View source for Uridine monophosphate synthase

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
The [[enzyme]] '''Uridine monophosphate synthase''' ({{EnzExplorer|4.1.1.23}}, '''UMPS''') ('''orotate phosphoribosyl transferase''' and '''orotidine-5'-decarboxylase''') catalyses the formation of [[uridine monophosphate]] (UMP), an energy-carrying molecule in many important biosynthetic pathways.<ref name="entrez">{{cite web | title = Entrez Gene: UMPS uridine monophosphate synthase (orotate phosphoribosyl transferase and orotidine-5'-decarboxylase)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7372}}</ref> In humans, the [[gene]] that codes for this enzyme is located on the long arm of [[chromosome 3]] (3q13).<ref name="pmid2767686">{{cite journal | vauthors = Qumsiyeh MB, Valentine MB, Suttle DP | title = Localization of the gene for uridine monophosphate synthase to human chromosome region 3q13 by in situ hybridization | journal = Genomics | volume = 5 | issue = 1 | pages = 160–2 | date = Jul 1989 | pmid = 2767686 | doi = 10.1016/0888-7543(89)90103-1}}</ref>

== Structure and function ==

This bifunctional enzyme has two main domains, an orotate phosphoribosyltransferase (OPRTase, {{EC number|2.4.2.10}}) subunit and an orotidine-5’-phosphate decarboxylase (ODCase, {{EC number|4.1.1.23}}) subunit.<ref name= "uracil metabolism">{{cite book | vauthors = Traut TW, Jones ME | title = Uracil metabolism--UMP synthesis from orotic acid or uridine and conversion of uracil to beta-alanine: enzymes and cDNAs | journal = Progress in Nucleic Acid Research and Molecular Biology | volume = 53 | pages = 1–78 | year = 1996 | pmid = 8650301 | doi = 10.1016/s0079-6603(08)60142-7 | isbn = 9780125400534 }}</ref> 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 synthase.<ref name=Jones_1980>{{cite journal | vauthors = Jones ME | title = Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis | journal = Annual Review of Biochemistry | volume = 49 | pages = 253–79 | year = 1980 | pmid = 6105839 | doi = 10.1146/annurev.bi.49.070180.001345 }}</ref>

UMPS exists in various forms, depending on external conditions. In vitro, monomeric UMPS, with a [[sedimentation coefficient]] S<sub>20,w</sub> of 3.6 will become a dimer, S<sub>20,w</sub> = 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 S<sub>20,w</sub> 5.6.<ref>{{cite journal | vauthors = Traut TW, Jones ME | title = Interconversion of different molecular weight forms of the orotate phosphoribosyltransferase.orotidine-5'-phosphate decarboxylase enzyme complex from mouse Ehrlich ascites cells | journal = The Journal of Biological Chemistry | volume = 254 | issue = 4 | pages = 1143–50 | date = Feb 1979 | doi = 10.1016/S0021-9258(17)34180-7 | pmid = 762120 | doi-access = free }}</ref><ref name=Traut_biochem>{{cite journal | vauthors = Traut TW, Payne RC, Jones ME | title = Dependence of the aggregation and conformation states of uridine 5'-phosphate synthase on pyrimidine nucleotides. Evidence for a regulatory site | journal = Biochemistry | volume = 19 | issue = 26 | pages = 6062–8 | date = Dec 1980 | pmid = 6894093 | doi = 10.1021/bi00567a018 }}</ref> 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.<ref>{{cite journal | vauthors = Traut TW, Payne RC | title = Dependence of the catalytic activities on the aggregation and conformation states of uridine 5'-phosphate synthase | journal = Biochemistry | volume = 19 | issue = 26 | pages = 6068–74 | date = Dec 1980 | pmid = 6894094 | doi = 10.1021/bi00567a019 }}</ref>

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 their more active dimeric form.<ref name = "Yablonski_1996">{{cite journal | vauthors = Yablonski MJ, Pasek DA, Han BD, Jones ME, Traut TW | title = Intrinsic activity and stability of bifunctional human UMP synthase and its two separate catalytic domains, orotate phosphoribosyltransferase and orotidine-5'-phosphate decarboxylase | journal = The Journal of Biological Chemistry | volume = 271 | issue = 18 | pages = 10704–8 | date = May 1996 | pmid = 8631878 | doi = 10.1074/jbc.271.18.10704 | doi-access = free }}</ref>

== Fusion ==

Fusion events between OPRTase and ODCase, which have led to the formation of the bifunctional enzyme UMPS, have occurred distinctly in different branches of the tree of life. For one thing, even though OPRTase is found at the ''N''-terminus and ODCase at the ''C''-terminus in most eukaryotes (e.g., Metazoa, Amoebozoa, Plantae, and Heterolobosea), the inverted fusion, which is to say OPRTase at the ''C''-terminus and ODCase at the N-terminus, has also been shown to exist (e.g., parasitic protists, trypanosomatids, and stramenopiles). Moreover, other eukaryotic groups, such as Fungi, conserve both enzymes as separate proteins.<ref name="Makiuchi, T. 2007">{{cite journal | vauthors = Makiuchi T, Nara T, Annoura T, Hashimoto T, Aoki T | title = Occurrence of multiple, independent gene fusion events for the fifth and sixth enzymes of pyrimidine biosynthesis in different eukaryotic groups | journal = Gene | volume = 394 | issue = 1–2 | pages = 78–86 | date = Jun 2007 | pmid = 17383832 | doi = 10.1016/j.gene.2007.02.009 }}</ref>
 
