Uridine monophosphate synthetase


Uridine monophosphate synthetase
Uridine monophosphate synthetase

PDB rendering based on 2eaw.
Identifiers
Symbols UMPS; OPRT
External IDs OMIM613891 MGI1298388 HomoloGene319 GeneCards: UMPS Gene
RNA expression pattern
PBB GE UMPS 202706 s at tn.png
PBB GE UMPS 202707 at tn.png
PBB GE UMPS 215165 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7372 22247
Ensembl ENSG00000114491 ENSMUSG00000022814
UniProt P11172 Q3TVV7
RefSeq (mRNA) NM_000373.3 NM_009471.2
RefSeq (protein) NP_000364.1 NP_033497.1
Location (UCSC) Chr 3:
124.45 – 124.46 Mb
Chr 16:
33.95 – 33.97 Mb
PubMed search [1] [2]

Uridine monophosphate synthetase (UMPS) (orotate phosphoribosyl transferase and orotidine-5'-decarboxylase) is the enzyme (EC 4.1.1.23) that catalyses the formation of uridine monophosphate (UMP), an energy-carrying molecule in many important biosynthetic pathways.[1] In humans, the gene that codes for this enzyme is located on the long arm of chromosome 3 (3q13).[2]

Contents

Structure and Function

This bifunctional enzyme has two main domains, an orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) subunit and an orotidine-5’-phosphate decarboxylase (ODCase, EC 4.1.1.23) subunit.[3] These two sites catalyze the last two steps of the de novo uridine monophosphate (UMP) biosynthetic pathway. After addition of ribose-P to orotate by OPRTase to form orotidine-5’-monophosphate (OMP), OMP is decarboxylated to form uridine monophosphate by ODCase. In microorganisms, these two domains are separate proteins, but in multicellular eukaryotes, the two catalytic sites are expressed on a single protein, uridine monophosphate synthetase.[4]

UMPS exists in various forms, depending on external conditions. In vitro, monomeric UMPS, with a sedimentation coefficient S20,w of 3.6 will become a dimer, S20,w = 5.1 after addition of anions such as phosphate. In the presence of OMP, the product of the OPRTase, the dimer changes to a faster sedimenting form S20,w 5.6.[5][6] These separate conformational forms display different enzymatic activities, with the UMP synthase monomer displaying low decarboxylase activity, and only the 5.6 S dimer exhibiting full decarboxylase activity.[7]

It is believed that the two separate catalytic sites fused into a single protein to stabilize its monomeric form. The covalent union in UMPS stabilizes the domains containing the respective catalytic centers, improving its activity in multicellular organisms where concentrations tend to be 1/10th of the separate counterparts in prokaryotes. Other microorganisms with separated enzymes must retain higher concentrations to keep their enzymes in its more active dimeric form.[8]

Regulation

OPRTase in Complex with OM

UMPS is subject to complex regulation by OMP, the product of its OPRTase and the substrate for the ODCase.[9] OMP is an allosteric activator of OMP decarboxylase activity.[6] At low enzyme concentration and low OMP concentrations, OMP decarboxylase shows negative cooperativity, while at higher OMP concentrations, the enzyme shows positive cooperativity. However, when enzyme concentrations are higher, these complex kinetics do not manifest.[9] Orotate PRTase activity is activated by low concentrations of OMP,[10] phosphate,[4] and ADP.[11]


Clinical significance

A UMP synthetase deficiency can result in a metabolic disorder called orotic aciduria.[12]

Deficiency of this enzyme is an inherited autosomal recessive trait in Holstein cattle, and it will cause death before birth.[13]

Deficiency of the enzyme can be studied in the model organism Caenorhabditis elegans. The rad-6 strain has a premature stop codon eliminating the orotidine 5’-decarboxylase domain of the protein; this domain does not occur in any other proteins encoded by the genome. The strain has a pleiotropic phenotype including reduced viability and fertility, slow growth and radiation sensitivity.[14]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective Wikipedia articles. [15]

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FluoropyrimidineActivity_WP1601 go to article go to article go to article go to article go to article go to article go to article go to article start new article go to article go to article go to article go to article start new article go to article start new article go to article go to article go to article go to article go to article go to article start new article go to article go to article go to article go to article go to article Go to HMDB Go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article
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FluoropyrimidineActivity_WP1601 go to article go to article go to article go to article go to article go to article go to article go to article start new article go to article go to article go to article go to article start new article go to article start new article go to article go to article go to article go to article go to article go to article start new article go to article go to article go to article go to article go to article Go to HMDB Go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article
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Fluorouracil (5-FU) Activity edit


See also

References

  1. ^ "Entrez Gene: UMPS uridine monophosphate synthetase (orotate phosphoribosyl transferase and orotidine-5'-decarboxylase)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7372. 
  2. ^ Qumsiyeh MB, Valentine MB, Suttle DP (July 1989). "Localization of the gene for uridine monophosphate synthase to human chromosome region 3q13 by in situ hybridization". Genomics 5 (1): 160–2. doi:10.1016/0888-7543(89)90103-1. PMID 2767686. 
  3. ^ "Uracil metabolism: UMP synthesis from orotic acid or uridine and conversion of uracil to beta-alanine: enzymes and cDNAs". http://www.ncbi.nlm.nih.gov/pubmed/8650301?dopt=Abstract. 
  4. ^ a b Jones, M. E. (1980) Annu. Rev. Biochem. 49, 253-279
  5. ^ Traut, T. W., and Jones, M. E. (1979) J. Biol. Chem. 254, 1143-1150
  6. ^ a b Traut, T. W., Payne, R. C., and Jones, M. E. (1980) Biochemistry 19, 6062-6068
  7. ^ Traut, T. W., and Payne, R. C. (1980) Biochemistry 19, 6068-6074
  8. ^ Yablonski, M. J., Pasek, D. A., Han, B., Jones. M., Traut, T. W. (1996) J. of Am. Biol. Chem. 10704-10708
  9. ^ a b Traut, T. W. (1989) Archives of Biochemistry and Biophysics, 268, 108-115
  10. ^ Traut, T. W., and Jones, M. E. (1977) J. Biol. Chem. 252, 8374-8381
  11. ^ Chen, J.-J., and Jones, M. E. (1979) J. Biol. Chem. 254, 2697-2704
  12. ^ Suchi M, Mizuno H, Kawai Y, Tsuboi T, Sumi S, Okajima K, Hodgson ME, Ogawa H, Wada Y (March 1997). "Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families". Am. J. Hum. Genet. 60 (3): 525–39. PMC 1712531. PMID 9042911. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1712531. 
  13. ^ Shanks RD, Robinson JL (November 1989). "Embryonic mortality attributed to inherited deficiency of uridine monophosphate synthase". J. Dairy Sci. 72 (11): 3035–9. doi:10.3168/jds.S0022-0302(89)79456-X. PMID 2625493. http://jds.fass.org/cgi/pmidlookup?view=long&pmid=2625493. 
  14. ^ Merry, A. (2007). Characterisation and Identification of a Radiation Sensitive Mutant in Caenorhabditis elegans. Biochemistry, Bristol. PhD.
  15. ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601". http://www.wikipathways.org/index.php/Pathway:WP1601. 

Further reading



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