2. 2 hits. PS00482. DIHYDROOROTASE_1. 1 hit. PS00483. DIHYDROOROTASE_2. 1 hit. PS51273. GATASE_TYPE_1. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB00128. L-Aspartic Acid. DB00130. L-Glutamine.
NextBio	3214.
SOURCE	Search...

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Entry information

Entry name

PYR1_HUMAN

Accession

Primary (citable) accession number: P27708
Secondary accession number(s): Q6P0Q0

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1992
Last sequence update:	July 19, 2004
Last modified:	November 25, 2008
This is version 103 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PATHWAY comments

Index of metabolic and biosynthesis pathways

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

Protein family/group databases

PTM databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents