Full text data of UMPS
UMPS
[Confidence: low (only semi-automatic identification from reviews)]
Uridine 5'-monophosphate synthase; UMP synthase; Orotate phosphoribosyltransferase; OPRT; OPRTase; 2.4.2.10; Orotidine 5'-phosphate decarboxylase; ODC; 4.1.1.23 (OMPdecase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Uridine 5'-monophosphate synthase; UMP synthase; Orotate phosphoribosyltransferase; OPRT; OPRTase; 2.4.2.10; Orotidine 5'-phosphate decarboxylase; ODC; 4.1.1.23 (OMPdecase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P11172
ID UMPS_HUMAN Reviewed; 480 AA.
AC P11172; B5LY68; B5LY72; O00758; O00759; O00760; Q16862; Q9H3Q2;
read moreAC Q9UG49;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Uridine 5'-monophosphate synthase;
DE Short=UMP synthase;
DE Includes:
DE RecName: Full=Orotate phosphoribosyltransferase;
DE Short=OPRT;
DE Short=OPRTase;
DE EC=2.4.2.10;
DE Includes:
DE RecName: Full=Orotidine 5'-phosphate decarboxylase;
DE Short=ODC;
DE EC=4.1.1.23;
DE AltName: Full=OMPdecase;
GN Name=UMPS; ORFNames=OK/SW-cl.21;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3279416; DOI=10.1073/pnas.85.6.1754;
RA Suttle D.P., Bugg B.Y., Winkler J.K., Kanalas J.J.;
RT "Molecular cloning and nucleotide sequence for the complete coding
RT region of human UMP synthase.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:1754-1758(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2624233;
RA Suchi M., Harada N., Tsuboi T., Asai K., Okajima K., Wada Y.,
RA Takagi Y.;
RT "Molecular cloning of human UMP synthase.";
RL Adv. Exp. Med. Biol. 253A:511-518(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ORAC1 GLY-96; GLY-109 AND
RP ARG-429, AND VARIANT ALA-213.
RC TISSUE=Leukocyte;
RX PubMed=9042911;
RA Suchi M., Mizuno H., Kawai Y., Tsuboi T., Sumi S., Okajima K.,
RA Hodgson M.E., Ogawa H., Wada Y.;
RT "Molecular cloning of the human UMP synthase gene and characterization
RT of point mutations in two hereditary orotic aciduria families.";
RL Am. J. Hum. Genet. 60:525-539(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4).
RA Griffith M., Pugh T.J., Tang M.J., Asano J.K., Ally A., Chan S.Y.,
RA Taylor G., Morin G.B., Tai I.T., Marra M.A.;
RT "Genomic analysis of UMPS expression and sequence reveals novel
RT isoforms and sequence polymorphisms associated with 5-FU resistance.";
RL Submitted (JUL-2008) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon adenocarcinoma;
RA Shichijo S., Itoh K.;
RT "Identification of immuno-peptidmics that are recognized by tumor-
RT reactive CTL generated from TIL of colon cancer patients.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Fetal brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-30; ALA-213 AND
RP VAL-446.
RG NIEHS SNPs program;
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 13-480 (ISOFORM 1).
RA Suchi M.;
RT "Molecular genetic studies on hereditary orotic aciduria: I.
RT Purification of human orotidine 5'-monophosphate decarboxylase and
RT cloning of its cDNA.";
RL Nagoya Med. J. 32:207-220(1988).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-214, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-214, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.22 ANGSTROMS) OF 224-480 IN COMPLEX WITH
RP SUBSTRATE, SUBUNIT, ACTIVE SITE, AND MUTAGENESIS OF ASP-312.
RX PubMed=18184586; DOI=10.1016/j.str.2007.10.020;
RA Wittmann J.G., Heinrich D., Gasow K., Frey A., Diederichsen U.,
RA Rudolph M.G.;
RT "Structures of the human orotidine-5'-monophosphate decarboxylase
RT support a covalent mechanism and provide a framework for drug
RT design.";
RL Structure 16:82-92(2008).
CC -!- CATALYTIC ACTIVITY: Orotidine 5'-phosphate + diphosphate = orotate
CC + 5-phospho-alpha-D-ribose 1-diphosphate.
CC -!- CATALYTIC ACTIVITY: Orotidine 5'-phosphate = UMP + CO(2).
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; UMP from orotate: step 1/2.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; UMP from orotate: step 2/2.
CC -!- SUBUNIT: Homodimer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P11172-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P11172-2; Sequence=VSP_009273;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P11172-3; Sequence=VSP_047611;
CC Name=4;
CC IsoId=P11172-4; Sequence=VSP_009273, VSP_047612;
CC -!- DISEASE: Orotic aciduria 1 (ORAC1) [MIM:258900]: A disorder of
CC pyrimidine metabolism resulting in megaloblastic anemia and orotic
CC acid crystalluria that is frequently associated with some degree
CC of physical and mental retardation. A minority of cases have
CC additional features, particularly congenital malformations and
CC immune deficiencies. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the
CC purine/pyrimidine phosphoribosyltransferase family.
CC -!- SIMILARITY: In the C-terminal section; belongs to the OMP
CC decarboxylase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB45710.3; Type=Erroneous termination; Positions=430; Note=Translated as Gln;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/UMPS";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/umps/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J03626; AAA61255.1; -; mRNA.
DR EMBL; D86227; BAA19920.1; -; mRNA.
DR EMBL; D86228; BAA19921.1; -; mRNA.
DR EMBL; D86230; BAA19923.1; -; mRNA.
DR EMBL; AB041359; BAB20663.1; -; Genomic_DNA.
DR EMBL; EU921891; ACH48229.1; -; mRNA.
DR EMBL; EU921895; ACH48233.1; -; mRNA.
DR EMBL; AB062285; BAB93468.1; -; mRNA.
DR EMBL; CR456787; CAG33068.1; -; mRNA.
DR EMBL; AL080099; CAB45710.3; ALT_SEQ; mRNA.
DR EMBL; AY691629; AAT85801.1; -; Genomic_DNA.
DR EMBL; AC022336; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000364; AAH00364.1; -; mRNA.
DR EMBL; BC007511; AAH07511.1; -; mRNA.
DR EMBL; M36661; AAA61256.1; -; mRNA.
DR PIR; A30148; A30148.
DR RefSeq; NP_000364.1; NM_000373.3.
DR RefSeq; XP_005247801.1; XM_005247744.1.
DR UniGene; Hs.2057; -.
DR PDB; 2EAW; X-ray; 2.88 A; A/B=190-480.
DR PDB; 2JGY; X-ray; 1.95 A; A/B=224-479.
DR PDB; 2P1F; X-ray; 1.76 A; A=190-480.
DR PDB; 2QCC; X-ray; 1.85 A; A/B=224-480.
DR PDB; 2QCD; X-ray; 2.03 A; A/B=224-480.
DR PDB; 2QCE; X-ray; 1.43 A; A=224-480.
DR PDB; 2QCF; X-ray; 1.22 A; A=224-480.
DR PDB; 2QCG; X-ray; 1.75 A; A/B=224-480.
DR PDB; 2QCH; X-ray; 1.95 A; A/B=224-480.
DR PDB; 2QCL; X-ray; 1.85 A; A/B=224-480.
DR PDB; 2QCM; X-ray; 1.67 A; A=224-480.
DR PDB; 2QCN; X-ray; 1.85 A; A/B=224-480.
DR PDB; 2V30; X-ray; 2.00 A; A/B=224-479.
DR PDB; 2WNS; X-ray; 1.90 A; A/B=7-203.
DR PDB; 3BGG; X-ray; 1.93 A; A=190-480.
DR PDB; 3BGJ; X-ray; 2.00 A; A/B=190-480.
DR PDB; 3BK0; X-ray; 1.60 A; A/B=223-480.
DR PDB; 3BVJ; X-ray; 1.80 A; A/B=190-480.
DR PDB; 3DBP; X-ray; 1.50 A; A/B=223-480.
DR PDB; 3EWU; X-ray; 1.60 A; A/B=224-480.
DR PDB; 3EWW; X-ray; 1.10 A; A/B=224-480.
DR PDB; 3EWX; X-ray; 1.40 A; A=224-480.
DR PDB; 3EWY; X-ray; 1.10 A; A=224-480.
DR PDB; 3EWZ; X-ray; 1.40 A; A/B/C/D=224-480.
DR PDB; 3EX1; X-ray; 1.40 A; A/B=224-480.
DR PDB; 3EX2; X-ray; 1.55 A; A/B=224-480.
DR PDB; 3EX3; X-ray; 1.45 A; A/B=224-480.
DR PDB; 3EX4; X-ray; 1.24 A; A=224-480.
DR PDB; 3EX6; X-ray; 1.30 A; A/B=224-480.
DR PDB; 3G3D; X-ray; 1.70 A; A/B=190-480.
DR PDB; 3G3M; X-ray; 1.40 A; A=223-480.
DR PDB; 3L0K; X-ray; 1.34 A; A/B=224-480.
DR PDB; 3L0N; X-ray; 1.74 A; A/B=224-480.
DR PDB; 3MI2; X-ray; 1.20 A; A/B=223-480.
DR PDB; 3MO7; X-ray; 1.35 A; A=223-480.
DR PDB; 3MW7; X-ray; 2.32 A; A/B=190-480.
DR PDB; 4HIB; X-ray; 1.80 A; A/B=190-480.
DR PDB; 4HKP; X-ray; 1.75 A; A/B=190-480.
DR PDBsum; 2EAW; -.
DR PDBsum; 2JGY; -.
DR PDBsum; 2P1F; -.
DR PDBsum; 2QCC; -.
DR PDBsum; 2QCD; -.
DR PDBsum; 2QCE; -.
DR PDBsum; 2QCF; -.
DR PDBsum; 2QCG; -.
DR PDBsum; 2QCH; -.
DR PDBsum; 2QCL; -.
DR PDBsum; 2QCM; -.
DR PDBsum; 2QCN; -.
DR PDBsum; 2V30; -.
DR PDBsum; 2WNS; -.
DR PDBsum; 3BGG; -.
DR PDBsum; 3BGJ; -.
DR PDBsum; 3BK0; -.
DR PDBsum; 3BVJ; -.
DR PDBsum; 3DBP; -.
DR PDBsum; 3EWU; -.
DR PDBsum; 3EWW; -.
DR PDBsum; 3EWX; -.
DR PDBsum; 3EWY; -.
DR PDBsum; 3EWZ; -.
DR PDBsum; 3EX1; -.
DR PDBsum; 3EX2; -.
DR PDBsum; 3EX3; -.
DR PDBsum; 3EX4; -.
DR PDBsum; 3EX6; -.
DR PDBsum; 3G3D; -.
DR PDBsum; 3G3M; -.
DR PDBsum; 3L0K; -.
DR PDBsum; 3L0N; -.
DR PDBsum; 3MI2; -.
DR PDBsum; 3MO7; -.
DR PDBsum; 3MW7; -.
DR PDBsum; 4HIB; -.
DR PDBsum; 4HKP; -.
DR ProteinModelPortal; P11172; -.
DR SMR; P11172; 7-203, 224-479.
DR DIP; DIP-29595N; -.
DR IntAct; P11172; 12.
DR MINT; MINT-1397000; -.
DR STRING; 9606.ENSP00000232607; -.
DR BindingDB; P11172; -.
DR ChEMBL; CHEMBL5216; -.
DR PhosphoSite; P11172; -.
DR DMDM; 131708; -.
DR PaxDb; P11172; -.
DR PeptideAtlas; P11172; -.
DR PRIDE; P11172; -.
DR DNASU; 7372; -.
DR Ensembl; ENST00000232607; ENSP00000232607; ENSG00000114491.
DR Ensembl; ENST00000413078; ENSP00000397965; ENSG00000114491.
DR Ensembl; ENST00000536109; ENSP00000443577; ENSG00000114491.
DR Ensembl; ENST00000538242; ENSP00000444988; ENSG00000114491.
DR GeneID; 7372; -.
DR KEGG; hsa:7372; -.
DR UCSC; uc011bkd.2; human.
DR CTD; 7372; -.
DR GeneCards; GC03P124449; -.
DR HGNC; HGNC:12563; UMPS.
DR HPA; HPA036178; -.
DR HPA; HPA036179; -.
DR MIM; 258900; phenotype.
DR MIM; 613891; gene.
DR neXtProt; NX_P11172; -.
DR Orphanet; 30; Hereditary orotic aciduria.
DR PharmGKB; PA363; -.
DR eggNOG; COG0284; -.
DR HOVERGEN; HBG000870; -.
DR InParanoid; P11172; -.
DR KO; K13421; -.
DR OMA; MKPEFLH; -.
DR OrthoDB; EOG754HPB; -.
DR PhylomeDB; P11172; -.
DR BRENDA; 4.1.1.23; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00070; UER00119.
DR UniPathway; UPA00070; UER00120.
DR EvolutionaryTrace; P11172; -.
DR GeneWiki; Uridine_monophosphate_synthetase; -.
DR GenomeRNAi; 7372; -.
DR NextBio; 28866; -.
DR PRO; PR:P11172; -.
DR ArrayExpress; P11172; -.
DR Bgee; P11172; -.
DR CleanEx; HS_UMPS; -.
DR Genevestigator; P11172; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0004588; F:orotate phosphoribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0004590; F:orotidine-5'-phosphate decarboxylase activity; IDA:UniProtKB.
DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IEA:InterPro.
DR GO; GO:0044205; P:'de novo' UMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0006206; P:pyrimidine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006222; P:UMP biosynthetic process; IDA:UniProtKB.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR014732; OMPdecase.
DR InterPro; IPR018089; OMPdecase_AS.
DR InterPro; IPR001754; OMPdeCOase_dom.
DR InterPro; IPR023031; OPRT.
DR InterPro; IPR004467; Or_phspho_trans_dom.
DR InterPro; IPR000836; PRibTrfase_dom.
DR InterPro; IPR011060; RibuloseP-bd_barrel.
DR Pfam; PF00215; OMPdecase; 1.
DR Pfam; PF00156; Pribosyltran; 1.
DR SMART; SM00934; OMPdecase; 1.
DR SUPFAM; SSF51366; SSF51366; 1.
DR TIGRFAMs; TIGR00336; pyrE; 1.
DR TIGRFAMs; TIGR01740; pyrF; 1.
DR PROSITE; PS00156; OMPDECASE; 1.
DR PROSITE; PS00103; PUR_PYR_PR_TRANSFER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Decarboxylase; Disease mutation; Glycosyltransferase; Lyase;
KW Multifunctional enzyme; Phosphoprotein; Polymorphism;
KW Pyrimidine biosynthesis; Reference proteome; Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 480 Uridine 5'-monophosphate synthase.
FT /FTId=PRO_0000139649.
FT REGION 2 214 OPRTase.
FT REGION 215 220 Domain linker.
FT REGION 221 480 OMPdecase.
FT ACT_SITE 312 312 For OMPdecase activity.
FT ACT_SITE 314 314 For OMPdecase activity.
FT ACT_SITE 317 317 For OMPdecase activity.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 214 214 Phosphoserine.
FT VAR_SEQ 1 178 Missing (in isoform 2 and isoform 4).
FT /FTId=VSP_009273.
FT VAR_SEQ 1 92 Missing (in isoform 3).
FT /FTId=VSP_047611.
FT VAR_SEQ 328 424 Missing (in isoform 4).
FT /FTId=VSP_047612.
FT VARIANT 30 30 S -> G (in dbSNP:rs17843776).
FT /FTId=VAR_020614.
FT VARIANT 96 96 R -> G (in ORAC1).
FT /FTId=VAR_006807.
FT VARIANT 109 109 V -> G (in ORAC1).
FT /FTId=VAR_006808.
FT VARIANT 213 213 G -> A (in dbSNP:rs1801019).
FT /FTId=VAR_006809.
FT VARIANT 429 429 G -> R (in ORAC1).
FT /FTId=VAR_006810.
FT VARIANT 446 446 I -> V (in dbSNP:rs3772809).
FT /FTId=VAR_020615.
FT MUTAGEN 312 312 D->N: Loss of OMPdecase activity.
FT CONFLICT 13 13 T -> G (in Ref. 11; AAA61256).
FT CONFLICT 377 377 L -> Q (in Ref. 11; AAA61256).
FT HELIX 8 16
FT TURN 17 19
FT STRAND 21 27
FT STRAND 33 38
FT HELIX 40 45
FT HELIX 47 63
FT STRAND 69 73
FT TURN 75 78
FT HELIX 79 89
FT STRAND 93 96
FT TURN 99 102
FT STRAND 103 105
FT STRAND 108 111
FT STRAND 118 129
FT HELIX 130 141
FT STRAND 148 154
FT HELIX 159 164
FT TURN 165 167
FT STRAND 169 175
FT HELIX 176 185
FT HELIX 191 202
FT HELIX 227 230
FT HELIX 238 250
FT STRAND 254 257
FT HELIX 263 273
FT HELIX 274 276
FT STRAND 278 282
FT HELIX 284 286
FT HELIX 292 305
FT STRAND 308 315
FT HELIX 319 327
FT TURN 329 331
FT HELIX 333 335
FT STRAND 338 344
FT HELIX 349 358
FT TURN 359 362
FT STRAND 364 368
FT HELIX 381 392
FT TURN 393 396
FT STRAND 397 401
FT STRAND 412 416
FT STRAND 421 425
FT STRAND 427 429
FT STRAND 431 433
FT HELIX 435 439
FT TURN 440 442
FT STRAND 445 450
FT HELIX 451 454
FT STRAND 456 458
FT HELIX 459 478
SQ SEQUENCE 480 AA; 52222 MW; D985CD566B72F5CA CRC64;
MAVARAALGP LVTGLYDVQA FKFGDFVLKS GLSSPIYIDL RGIVSRPRLL SQVADILFQT
AQNAGISFDT VCGVPYTALP LATVICSTNQ IPMLIRRKET KDYGTKRLVE GTINPGETCL
IIEDVVTSGS SVLETVEVLQ KEGLKVTDAI VLLDREQGGK DKLQAHGIRL HSVCTLSKML
EILEQQKKVD AETVGRVKRF IQENVFVAAN HNGSPLSIKE APKELSFGAR AELPRIHPVA
SKLLRLMQKK ETNLCLSADV SLARELLQLA DALGPSICML KTHVDILNDF TLDVMKELIT
LAKCHEFLIF EDRKFADIGN TVKKQYEGGI FKIASWADLV NAHVVPGSGV VKGLQEVGLP
LHRGCLLIAE MSSTGSLATG DYTRAAVRMA EEHSEFVVGF ISGSRVSMKP EFLHLTPGVQ
LEAGGDNLGQ QYNSPQEVIG KRGSDIIIVG RGIISAADRL EAAEMYRKAA WEAYLSRLGV
//
ID UMPS_HUMAN Reviewed; 480 AA.
AC P11172; B5LY68; B5LY72; O00758; O00759; O00760; Q16862; Q9H3Q2;
read moreAC Q9UG49;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Uridine 5'-monophosphate synthase;
DE Short=UMP synthase;
DE Includes:
DE RecName: Full=Orotate phosphoribosyltransferase;
DE Short=OPRT;
DE Short=OPRTase;
DE EC=2.4.2.10;
DE Includes:
DE RecName: Full=Orotidine 5'-phosphate decarboxylase;
DE Short=ODC;
DE EC=4.1.1.23;
DE AltName: Full=OMPdecase;
GN Name=UMPS; ORFNames=OK/SW-cl.21;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3279416; DOI=10.1073/pnas.85.6.1754;
RA Suttle D.P., Bugg B.Y., Winkler J.K., Kanalas J.J.;
RT "Molecular cloning and nucleotide sequence for the complete coding
RT region of human UMP synthase.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:1754-1758(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2624233;
RA Suchi M., Harada N., Tsuboi T., Asai K., Okajima K., Wada Y.,
RA Takagi Y.;
RT "Molecular cloning of human UMP synthase.";
RL Adv. Exp. Med. Biol. 253A:511-518(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ORAC1 GLY-96; GLY-109 AND
RP ARG-429, AND VARIANT ALA-213.
RC TISSUE=Leukocyte;
RX PubMed=9042911;
RA Suchi M., Mizuno H., Kawai Y., Tsuboi T., Sumi S., Okajima K.,
RA Hodgson M.E., Ogawa H., Wada Y.;
RT "Molecular cloning of the human UMP synthase gene and characterization
RT of point mutations in two hereditary orotic aciduria families.";
RL Am. J. Hum. Genet. 60:525-539(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4).
RA Griffith M., Pugh T.J., Tang M.J., Asano J.K., Ally A., Chan S.Y.,
RA Taylor G., Morin G.B., Tai I.T., Marra M.A.;
RT "Genomic analysis of UMPS expression and sequence reveals novel
RT isoforms and sequence polymorphisms associated with 5-FU resistance.";
RL Submitted (JUL-2008) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon adenocarcinoma;
RA Shichijo S., Itoh K.;
RT "Identification of immuno-peptidmics that are recognized by tumor-
RT reactive CTL generated from TIL of colon cancer patients.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Fetal brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-30; ALA-213 AND
RP VAL-446.
RG NIEHS SNPs program;
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 13-480 (ISOFORM 1).
RA Suchi M.;
RT "Molecular genetic studies on hereditary orotic aciduria: I.
RT Purification of human orotidine 5'-monophosphate decarboxylase and
RT cloning of its cDNA.";
RL Nagoya Med. J. 32:207-220(1988).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-214, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-214, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.22 ANGSTROMS) OF 224-480 IN COMPLEX WITH
RP SUBSTRATE, SUBUNIT, ACTIVE SITE, AND MUTAGENESIS OF ASP-312.
RX PubMed=18184586; DOI=10.1016/j.str.2007.10.020;
RA Wittmann J.G., Heinrich D., Gasow K., Frey A., Diederichsen U.,
RA Rudolph M.G.;
RT "Structures of the human orotidine-5'-monophosphate decarboxylase
RT support a covalent mechanism and provide a framework for drug
RT design.";
RL Structure 16:82-92(2008).
CC -!- CATALYTIC ACTIVITY: Orotidine 5'-phosphate + diphosphate = orotate
CC + 5-phospho-alpha-D-ribose 1-diphosphate.
CC -!- CATALYTIC ACTIVITY: Orotidine 5'-phosphate = UMP + CO(2).
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; UMP from orotate: step 1/2.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; UMP from orotate: step 2/2.
CC -!- SUBUNIT: Homodimer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P11172-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P11172-2; Sequence=VSP_009273;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P11172-3; Sequence=VSP_047611;
CC Name=4;
CC IsoId=P11172-4; Sequence=VSP_009273, VSP_047612;
CC -!- DISEASE: Orotic aciduria 1 (ORAC1) [MIM:258900]: A disorder of
CC pyrimidine metabolism resulting in megaloblastic anemia and orotic
CC acid crystalluria that is frequently associated with some degree
CC of physical and mental retardation. A minority of cases have
CC additional features, particularly congenital malformations and
CC immune deficiencies. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the
CC purine/pyrimidine phosphoribosyltransferase family.
CC -!- SIMILARITY: In the C-terminal section; belongs to the OMP
CC decarboxylase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB45710.3; Type=Erroneous termination; Positions=430; Note=Translated as Gln;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/UMPS";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/umps/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J03626; AAA61255.1; -; mRNA.
DR EMBL; D86227; BAA19920.1; -; mRNA.
DR EMBL; D86228; BAA19921.1; -; mRNA.
DR EMBL; D86230; BAA19923.1; -; mRNA.
DR EMBL; AB041359; BAB20663.1; -; Genomic_DNA.
DR EMBL; EU921891; ACH48229.1; -; mRNA.
DR EMBL; EU921895; ACH48233.1; -; mRNA.
DR EMBL; AB062285; BAB93468.1; -; mRNA.
DR EMBL; CR456787; CAG33068.1; -; mRNA.
DR EMBL; AL080099; CAB45710.3; ALT_SEQ; mRNA.
DR EMBL; AY691629; AAT85801.1; -; Genomic_DNA.
DR EMBL; AC022336; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000364; AAH00364.1; -; mRNA.
DR EMBL; BC007511; AAH07511.1; -; mRNA.
DR EMBL; M36661; AAA61256.1; -; mRNA.
DR PIR; A30148; A30148.
DR RefSeq; NP_000364.1; NM_000373.3.
DR RefSeq; XP_005247801.1; XM_005247744.1.
DR UniGene; Hs.2057; -.
DR PDB; 2EAW; X-ray; 2.88 A; A/B=190-480.
DR PDB; 2JGY; X-ray; 1.95 A; A/B=224-479.
DR PDB; 2P1F; X-ray; 1.76 A; A=190-480.
DR PDB; 2QCC; X-ray; 1.85 A; A/B=224-480.
DR PDB; 2QCD; X-ray; 2.03 A; A/B=224-480.
DR PDB; 2QCE; X-ray; 1.43 A; A=224-480.
DR PDB; 2QCF; X-ray; 1.22 A; A=224-480.
DR PDB; 2QCG; X-ray; 1.75 A; A/B=224-480.
DR PDB; 2QCH; X-ray; 1.95 A; A/B=224-480.
DR PDB; 2QCL; X-ray; 1.85 A; A/B=224-480.
DR PDB; 2QCM; X-ray; 1.67 A; A=224-480.
DR PDB; 2QCN; X-ray; 1.85 A; A/B=224-480.
DR PDB; 2V30; X-ray; 2.00 A; A/B=224-479.
DR PDB; 2WNS; X-ray; 1.90 A; A/B=7-203.
DR PDB; 3BGG; X-ray; 1.93 A; A=190-480.
DR PDB; 3BGJ; X-ray; 2.00 A; A/B=190-480.
DR PDB; 3BK0; X-ray; 1.60 A; A/B=223-480.
DR PDB; 3BVJ; X-ray; 1.80 A; A/B=190-480.
DR PDB; 3DBP; X-ray; 1.50 A; A/B=223-480.
DR PDB; 3EWU; X-ray; 1.60 A; A/B=224-480.
DR PDB; 3EWW; X-ray; 1.10 A; A/B=224-480.
DR PDB; 3EWX; X-ray; 1.40 A; A=224-480.
DR PDB; 3EWY; X-ray; 1.10 A; A=224-480.
DR PDB; 3EWZ; X-ray; 1.40 A; A/B/C/D=224-480.
DR PDB; 3EX1; X-ray; 1.40 A; A/B=224-480.
DR PDB; 3EX2; X-ray; 1.55 A; A/B=224-480.
DR PDB; 3EX3; X-ray; 1.45 A; A/B=224-480.
DR PDB; 3EX4; X-ray; 1.24 A; A=224-480.
DR PDB; 3EX6; X-ray; 1.30 A; A/B=224-480.
DR PDB; 3G3D; X-ray; 1.70 A; A/B=190-480.
DR PDB; 3G3M; X-ray; 1.40 A; A=223-480.
DR PDB; 3L0K; X-ray; 1.34 A; A/B=224-480.
DR PDB; 3L0N; X-ray; 1.74 A; A/B=224-480.
DR PDB; 3MI2; X-ray; 1.20 A; A/B=223-480.
DR PDB; 3MO7; X-ray; 1.35 A; A=223-480.
DR PDB; 3MW7; X-ray; 2.32 A; A/B=190-480.
DR PDB; 4HIB; X-ray; 1.80 A; A/B=190-480.
DR PDB; 4HKP; X-ray; 1.75 A; A/B=190-480.
DR PDBsum; 2EAW; -.
DR PDBsum; 2JGY; -.
DR PDBsum; 2P1F; -.
DR PDBsum; 2QCC; -.
DR PDBsum; 2QCD; -.
DR PDBsum; 2QCE; -.
DR PDBsum; 2QCF; -.
DR PDBsum; 2QCG; -.
DR PDBsum; 2QCH; -.
DR PDBsum; 2QCL; -.
DR PDBsum; 2QCM; -.
DR PDBsum; 2QCN; -.
DR PDBsum; 2V30; -.
DR PDBsum; 2WNS; -.
DR PDBsum; 3BGG; -.
DR PDBsum; 3BGJ; -.
DR PDBsum; 3BK0; -.
DR PDBsum; 3BVJ; -.
DR PDBsum; 3DBP; -.
DR PDBsum; 3EWU; -.
DR PDBsum; 3EWW; -.
DR PDBsum; 3EWX; -.
DR PDBsum; 3EWY; -.
DR PDBsum; 3EWZ; -.
DR PDBsum; 3EX1; -.
DR PDBsum; 3EX2; -.
DR PDBsum; 3EX3; -.
DR PDBsum; 3EX4; -.
DR PDBsum; 3EX6; -.
DR PDBsum; 3G3D; -.
DR PDBsum; 3G3M; -.
DR PDBsum; 3L0K; -.
DR PDBsum; 3L0N; -.
DR PDBsum; 3MI2; -.
DR PDBsum; 3MO7; -.
DR PDBsum; 3MW7; -.
DR PDBsum; 4HIB; -.
DR PDBsum; 4HKP; -.
DR ProteinModelPortal; P11172; -.
DR SMR; P11172; 7-203, 224-479.
DR DIP; DIP-29595N; -.
DR IntAct; P11172; 12.
DR MINT; MINT-1397000; -.
DR STRING; 9606.ENSP00000232607; -.
DR BindingDB; P11172; -.
DR ChEMBL; CHEMBL5216; -.
DR PhosphoSite; P11172; -.
DR DMDM; 131708; -.
DR PaxDb; P11172; -.
DR PeptideAtlas; P11172; -.
DR PRIDE; P11172; -.
DR DNASU; 7372; -.
DR Ensembl; ENST00000232607; ENSP00000232607; ENSG00000114491.
DR Ensembl; ENST00000413078; ENSP00000397965; ENSG00000114491.
DR Ensembl; ENST00000536109; ENSP00000443577; ENSG00000114491.
DR Ensembl; ENST00000538242; ENSP00000444988; ENSG00000114491.
DR GeneID; 7372; -.
DR KEGG; hsa:7372; -.
DR UCSC; uc011bkd.2; human.
DR CTD; 7372; -.
DR GeneCards; GC03P124449; -.
DR HGNC; HGNC:12563; UMPS.
DR HPA; HPA036178; -.
DR HPA; HPA036179; -.
DR MIM; 258900; phenotype.
DR MIM; 613891; gene.
DR neXtProt; NX_P11172; -.
DR Orphanet; 30; Hereditary orotic aciduria.
DR PharmGKB; PA363; -.
DR eggNOG; COG0284; -.
DR HOVERGEN; HBG000870; -.
DR InParanoid; P11172; -.
DR KO; K13421; -.
DR OMA; MKPEFLH; -.
DR OrthoDB; EOG754HPB; -.
DR PhylomeDB; P11172; -.
DR BRENDA; 4.1.1.23; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00070; UER00119.
DR UniPathway; UPA00070; UER00120.
DR EvolutionaryTrace; P11172; -.
DR GeneWiki; Uridine_monophosphate_synthetase; -.
DR GenomeRNAi; 7372; -.
DR NextBio; 28866; -.
DR PRO; PR:P11172; -.
DR ArrayExpress; P11172; -.
DR Bgee; P11172; -.
DR CleanEx; HS_UMPS; -.
DR Genevestigator; P11172; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0004588; F:orotate phosphoribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0004590; F:orotidine-5'-phosphate decarboxylase activity; IDA:UniProtKB.
DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IEA:InterPro.
DR GO; GO:0044205; P:'de novo' UMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0006206; P:pyrimidine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006222; P:UMP biosynthetic process; IDA:UniProtKB.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR014732; OMPdecase.
DR InterPro; IPR018089; OMPdecase_AS.
DR InterPro; IPR001754; OMPdeCOase_dom.
DR InterPro; IPR023031; OPRT.
DR InterPro; IPR004467; Or_phspho_trans_dom.
DR InterPro; IPR000836; PRibTrfase_dom.
DR InterPro; IPR011060; RibuloseP-bd_barrel.
DR Pfam; PF00215; OMPdecase; 1.
DR Pfam; PF00156; Pribosyltran; 1.
DR SMART; SM00934; OMPdecase; 1.
DR SUPFAM; SSF51366; SSF51366; 1.
DR TIGRFAMs; TIGR00336; pyrE; 1.
DR TIGRFAMs; TIGR01740; pyrF; 1.
DR PROSITE; PS00156; OMPDECASE; 1.
DR PROSITE; PS00103; PUR_PYR_PR_TRANSFER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Decarboxylase; Disease mutation; Glycosyltransferase; Lyase;
KW Multifunctional enzyme; Phosphoprotein; Polymorphism;
KW Pyrimidine biosynthesis; Reference proteome; Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 480 Uridine 5'-monophosphate synthase.
FT /FTId=PRO_0000139649.
FT REGION 2 214 OPRTase.
FT REGION 215 220 Domain linker.
FT REGION 221 480 OMPdecase.
FT ACT_SITE 312 312 For OMPdecase activity.
FT ACT_SITE 314 314 For OMPdecase activity.
FT ACT_SITE 317 317 For OMPdecase activity.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 214 214 Phosphoserine.
FT VAR_SEQ 1 178 Missing (in isoform 2 and isoform 4).
FT /FTId=VSP_009273.
FT VAR_SEQ 1 92 Missing (in isoform 3).
FT /FTId=VSP_047611.
FT VAR_SEQ 328 424 Missing (in isoform 4).
FT /FTId=VSP_047612.
FT VARIANT 30 30 S -> G (in dbSNP:rs17843776).
FT /FTId=VAR_020614.
FT VARIANT 96 96 R -> G (in ORAC1).
FT /FTId=VAR_006807.
FT VARIANT 109 109 V -> G (in ORAC1).
FT /FTId=VAR_006808.
FT VARIANT 213 213 G -> A (in dbSNP:rs1801019).
FT /FTId=VAR_006809.
FT VARIANT 429 429 G -> R (in ORAC1).
FT /FTId=VAR_006810.
FT VARIANT 446 446 I -> V (in dbSNP:rs3772809).
FT /FTId=VAR_020615.
FT MUTAGEN 312 312 D->N: Loss of OMPdecase activity.
FT CONFLICT 13 13 T -> G (in Ref. 11; AAA61256).
FT CONFLICT 377 377 L -> Q (in Ref. 11; AAA61256).
FT HELIX 8 16
FT TURN 17 19
FT STRAND 21 27
FT STRAND 33 38
FT HELIX 40 45
FT HELIX 47 63
FT STRAND 69 73
FT TURN 75 78
FT HELIX 79 89
FT STRAND 93 96
FT TURN 99 102
FT STRAND 103 105
FT STRAND 108 111
FT STRAND 118 129
FT HELIX 130 141
FT STRAND 148 154
FT HELIX 159 164
FT TURN 165 167
FT STRAND 169 175
FT HELIX 176 185
FT HELIX 191 202
FT HELIX 227 230
FT HELIX 238 250
FT STRAND 254 257
FT HELIX 263 273
FT HELIX 274 276
FT STRAND 278 282
FT HELIX 284 286
FT HELIX 292 305
FT STRAND 308 315
FT HELIX 319 327
FT TURN 329 331
FT HELIX 333 335
FT STRAND 338 344
FT HELIX 349 358
FT TURN 359 362
FT STRAND 364 368
FT HELIX 381 392
FT TURN 393 396
FT STRAND 397 401
FT STRAND 412 416
FT STRAND 421 425
FT STRAND 427 429
FT STRAND 431 433
FT HELIX 435 439
FT TURN 440 442
FT STRAND 445 450
FT HELIX 451 454
FT STRAND 456 458
FT HELIX 459 478
SQ SEQUENCE 480 AA; 52222 MW; D985CD566B72F5CA CRC64;
MAVARAALGP LVTGLYDVQA FKFGDFVLKS GLSSPIYIDL RGIVSRPRLL SQVADILFQT
AQNAGISFDT VCGVPYTALP LATVICSTNQ IPMLIRRKET KDYGTKRLVE GTINPGETCL
IIEDVVTSGS SVLETVEVLQ KEGLKVTDAI VLLDREQGGK DKLQAHGIRL HSVCTLSKML
EILEQQKKVD AETVGRVKRF IQENVFVAAN HNGSPLSIKE APKELSFGAR AELPRIHPVA
SKLLRLMQKK ETNLCLSADV SLARELLQLA DALGPSICML KTHVDILNDF TLDVMKELIT
LAKCHEFLIF EDRKFADIGN TVKKQYEGGI FKIASWADLV NAHVVPGSGV VKGLQEVGLP
LHRGCLLIAE MSSTGSLATG DYTRAAVRMA EEHSEFVVGF ISGSRVSMKP EFLHLTPGVQ
LEAGGDNLGQ QYNSPQEVIG KRGSDIIIVG RGIISAADRL EAAEMYRKAA WEAYLSRLGV
//
MIM
258900
*RECORD*
*FIELD* NO
258900
*FIELD* TI
#258900 OROTIC ACIDURIA
;;OROTIC ACIDURIA I;;
OROTATE PHOSPHORIBOSYLTRANSFERASE AND OROTIDYLIC DECARBOXYLASE DEFICIENCY;;
read moreOPRT AND ODC DEFICIENCY;;
OROTIDYLIC PYROPHOSPHORYLASE AND OROTIDYLIC DECARBOXYLASE DEFICIENCY;;
URIDINE MONOPHOSPHATE SYNTHASE DEFICIENCY;;
UMP SYNTHASE DEFICIENCY;;
UMPS DEFICIENCY
OROTIC ACIDURIA WITHOUT MEGALOBLASTIC ANEMIA, INCLUDED; OAWA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because orotic aciduria can be
caused by compound heterozygous mutation in the UMPS gene (613891),
which encodes a bifunctional enzyme with orotate
phosphoribosyltransferase (OPRT) and orotidylic decarboxylase (ODC)
activity, on chromosome 3q13.
DESCRIPTION
Orotic aciduria is a rare autosomal recessive disorder characterized by
megaloblastic anemia and orotic acid crystalluria that is frequently
associated with some degree of physical and mental retardation. These
features respond to appropriate pyrimidine replacement therapy, and most
cases appear to have a good prognosis. A minority of cases have
additional features, particularly congenital malformations and immune
deficiencies, which may adversely affect this prognosis (summary by
Webster et al., 2001).
Bailey (2009) reported that to that time, 2 cases of orotic aciduria
without megaloblastic anemia (OAWA) had been reported.
CLINICAL FEATURES
The phenotypic features of orotic aciduria are megaloblastic anemia that
is unresponsive to vitamin B12 and folic acid, hypochromic, microcytic
circulating erythrocytes that persist with administration of iron or
pyridoxine, large amounts of orotic acid in the urine, and correction of
anemia and reduction in orotic acid excretion when uridylic acid and
cytidylic acid are administered (Huguley et al., 1959). Fallon et al.
(1964) studied extensively the heterozygotes in the first family
described (Huguley et al., 1959). A second family was discovered in New
Zealand and a third in Texas (Haggard and Lockhart, 1965). In the last
patient, urinary obstruction was produced by the high urinary excretion
of orotic acid. Rogers et al. (1968) described another case, from North
Carolina.
Girot et al. (1983) stated that only 9 cases had been reported; they
added 2 more, sibs with a defect in cellular immunity. Humoral immunity
was normal. Severe infections had been reported in some patients; 1 died
of varicella and another of meningitis. The patients reported by Girot
et al. (1983) were Senegalese and the offspring of first cousins.
Becroft et al. (1984) questioned the conclusion of Girot et al. (1983)
that immunodeficiency can be an integral feature of orotic aciduria.
They provided follow-up on the longest surviving patient, aged 21 years,
treated with uridine from the age of 17 months (Becroft et al., 1969).
In later years his dose of uridine had been 3 g/d by mouth and he was in
good health and had regular employment. No evidence of immunodeficiency
was found with or without uridine therapy.
DIAGNOSIS
Rogers and Porter (1968) devised a screening test for orotic aciduria
that is effective in detecting either homozygotes or heterozygotes.
BIOCHEMICAL FEATURES
- Orotic Aciduria
Two enzymatic functions are defective in this disorder: orotate
phosphoribosyltransferase (OPRT; EC 2.4.2.10) and OMP decarboxylase
(ODC; EC 4.1.1.23), which catalyze the last 2 steps in uridine
monophosphate biosynthesis (Fallon et al., 1964). These 2 enzymes are
present in a single polypeptide, so that there is a single bifunctional
enzyme (UMPS) (summary by Bailey, 2009).
Worthy et al. (1974) concluded that the mutation causing orotic aciduria
is structural because orotidine-5-prime-phosphate decarboxylase from
homozygous cells was abnormally thermolabile and showed electrophoretic
abnormality.
Winkler and Suttle (1988) found no decrease in the amount of UMP
synthase mRNA and no detectable difference in the size of UMP synthase
mRNA from cultured cells deficient in the enzyme activity (which varied
from 2 to 7% of normal). Analysis of the mRNA by hybridization with a
nearly full-length UMP synthase cDNA followed by S1 nuclease digestion
showed no alteration in the mRNA structure. The mRNA appears to code for
a mutant enzyme that has reduced stability or altered kinetic
properties.
- Proposed Type II Orotic Aciduria
Fox et al. (1969) identified a case of orotic aciduria in which only 1
enzyme, orotidine-5-prime-phosphate decarboxylase (ODC), was proposed to
be defective. Recessive inheritance was supported by intermediate enzyme
activity or urinary excretion of orotic acid in the patient's mother and
brother and probably father. Orotidine-5-prime-pyrophosphorylase (also
known as orotate phosphoribosyltransferase, OPRT) activity was
increased. This case had been classified as type II orotic aciduria (Fox
et al., 1973). Fox et al. (1973) provided follow-up on this patient.
Over a 3-year period with uridine therapy, red cell OPRT, which was high
normal on first determination, decreased to a level about 2% of normal.
Bailey (2009) showed that the ratio of urinary outputs of orotidine to
orotate provides a means of testing for particular forms of enzyme
defect, and found that experimental urinary orotate/orotidine (OA/OR)
values in the patient of Fox et al. (1969) were in disagreement with the
product spectrum expected for a selective defect in ODC. However, the
ratio was in satisfactory agreement for the type I defect. Given that
the measured enzyme ratios did not remain consistent, that this apparent
type II case was 'clinically indistinguishable' from a type I case
diagnosed by the same team, that no confirmatory report had been found
in the forty years since the initial report, and that the urinary OA/OR
values did not indicate a selective defect in ODC, Bailey (2009)
concluded that evidence for a separate category for this case was
insecure.
- Orotic Aciduria Without Megaloblastic Anemia
Bailey (2009) noted that 2 cases of orotic aciduria without
megaloblastic anemia (OAWA) had been reported. They pointed out that in
type I cases the ratio of urinary OA/OR was greater than 10, whereas in
the OAWA patients it was approximately equal to 1. This is the product
spectrum expected of a defect in ODC. This form is the only one that
appears to have a qualitatively different UMPS. Bailey (2009) suggested
that in these cases the UMPS is sufficiently active to relieve potential
anemia.
CYTOGENETICS
Bensen et al. (1989) described the occurrence of hereditary orotic
aciduria in a family carrying a pericentric inversion of chromosome 4.
Bensen et al. (1991) described 2 pregnancies in a 25-year-old woman
whose hereditary orotic aciduria was managed prenatally with uridine
supplementation. The first pregnancy resulted in an infant with multiple
congenital anomalies and a bizarre karyotype. The proposita was found to
be the carrier of a de novo 11;22 translocation and a pericentric
inversion of chromosome 4. Subsequently, several carriers of orotic
aciduria in this family were identified with the inverted chromosome 4.
The second pregnancy resulted in a normal male with an inverted
chromosome 4.
POPULATION GENETICS
Webster et al. (2001) stated that they knew of only 15 cases of orotic
aciduria, of which 14 had been established by direct measurement of
UMPS.
CLINICAL MANAGEMENT
Girot et al. (1983) noted that replacement therapy with uridine usually
leads to a clinical and hematologic remission and reduction in the
urinary excretion of orotic acid.
MOLECULAR GENETICS
Suchi et al. (1997) detected compound heterozygosity for mutations in
the UMPS gene (613891.0001-613891.0002) in a Japanese patient with
orotic aciduria who was originally described by Morishita et al. (1986).
Expression of human UMPS cDNAs containing these mutations in pyrimidine
auxotrophic E. coli and in recombinant baculovirus-infected Sf21 cells
demonstrated impaired activity presumably associated with the urinary
orotic acid substrate accumulations observed in vivo.
ANIMAL MODEL
Orotate is a normal constituent of bovine milk and is produced in the
udder. Robinson et al. (1983) demonstrated heterozygosity for deficiency
of this enzyme in many cows of the Holstein-Friesian breed, descendant
from what was called 'America's Favorite Brood Cow' (Shanks et al.,
1984), and postulated that homozygosity might be responsible for fetal
wastage. Heterozygous cows show orotic aciduria during lactation, as
well as orotic acidemia and concentrations of orotate in the milk that
are 4 to 12 times normal (Shanks et al., 1984). Longevity and milk
production are not affected. Cattle homozygotes are stillborn or die
shortly after birth. Harden and Robinson (1987) reported new findings in
cattle heterozygous for UMP synthase deficiency. Deficiency of UMP
synthase (DUMPS) in cattle results in early embryonic death of
homozygotes. Schwenger et al. (1993) demonstrated a C-to-T transition
that converted codon 405 from CGA (arg) to TGA (stop). The loss of an
AvaI site permitted development of a direct DNA test, which was applied
to 102 animals. Complete concordance between DUMPS and the presence of
the point mutation in heterozygous animals was observed.
*FIELD* SA
Iinuma et al. (1975); Jones (1980); Kelley (1983); Smith (1965);
Tubergen et al. (1969)
*FIELD* RF
1. Bailey, C. J.: Orotic aciduria and uridine monophosphate synthase:
a reappraisal. J. Inherit. Metab. Dis. 27June, 2009. Note: Electronic
Article.
2. Becroft, D. M. O.; Phillips, L. I.; Simmonds, A.: Hereditary orotic
aciduria: long-term therapy with uridine and a trial of uracil. J.
Pediat. 75: 885-891, 1969.
3. Becroft, D. M. O.; Phillips, L. I.; Webster, D. R.; Wilson, J.
D.: Absence of immune deficiency in hereditary orotic aciduria. (Letter) New
Eng. J. Med. 310: 1333 only, 1984.
4. Bensen, J. T.; Nelson, L. H.; Pettenati, M. J.; Block, S. M.; Brusilow,
S. W.; Livingstone, L. R.; Burton, B. K.: First report of management
and outcome of pregnancies associated with hereditary orotic aciduria. Am.
J. Med. Genet. 41: 426-431, 1991.
5. Bensen, J. T.; Pettenati, M. J.; Nelson, L. H.; Brusilow, S. W.;
Burton, B. K.: Hereditary orotic aciduria: an association with an
11:22 balanced translocation and familial inversion of chromosome
4. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A39 only, 1989.
6. Fallon, H. J.; Smith, L. H., Jr.; Graham, J. B.; Burnett, C. H.
: A genetic study of hereditary orotic aciduria. New Eng. J. Med. 270:
878-881, 1964.
7. Fox, R. M.; O'Sullivan, W. J.; Firkin, B. G.: Orotic aciduria:
differing enzyme patterns. Am. J. Med. 47: 332-336, 1969.
8. Fox, R. M.; Wood, M. J.; Royse-Smith, D.; O'Sullivan, W. J.: Hereditary
orotic aciduria: type I and II. Am. J. Med. 55: 791-798, 1973.
9. Girot, R.; Hamet, M.; Perignon, J.-L.; Guesnu, M.; Fox, R. M.;
Cartier, P.; Durandy, A.; Griscelli, C.: Cellular immune deficiency
in two siblings with hereditary orotic aciduria. New Eng. J. Med. 308:
700-704, 1983.
10. Haggard, M. E.; Lockhart, L. H.: Hereditary orotic aciduria,
a disorder of pyrimidine metabolism responsive to uridine therapy.
(Abstract) J. Pediat. 67: 906 only, 1965.
11. Harden, K. K.; Robinson, J. L.: Deficiency of UMP synthase in
dairy cattle: a model for hereditary orotic aciduria. J. Inherit.
Metab. Dis. 10: 201-209, 1987.
12. Huguley, C. M., Jr.; Bain, J. A.; Rivers, S. L.; Scoggins, R.
B.: Refractory megaloblastic anemia associated with excretion of
orotic acid. Blood 14: 615-634, 1959.
13. Iinuma, K.; Wada, Y.; Onuma, A.; Tanabu, M.: Electroencephalographic
study of an infant with phosphoribosylpyrophosphate synthetase deficiency. Tohoku
J. Exp. Med. 116: 53-55, 1975.
14. Jones, M. E.: Pyrimidine nucleotide biosynthesis in animals:
genes, enzymes, and regulation of UMP biosynthesis. Ann. Rev. Biochem. 49:
253-279, 1980.
15. Kelley, W. N.: Hereditary orotic aciduria.In: Stanbury, J. B.;
Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M.
S.: The Metabolic Basis of Inherited Disease. New York: McGraw-Hill
(pub.) (5th ed.): 1983. Pp. 1202-1226.
16. Morishita, H.; Kokubo, M.; Sumi, S.; Suchi, M.; Wada, Y.: The
first case of hereditary orotic aciduria in Japan. J. Jpn. Pediat.
Soc. 90: 2775-2778, 1986.
17. Robinson, J. L.; Drabik, M. R.; Dombrowski, D. B.; Clark, J. H.
: Consequences of UMP synthase deficiency in cattle. Proc. Nat. Acad.
Sci. 80: 321-323, 1983.
18. Rogers, L. E.; Porter, F. S.: Hereditary orotic aciduria. II.
A urinary screening test. Pediatrics 42: 423-428, 1968.
19. Rogers, L. E.; Warford, L. R.; Patterson, R. B.; Porter, F. S.
: Hereditary orotic aciduria. I. A new case with family studies. Pediatrics 42:
415-422, 1968.
20. Schwenger, B.; Schober, S.; Simon, D.: DUMPS cattle carry a point
mutation in the uridine monophosphate synthase gene. Genomics 16:
241-244, 1993.
21. Shanks, R. D.; Dombrowski, D. B.; Harpestad, G. W.; Robinson,
J. L.: Inheritance of UMP synthase in dairy cattle. J. Hered. 75:
337-340, 1984.
22. Smith, L. H., Jr.: Hereditary orotic aciduria-pyrimidine auxotrophism
in man. (Editorial) Am. J. Med. 38: 1-6, 1965.
23. Suchi, M.; Mizuno, H.; Kawai, Y.; Tsuboi, T.; Sumi, S.; Okajima,
K.; Hodgson, M. E.; Ogawa, H.; Wada, Y.: Molecular cloning of the
human UMP synthase gene and characterization of point mutations in
two hereditary orotic aciduria families. Am. J. Hum. Genet. 60:
525-539, 1997.
24. Tubergen, D. G.; Krooth, R. S.; Heyn, R. M.: Hereditary orotic
aciduria with normal growth and development. Am. J. Dis. Child. 118:
864-870, 1969.
25. Webster, D. R.; Becroft, D. M.; van Gennip, A. H.; Van Kuilenburg,
A. B. P.: Hereditary orotic aciduria and other disorders of pyrimidine
metabolism.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle,
D. (eds.): The Metabolic and Molecular Bases of Inherited Disease.
Vol. 2. New York: McGraw-Hill (pub.) (8th ed.): 2001. Pp. 2661-2684.
26. Winkler, J. K.; Suttle, D. P.: Analysis of UMP synthase gene
and mRNA structure in hereditary orotic aciduria fibroblasts. Am.
J. Hum. Genet. 43: 86-94, 1988.
27. Worthy, T. E.; Grobner, W.; Kelley, W. N.: Hereditary orotic
aciduria: evidence for a structural gene mutation. Proc. Nat. Acad.
Sci. 71: 3031-3035, 1974.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive (in some patients)
CARDIOVASCULAR:
[Heart];
Atrial septal defect (in 1 patient);
Ventricular septal defect (in 1 patient)
GENITOURINARY:
Orotic acid urinary obstruction
NEUROLOGIC:
[Central nervous system];
Developmental delay (in some patients)
METABOLIC FEATURES:
Orotic aciduria
HEMATOLOGY:
Megaloblastic anemia;
Low to normal reticulocyte count;
Anisocytosis;
Poikilocytosis;
Hypochromia;
Platelet count normal
IMMUNOLOGY:
T-cell dysfunction, variable (in some patients)
LABORATORY ABNORMALITIES:
Orotic aciduria;
Orotic acid crystalluria;
Hematuria
MOLECULAR BASIS:
Caused by mutation in the uridine monophosphate synthetase gene (UMPS,
613891.0001)
*FIELD* CN
Joanna S. Amberger - revised: 9/16/2011
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 09/16/2011
joanna: 9/16/2011
*FIELD* CN
Ada Hamosh - updated: 5/2/2011
Carol A. Bocchini - updated: 4/12/2011
Victor A. McKusick - updated: 3/12/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 09/15/2011
terry: 5/2/2011
carol: 4/12/2011
alopez: 10/19/2010
ckniffin: 8/15/2007
terry: 4/20/2005
joanna: 3/17/2004
terry: 1/22/2001
terry: 3/17/1997
terry: 3/12/1997
terry: 3/11/1997
davew: 7/26/1994
carol: 4/26/1994
mimadm: 3/11/1994
carol: 5/4/1993
carol: 12/22/1992
*RECORD*
*FIELD* NO
258900
*FIELD* TI
#258900 OROTIC ACIDURIA
;;OROTIC ACIDURIA I;;
OROTATE PHOSPHORIBOSYLTRANSFERASE AND OROTIDYLIC DECARBOXYLASE DEFICIENCY;;
read moreOPRT AND ODC DEFICIENCY;;
OROTIDYLIC PYROPHOSPHORYLASE AND OROTIDYLIC DECARBOXYLASE DEFICIENCY;;
URIDINE MONOPHOSPHATE SYNTHASE DEFICIENCY;;
UMP SYNTHASE DEFICIENCY;;
UMPS DEFICIENCY
OROTIC ACIDURIA WITHOUT MEGALOBLASTIC ANEMIA, INCLUDED; OAWA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because orotic aciduria can be
caused by compound heterozygous mutation in the UMPS gene (613891),
which encodes a bifunctional enzyme with orotate
phosphoribosyltransferase (OPRT) and orotidylic decarboxylase (ODC)
activity, on chromosome 3q13.
DESCRIPTION
Orotic aciduria is a rare autosomal recessive disorder characterized by
megaloblastic anemia and orotic acid crystalluria that is frequently
associated with some degree of physical and mental retardation. These
features respond to appropriate pyrimidine replacement therapy, and most
cases appear to have a good prognosis. A minority of cases have
additional features, particularly congenital malformations and immune
deficiencies, which may adversely affect this prognosis (summary by
Webster et al., 2001).
Bailey (2009) reported that to that time, 2 cases of orotic aciduria
without megaloblastic anemia (OAWA) had been reported.
CLINICAL FEATURES
The phenotypic features of orotic aciduria are megaloblastic anemia that
is unresponsive to vitamin B12 and folic acid, hypochromic, microcytic
circulating erythrocytes that persist with administration of iron or
pyridoxine, large amounts of orotic acid in the urine, and correction of
anemia and reduction in orotic acid excretion when uridylic acid and
cytidylic acid are administered (Huguley et al., 1959). Fallon et al.
(1964) studied extensively the heterozygotes in the first family
described (Huguley et al., 1959). A second family was discovered in New
Zealand and a third in Texas (Haggard and Lockhart, 1965). In the last
patient, urinary obstruction was produced by the high urinary excretion
of orotic acid. Rogers et al. (1968) described another case, from North
Carolina.
Girot et al. (1983) stated that only 9 cases had been reported; they
added 2 more, sibs with a defect in cellular immunity. Humoral immunity
was normal. Severe infections had been reported in some patients; 1 died
of varicella and another of meningitis. The patients reported by Girot
et al. (1983) were Senegalese and the offspring of first cousins.
Becroft et al. (1984) questioned the conclusion of Girot et al. (1983)
that immunodeficiency can be an integral feature of orotic aciduria.
They provided follow-up on the longest surviving patient, aged 21 years,
treated with uridine from the age of 17 months (Becroft et al., 1969).
In later years his dose of uridine had been 3 g/d by mouth and he was in
good health and had regular employment. No evidence of immunodeficiency
was found with or without uridine therapy.
DIAGNOSIS
Rogers and Porter (1968) devised a screening test for orotic aciduria
that is effective in detecting either homozygotes or heterozygotes.
BIOCHEMICAL FEATURES
- Orotic Aciduria
Two enzymatic functions are defective in this disorder: orotate
phosphoribosyltransferase (OPRT; EC 2.4.2.10) and OMP decarboxylase
(ODC; EC 4.1.1.23), which catalyze the last 2 steps in uridine
monophosphate biosynthesis (Fallon et al., 1964). These 2 enzymes are
present in a single polypeptide, so that there is a single bifunctional
enzyme (UMPS) (summary by Bailey, 2009).
Worthy et al. (1974) concluded that the mutation causing orotic aciduria
is structural because orotidine-5-prime-phosphate decarboxylase from
homozygous cells was abnormally thermolabile and showed electrophoretic
abnormality.
Winkler and Suttle (1988) found no decrease in the amount of UMP
synthase mRNA and no detectable difference in the size of UMP synthase
mRNA from cultured cells deficient in the enzyme activity (which varied
from 2 to 7% of normal). Analysis of the mRNA by hybridization with a
nearly full-length UMP synthase cDNA followed by S1 nuclease digestion
showed no alteration in the mRNA structure. The mRNA appears to code for
a mutant enzyme that has reduced stability or altered kinetic
properties.
- Proposed Type II Orotic Aciduria
Fox et al. (1969) identified a case of orotic aciduria in which only 1
enzyme, orotidine-5-prime-phosphate decarboxylase (ODC), was proposed to
be defective. Recessive inheritance was supported by intermediate enzyme
activity or urinary excretion of orotic acid in the patient's mother and
brother and probably father. Orotidine-5-prime-pyrophosphorylase (also
known as orotate phosphoribosyltransferase, OPRT) activity was
increased. This case had been classified as type II orotic aciduria (Fox
et al., 1973). Fox et al. (1973) provided follow-up on this patient.
Over a 3-year period with uridine therapy, red cell OPRT, which was high
normal on first determination, decreased to a level about 2% of normal.
Bailey (2009) showed that the ratio of urinary outputs of orotidine to
orotate provides a means of testing for particular forms of enzyme
defect, and found that experimental urinary orotate/orotidine (OA/OR)
values in the patient of Fox et al. (1969) were in disagreement with the
product spectrum expected for a selective defect in ODC. However, the
ratio was in satisfactory agreement for the type I defect. Given that
the measured enzyme ratios did not remain consistent, that this apparent
type II case was 'clinically indistinguishable' from a type I case
diagnosed by the same team, that no confirmatory report had been found
in the forty years since the initial report, and that the urinary OA/OR
values did not indicate a selective defect in ODC, Bailey (2009)
concluded that evidence for a separate category for this case was
insecure.
- Orotic Aciduria Without Megaloblastic Anemia
Bailey (2009) noted that 2 cases of orotic aciduria without
megaloblastic anemia (OAWA) had been reported. They pointed out that in
type I cases the ratio of urinary OA/OR was greater than 10, whereas in
the OAWA patients it was approximately equal to 1. This is the product
spectrum expected of a defect in ODC. This form is the only one that
appears to have a qualitatively different UMPS. Bailey (2009) suggested
that in these cases the UMPS is sufficiently active to relieve potential
anemia.
CYTOGENETICS
Bensen et al. (1989) described the occurrence of hereditary orotic
aciduria in a family carrying a pericentric inversion of chromosome 4.
Bensen et al. (1991) described 2 pregnancies in a 25-year-old woman
whose hereditary orotic aciduria was managed prenatally with uridine
supplementation. The first pregnancy resulted in an infant with multiple
congenital anomalies and a bizarre karyotype. The proposita was found to
be the carrier of a de novo 11;22 translocation and a pericentric
inversion of chromosome 4. Subsequently, several carriers of orotic
aciduria in this family were identified with the inverted chromosome 4.
The second pregnancy resulted in a normal male with an inverted
chromosome 4.
POPULATION GENETICS
Webster et al. (2001) stated that they knew of only 15 cases of orotic
aciduria, of which 14 had been established by direct measurement of
UMPS.
CLINICAL MANAGEMENT
Girot et al. (1983) noted that replacement therapy with uridine usually
leads to a clinical and hematologic remission and reduction in the
urinary excretion of orotic acid.
MOLECULAR GENETICS
Suchi et al. (1997) detected compound heterozygosity for mutations in
the UMPS gene (613891.0001-613891.0002) in a Japanese patient with
orotic aciduria who was originally described by Morishita et al. (1986).
Expression of human UMPS cDNAs containing these mutations in pyrimidine
auxotrophic E. coli and in recombinant baculovirus-infected Sf21 cells
demonstrated impaired activity presumably associated with the urinary
orotic acid substrate accumulations observed in vivo.
ANIMAL MODEL
Orotate is a normal constituent of bovine milk and is produced in the
udder. Robinson et al. (1983) demonstrated heterozygosity for deficiency
of this enzyme in many cows of the Holstein-Friesian breed, descendant
from what was called 'America's Favorite Brood Cow' (Shanks et al.,
1984), and postulated that homozygosity might be responsible for fetal
wastage. Heterozygous cows show orotic aciduria during lactation, as
well as orotic acidemia and concentrations of orotate in the milk that
are 4 to 12 times normal (Shanks et al., 1984). Longevity and milk
production are not affected. Cattle homozygotes are stillborn or die
shortly after birth. Harden and Robinson (1987) reported new findings in
cattle heterozygous for UMP synthase deficiency. Deficiency of UMP
synthase (DUMPS) in cattle results in early embryonic death of
homozygotes. Schwenger et al. (1993) demonstrated a C-to-T transition
that converted codon 405 from CGA (arg) to TGA (stop). The loss of an
AvaI site permitted development of a direct DNA test, which was applied
to 102 animals. Complete concordance between DUMPS and the presence of
the point mutation in heterozygous animals was observed.
*FIELD* SA
Iinuma et al. (1975); Jones (1980); Kelley (1983); Smith (1965);
Tubergen et al. (1969)
*FIELD* RF
1. Bailey, C. J.: Orotic aciduria and uridine monophosphate synthase:
a reappraisal. J. Inherit. Metab. Dis. 27June, 2009. Note: Electronic
Article.
2. Becroft, D. M. O.; Phillips, L. I.; Simmonds, A.: Hereditary orotic
aciduria: long-term therapy with uridine and a trial of uracil. J.
Pediat. 75: 885-891, 1969.
3. Becroft, D. M. O.; Phillips, L. I.; Webster, D. R.; Wilson, J.
D.: Absence of immune deficiency in hereditary orotic aciduria. (Letter) New
Eng. J. Med. 310: 1333 only, 1984.
4. Bensen, J. T.; Nelson, L. H.; Pettenati, M. J.; Block, S. M.; Brusilow,
S. W.; Livingstone, L. R.; Burton, B. K.: First report of management
and outcome of pregnancies associated with hereditary orotic aciduria. Am.
J. Med. Genet. 41: 426-431, 1991.
5. Bensen, J. T.; Pettenati, M. J.; Nelson, L. H.; Brusilow, S. W.;
Burton, B. K.: Hereditary orotic aciduria: an association with an
11:22 balanced translocation and familial inversion of chromosome
4. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A39 only, 1989.
6. Fallon, H. J.; Smith, L. H., Jr.; Graham, J. B.; Burnett, C. H.
: A genetic study of hereditary orotic aciduria. New Eng. J. Med. 270:
878-881, 1964.
7. Fox, R. M.; O'Sullivan, W. J.; Firkin, B. G.: Orotic aciduria:
differing enzyme patterns. Am. J. Med. 47: 332-336, 1969.
8. Fox, R. M.; Wood, M. J.; Royse-Smith, D.; O'Sullivan, W. J.: Hereditary
orotic aciduria: type I and II. Am. J. Med. 55: 791-798, 1973.
9. Girot, R.; Hamet, M.; Perignon, J.-L.; Guesnu, M.; Fox, R. M.;
Cartier, P.; Durandy, A.; Griscelli, C.: Cellular immune deficiency
in two siblings with hereditary orotic aciduria. New Eng. J. Med. 308:
700-704, 1983.
10. Haggard, M. E.; Lockhart, L. H.: Hereditary orotic aciduria,
a disorder of pyrimidine metabolism responsive to uridine therapy.
(Abstract) J. Pediat. 67: 906 only, 1965.
11. Harden, K. K.; Robinson, J. L.: Deficiency of UMP synthase in
dairy cattle: a model for hereditary orotic aciduria. J. Inherit.
Metab. Dis. 10: 201-209, 1987.
12. Huguley, C. M., Jr.; Bain, J. A.; Rivers, S. L.; Scoggins, R.
B.: Refractory megaloblastic anemia associated with excretion of
orotic acid. Blood 14: 615-634, 1959.
13. Iinuma, K.; Wada, Y.; Onuma, A.; Tanabu, M.: Electroencephalographic
study of an infant with phosphoribosylpyrophosphate synthetase deficiency. Tohoku
J. Exp. Med. 116: 53-55, 1975.
14. Jones, M. E.: Pyrimidine nucleotide biosynthesis in animals:
genes, enzymes, and regulation of UMP biosynthesis. Ann. Rev. Biochem. 49:
253-279, 1980.
15. Kelley, W. N.: Hereditary orotic aciduria.In: Stanbury, J. B.;
Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M.
S.: The Metabolic Basis of Inherited Disease. New York: McGraw-Hill
(pub.) (5th ed.): 1983. Pp. 1202-1226.
16. Morishita, H.; Kokubo, M.; Sumi, S.; Suchi, M.; Wada, Y.: The
first case of hereditary orotic aciduria in Japan. J. Jpn. Pediat.
Soc. 90: 2775-2778, 1986.
17. Robinson, J. L.; Drabik, M. R.; Dombrowski, D. B.; Clark, J. H.
: Consequences of UMP synthase deficiency in cattle. Proc. Nat. Acad.
Sci. 80: 321-323, 1983.
18. Rogers, L. E.; Porter, F. S.: Hereditary orotic aciduria. II.
A urinary screening test. Pediatrics 42: 423-428, 1968.
19. Rogers, L. E.; Warford, L. R.; Patterson, R. B.; Porter, F. S.
: Hereditary orotic aciduria. I. A new case with family studies. Pediatrics 42:
415-422, 1968.
20. Schwenger, B.; Schober, S.; Simon, D.: DUMPS cattle carry a point
mutation in the uridine monophosphate synthase gene. Genomics 16:
241-244, 1993.
21. Shanks, R. D.; Dombrowski, D. B.; Harpestad, G. W.; Robinson,
J. L.: Inheritance of UMP synthase in dairy cattle. J. Hered. 75:
337-340, 1984.
22. Smith, L. H., Jr.: Hereditary orotic aciduria-pyrimidine auxotrophism
in man. (Editorial) Am. J. Med. 38: 1-6, 1965.
23. Suchi, M.; Mizuno, H.; Kawai, Y.; Tsuboi, T.; Sumi, S.; Okajima,
K.; Hodgson, M. E.; Ogawa, H.; Wada, Y.: Molecular cloning of the
human UMP synthase gene and characterization of point mutations in
two hereditary orotic aciduria families. Am. J. Hum. Genet. 60:
525-539, 1997.
24. Tubergen, D. G.; Krooth, R. S.; Heyn, R. M.: Hereditary orotic
aciduria with normal growth and development. Am. J. Dis. Child. 118:
864-870, 1969.
25. Webster, D. R.; Becroft, D. M.; van Gennip, A. H.; Van Kuilenburg,
A. B. P.: Hereditary orotic aciduria and other disorders of pyrimidine
metabolism.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle,
D. (eds.): The Metabolic and Molecular Bases of Inherited Disease.
Vol. 2. New York: McGraw-Hill (pub.) (8th ed.): 2001. Pp. 2661-2684.
26. Winkler, J. K.; Suttle, D. P.: Analysis of UMP synthase gene
and mRNA structure in hereditary orotic aciduria fibroblasts. Am.
J. Hum. Genet. 43: 86-94, 1988.
27. Worthy, T. E.; Grobner, W.; Kelley, W. N.: Hereditary orotic
aciduria: evidence for a structural gene mutation. Proc. Nat. Acad.
Sci. 71: 3031-3035, 1974.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive (in some patients)
CARDIOVASCULAR:
[Heart];
Atrial septal defect (in 1 patient);
Ventricular septal defect (in 1 patient)
GENITOURINARY:
Orotic acid urinary obstruction
NEUROLOGIC:
[Central nervous system];
Developmental delay (in some patients)
METABOLIC FEATURES:
Orotic aciduria
HEMATOLOGY:
Megaloblastic anemia;
Low to normal reticulocyte count;
Anisocytosis;
Poikilocytosis;
Hypochromia;
Platelet count normal
IMMUNOLOGY:
T-cell dysfunction, variable (in some patients)
LABORATORY ABNORMALITIES:
Orotic aciduria;
Orotic acid crystalluria;
Hematuria
MOLECULAR BASIS:
Caused by mutation in the uridine monophosphate synthetase gene (UMPS,
613891.0001)
*FIELD* CN
Joanna S. Amberger - revised: 9/16/2011
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 09/16/2011
joanna: 9/16/2011
*FIELD* CN
Ada Hamosh - updated: 5/2/2011
Carol A. Bocchini - updated: 4/12/2011
Victor A. McKusick - updated: 3/12/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 09/15/2011
terry: 5/2/2011
carol: 4/12/2011
alopez: 10/19/2010
ckniffin: 8/15/2007
terry: 4/20/2005
joanna: 3/17/2004
terry: 1/22/2001
terry: 3/17/1997
terry: 3/12/1997
terry: 3/11/1997
davew: 7/26/1994
carol: 4/26/1994
mimadm: 3/11/1994
carol: 5/4/1993
carol: 12/22/1992
MIM
613891
*RECORD*
*FIELD* NO
613891
*FIELD* TI
*613891 URIDINE MONOPHOSPHATE SYNTHETASE; UMPS
;;OROTATE PHOSPHORIBOSYLTRANSFERASE; OPRT;;
read moreOROTIDYLIC DECARBOXYLASE; ODC
*FIELD* TX
DESCRIPTION
In mammalian cells, the last step of pyrimidine nucleotide synthesis
involves the conversion of orotate to uridine monophosphate (UMP) and is
catalyzed by UMP synthase (McClard et al., 1980). This bifunctional
enzyme has 2 sequential activities, orotate phosphoribosyltransferase
(OPRT; EC 2.4.2.10) and orotidine-5-monophosphate decarboxylase (ODC; EC
4.1.1.23) (Jones et al., 1984).
CLONING
Suttle et al. (1988) cloned and sequenced the complete coding region for
human UMP synthase. The deduced protein contains 480 amino acids with a
molecular mass of 52,199 Da. The 2 activities of UMP synthase reside in
distinct domains encoded by the 3-prime and 5-prime halves of the mRNA.
The N-terminal 214 amino acids contain the OPRT domain. The C-terminal
258 amino acids contain the ODC catalytic domain.
GENE STRUCTURE
Floyd and Jones (1985) studied the OMP decarboxylase (OMPD, ODC) domain
of the multifunctional protein uridine 5-prime-monophosphate synthase,
which catalyzes the last 2 reactions of the de novo synthesis of UMP.
The domain of the UMP synthase molecule with OMP decarboxylase activity
is coded by the 3-prime end of the gene (Suttle, 1985). Thus, the
sequence of the 2 functional domains in the gene appears to be the same
as the sequence of enzymatic function.
Suchi et al. (1997) isolated the UMPS gene from a human genomic library
and reported a single-copy gene spanning approximately 15 kb. The gene
contains 6 exons ranging in size from 115 bp to 672 bp and all splicing
junctions adhere to the canonical GT/AG rule. Cognate promoter elements
implicated in glucocorticoid- and cAMP-mediated regulation, as well as
in liver-, myeloid-, and lymphocyte-specific expression, are located
within the 5-prime flanking sequence.
MAPPING
In hamster-human somatic cell hybrids, Patterson et al. (1983) studied
the Urd(-)C mutant Chinese hamster ovary (CHO) cells (which have
deficiency of OPRT and ODC activities). Complementation of the CHO
auxotrophic defect in CHO-human hybrid cells correlated with the
presence of human chromosome 3. Thus, Patterson et al. (1983) assigned
the gene for orotate phosphoribosyltransferase and OMP decarboxylase to
chromosome 3. Jones et al. (1984) narrowed the assignment to 3cen-q21.
This was done by isolating various induced deletion mutants of
chromosome 3 from a hamster-human cell hybrid with chromosome 3 as its
only human chromosome. By in situ hybridization, Qumsiyeh et al. (1989)
narrowed the assignment of UMPS to 3q13.
MOLECULAR GENETICS
Suchi et al. (1997) detected compound heterozygosity for mutations in
the UMPS gene (613891.0001-613891.0002) in a Japanese patient with
orotic aciduria (258900) who was originally described by Morishita et
al. (1986). Expression of human UMPS cDNAs containing these mutations in
pyrimidine auxotrophic E. coli and in recombinant baculovirus-infected
Sf21 cells demonstrated impaired activity presumably associated with the
urinary orotic acid substrate accumulations observed in vivo.
ANIMAL MODEL
Defects in OPRT and ODC are associated with mutations in Drosophila at
the 'rudimentary-like' locus that result in unusual wing morphology; one
or both enzyme activities may be lacking in these mutants (Rawls, 1981).
*FIELD* AV
.0001
OROTIC ACIDURIA
UMPS, ARG96GLY AND GLY429ARG
Suchi et al. (1997) identified compound heterozygosity for UMPS
mutations in a Japanese patient with orotic aciduria (258900), the first
patient in whom the diagnosis had been made by Morishita et al. (1986).
The patient was under a physician-supervised regimen of oral uridine
supplementation and doing well. One allele contained 2 mutations: an
A-to-G transition at nucleotide 286 resulting in an R96G substitution
and a G-to-C transversion at nucleotide 1285 resulting in a G429R
substitution. The other allele carried a T-to-G transversion at
nucleotide 326, resulting in a V109G substitution (613891.0002).
.0002
OROTIC ACIDURIA
UMPS, VAL109GLY
See 613891.0001 and Suchi et al. (1997).
*FIELD* RF
1. Floyd, E. E.; Jones, M. E.: Isolation and characterization of
the orotidine 5-prime-monophosphate decarboxylase domain of the multifunctional
protein uridine 5-prime-monophosphate synthase. J. Biol. Chem. 260:
9443-9451, 1985.
2. Jones, C.; Miller, Y. E.; Palmer, D.; Morse, H.; Kirby, M.; Patterson,
D.: Regional mapping of human chromosome 3. (Abstract) Cytogenet.
Cell Genet. 37: 500 only, 1984.
3. McClard, R. W.; Black, M. J.; Livingstone, L. R.; Jones, M. E.
: Isolation and initial characterization of the single polypeptide
that synthesizes uridine 5-prime-monophosphate from orotate in Ehrlich
ascites carcinoma: purification by tandem affinity chromatography
of uridine-5-prime-monophosphate synthase. Biochemistry 19: 4699-4706,
1980.
4. Morishita, H.; Kokubo, M.; Sumi, S.; Suchi, M.; Wada, Y.: The
first case of hereditary orotic aciduria in Japan. J. Jpn. Pediat.
Soc. 90: 2775-2778, 1986.
5. Patterson, D.; Jones, C.; Morse, H.; Rumsby, P.; Miller, Y.; Davis,
R.: Structural gene coding for multifunctional protein carrying orotate
phosphoribosyltransferase and OMP decarboxylase activity is located
on long arm of human chromosome 3. Somat. Cell Genet. 9: 359-374,
1983.
6. Qumsiyeh, M. B.; Valentine, M. B.; Suttle, D. P.: Localization
of the gene for uridine monophosphate synthase to human chromosome
region 3q13 by in situ hybridization. Genomics 5: 160-162, 1989.
7. Rawls, J. M., Jr.: Genetic complementation and enzyme correlates
at the locus encoding the last two steps of de novo pyrimidine biosynthesis
in Drosophila melanogaster. Molec. Gen. Genet. 184: 174-179, 1981.
8. Suchi, M.; Mizuno, H.; Kawai, Y.; Tsuboi, T.; Sumi, S.; Okajima,
K.; Hodgson, M. E.; Ogawa, H.; Wada, Y.: Molecular cloning of the
human UMP synthase gene and characterization of point mutations in
two hereditary orotic aciduria families. Am. J. Hum. Genet. 60:
525-539, 1997.
9. Suttle, D. P.: Molecular basis for the deficiency of the de novo
pyrimidine enzyme UMP synthase in hereditary orotic aciduria. (Abstract) Am.
J. Hum. Genet. 37: A178 only, 1985.
10. Suttle, D. P.; Bugg, B. Y.; Winkler, J. K.; Kanalas, J. J.: Molecular
cloning and nucleotide sequence for the complete coding region of
human UMP synthase. Proc. Nat. Acad. Sci. 85: 1754-1758, 1988.
*FIELD* CD
Carol A. Bocchini: 4/11/2011
*FIELD* ED
alopez: 09/15/2011
carol: 4/12/2011
*RECORD*
*FIELD* NO
613891
*FIELD* TI
*613891 URIDINE MONOPHOSPHATE SYNTHETASE; UMPS
;;OROTATE PHOSPHORIBOSYLTRANSFERASE; OPRT;;
read moreOROTIDYLIC DECARBOXYLASE; ODC
*FIELD* TX
DESCRIPTION
In mammalian cells, the last step of pyrimidine nucleotide synthesis
involves the conversion of orotate to uridine monophosphate (UMP) and is
catalyzed by UMP synthase (McClard et al., 1980). This bifunctional
enzyme has 2 sequential activities, orotate phosphoribosyltransferase
(OPRT; EC 2.4.2.10) and orotidine-5-monophosphate decarboxylase (ODC; EC
4.1.1.23) (Jones et al., 1984).
CLONING
Suttle et al. (1988) cloned and sequenced the complete coding region for
human UMP synthase. The deduced protein contains 480 amino acids with a
molecular mass of 52,199 Da. The 2 activities of UMP synthase reside in
distinct domains encoded by the 3-prime and 5-prime halves of the mRNA.
The N-terminal 214 amino acids contain the OPRT domain. The C-terminal
258 amino acids contain the ODC catalytic domain.
GENE STRUCTURE
Floyd and Jones (1985) studied the OMP decarboxylase (OMPD, ODC) domain
of the multifunctional protein uridine 5-prime-monophosphate synthase,
which catalyzes the last 2 reactions of the de novo synthesis of UMP.
The domain of the UMP synthase molecule with OMP decarboxylase activity
is coded by the 3-prime end of the gene (Suttle, 1985). Thus, the
sequence of the 2 functional domains in the gene appears to be the same
as the sequence of enzymatic function.
Suchi et al. (1997) isolated the UMPS gene from a human genomic library
and reported a single-copy gene spanning approximately 15 kb. The gene
contains 6 exons ranging in size from 115 bp to 672 bp and all splicing
junctions adhere to the canonical GT/AG rule. Cognate promoter elements
implicated in glucocorticoid- and cAMP-mediated regulation, as well as
in liver-, myeloid-, and lymphocyte-specific expression, are located
within the 5-prime flanking sequence.
MAPPING
In hamster-human somatic cell hybrids, Patterson et al. (1983) studied
the Urd(-)C mutant Chinese hamster ovary (CHO) cells (which have
deficiency of OPRT and ODC activities). Complementation of the CHO
auxotrophic defect in CHO-human hybrid cells correlated with the
presence of human chromosome 3. Thus, Patterson et al. (1983) assigned
the gene for orotate phosphoribosyltransferase and OMP decarboxylase to
chromosome 3. Jones et al. (1984) narrowed the assignment to 3cen-q21.
This was done by isolating various induced deletion mutants of
chromosome 3 from a hamster-human cell hybrid with chromosome 3 as its
only human chromosome. By in situ hybridization, Qumsiyeh et al. (1989)
narrowed the assignment of UMPS to 3q13.
MOLECULAR GENETICS
Suchi et al. (1997) detected compound heterozygosity for mutations in
the UMPS gene (613891.0001-613891.0002) in a Japanese patient with
orotic aciduria (258900) who was originally described by Morishita et
al. (1986). Expression of human UMPS cDNAs containing these mutations in
pyrimidine auxotrophic E. coli and in recombinant baculovirus-infected
Sf21 cells demonstrated impaired activity presumably associated with the
urinary orotic acid substrate accumulations observed in vivo.
ANIMAL MODEL
Defects in OPRT and ODC are associated with mutations in Drosophila at
the 'rudimentary-like' locus that result in unusual wing morphology; one
or both enzyme activities may be lacking in these mutants (Rawls, 1981).
*FIELD* AV
.0001
OROTIC ACIDURIA
UMPS, ARG96GLY AND GLY429ARG
Suchi et al. (1997) identified compound heterozygosity for UMPS
mutations in a Japanese patient with orotic aciduria (258900), the first
patient in whom the diagnosis had been made by Morishita et al. (1986).
The patient was under a physician-supervised regimen of oral uridine
supplementation and doing well. One allele contained 2 mutations: an
A-to-G transition at nucleotide 286 resulting in an R96G substitution
and a G-to-C transversion at nucleotide 1285 resulting in a G429R
substitution. The other allele carried a T-to-G transversion at
nucleotide 326, resulting in a V109G substitution (613891.0002).
.0002
OROTIC ACIDURIA
UMPS, VAL109GLY
See 613891.0001 and Suchi et al. (1997).
*FIELD* RF
1. Floyd, E. E.; Jones, M. E.: Isolation and characterization of
the orotidine 5-prime-monophosphate decarboxylase domain of the multifunctional
protein uridine 5-prime-monophosphate synthase. J. Biol. Chem. 260:
9443-9451, 1985.
2. Jones, C.; Miller, Y. E.; Palmer, D.; Morse, H.; Kirby, M.; Patterson,
D.: Regional mapping of human chromosome 3. (Abstract) Cytogenet.
Cell Genet. 37: 500 only, 1984.
3. McClard, R. W.; Black, M. J.; Livingstone, L. R.; Jones, M. E.
: Isolation and initial characterization of the single polypeptide
that synthesizes uridine 5-prime-monophosphate from orotate in Ehrlich
ascites carcinoma: purification by tandem affinity chromatography
of uridine-5-prime-monophosphate synthase. Biochemistry 19: 4699-4706,
1980.
4. Morishita, H.; Kokubo, M.; Sumi, S.; Suchi, M.; Wada, Y.: The
first case of hereditary orotic aciduria in Japan. J. Jpn. Pediat.
Soc. 90: 2775-2778, 1986.
5. Patterson, D.; Jones, C.; Morse, H.; Rumsby, P.; Miller, Y.; Davis,
R.: Structural gene coding for multifunctional protein carrying orotate
phosphoribosyltransferase and OMP decarboxylase activity is located
on long arm of human chromosome 3. Somat. Cell Genet. 9: 359-374,
1983.
6. Qumsiyeh, M. B.; Valentine, M. B.; Suttle, D. P.: Localization
of the gene for uridine monophosphate synthase to human chromosome
region 3q13 by in situ hybridization. Genomics 5: 160-162, 1989.
7. Rawls, J. M., Jr.: Genetic complementation and enzyme correlates
at the locus encoding the last two steps of de novo pyrimidine biosynthesis
in Drosophila melanogaster. Molec. Gen. Genet. 184: 174-179, 1981.
8. Suchi, M.; Mizuno, H.; Kawai, Y.; Tsuboi, T.; Sumi, S.; Okajima,
K.; Hodgson, M. E.; Ogawa, H.; Wada, Y.: Molecular cloning of the
human UMP synthase gene and characterization of point mutations in
two hereditary orotic aciduria families. Am. J. Hum. Genet. 60:
525-539, 1997.
9. Suttle, D. P.: Molecular basis for the deficiency of the de novo
pyrimidine enzyme UMP synthase in hereditary orotic aciduria. (Abstract) Am.
J. Hum. Genet. 37: A178 only, 1985.
10. Suttle, D. P.; Bugg, B. Y.; Winkler, J. K.; Kanalas, J. J.: Molecular
cloning and nucleotide sequence for the complete coding region of
human UMP synthase. Proc. Nat. Acad. Sci. 85: 1754-1758, 1988.
*FIELD* CD
Carol A. Bocchini: 4/11/2011
*FIELD* ED
alopez: 09/15/2011
carol: 4/12/2011