However important the fusion order is, the evolutionary origin of each catalytic domain in UMPS is also a matter of study. Both OPRTase and ODCase have passed through lateral gene transfer, resulting in eukaryotes' having enzymes from bacterial and eukaryotic origin. For instance, Metazoa, Amoebozoa, Plantae, and Heterolobosea have eukaryotic ODCase and OPRTase, whereas Alveolata and stramenopiles have bacterial ones. Other rearrangements are also possible, since Fungi have bacterial OPRTase and eukaryotic ODCase, whereas kinetoplastids have the inverse combination.<ref name="Makiuchi, T. 2007"/>

Merging both the fusion order and evolutionary origin, organisms end up having fused UMPS where one of its catalytic domains comes from bacteria and the other from eukaryotes.<ref name="Makiuchi, T. 2007"/>

The driving force for these fusion events seems to be the acquired thermal stability. ''Homo sapiens'' OPRTase and ODCase activities lower to a greater extent when heated than the fused protein does.<ref name="ReferenceA">{{cite journal | vauthors = Lin T, Suttle DP | title = UMP synthase activity expressed in deficient hamster cells by separate transferase and decarboxylase proteins or by linker-deleted bifunctional protein | journal = Somatic Cell and Molecular Genetics | volume = 21 | issue = 3 | pages = 161–75 | date = May 1995 | pmid = 7482031 | doi = 10.1007/bf02254768 | s2cid = 21932938 }}</ref>

To determine the driving force of protein association, several experiments have been performed separating both domains and changing the linker peptide that keeps them together. In ''Plasmodium falciparum'', the OPRTase-OMPDCase complex increases the kinetic and thermal stability when compared to monofunctional enzymes.<ref>{{cite journal | vauthors = Kanchanaphum P, Krungkrai J | title = Kinetic benefits and thermal stability of orotate phosphoribosyltransferase and orotidine 5'-monophosphate decarboxylase enzyme complex in human malaria parasite Plasmodium falciparum | journal = Biochemical and Biophysical Research Communications | volume = 390 | issue = 2 | pages = 337–41 | date = Dec 2009 | pmid = 19800871 | doi = 10.1016/j.bbrc.2009.09.128 | bibcode = 2009BBRC..390..337K }}</ref> In ''H. sapiens'', even though separate and fused domains have a similar activity, the former have a higher sensitivity to conditions promoting monomer dissociation.<ref name = "Yablonski_1996"/> Also, the linker peptide can be removed without inactivating catalysis.<ref name="ReferenceA"/> In Leishmania donovani, separate OPRTase does not have detectable activity possibly due to lower thermal stability or lack of its linker peptide.<ref name="French, JB. 2011">{{cite journal | vauthors = French JB, Yates PA, Soysa DR, Boitz JM, Carter NS, Chang B, Ullman B, Ealick SE | title = The Leishmania donovani UMP synthase is essential for promastigote viability and has an unusual tetrameric structure that exhibits substrate-controlled oligomerization | journal = The Journal of Biological Chemistry | volume = 286 | issue = 23 | pages = 20930–41 | date = Jun 2011 | pmid = 21507942 | doi = 10.1074/jbc.m111.228213 | pmc=3121495| doi-access = free }}</ref>

== Regulation ==

[[File:OPRTase in Complex with OMP.jpg|thumb|OPRTase in Complex with OM]]
UMPS is subject to complex regulation by OMP, the product of its OPRTase and the substrate for the ODCase.<ref name=Traut_archives>{{cite journal | vauthors = Traut TW | title = Uridine-5'-phosphate synthase: evidence for substrate cycling involving this bifunctional protein | journal = Archives of Biochemistry and Biophysics | volume = 268 | issue = 1 | pages = 108–15 | date = Jan 1989 | pmid = 2912371 | doi = 10.1016/0003-9861(89)90570-5 }}</ref> OMP is an allosteric activator of OMP decarboxylase activity.<ref name=Traut_biochem /> At low enzyme concentration and low OMP concentrations, OMP decarboxylase shows negative cooperativity, whereas, at higher OMP concentrations, the enzyme shows positive cooperativity. However, when enzyme concentrations are higher, these complex kinetics do not manifest.<ref name=Traut_archives /> Orotate PRTase activity is activated by low concentrations of OMP,<ref>{{cite journal | vauthors = Traut TW, Jones ME | title = Kinetic and conformational studies of the orotate phosphoribosyltransferase:orotidine-5'-phosphate decarboxylase enzyme complex from mouse Ehrlich ascites cells | journal = The Journal of Biological Chemistry | volume = 252 | issue = 23 | pages = 8372–81 | date = Dec 1977 | doi = 10.1016/S0021-9258(19)75229-6 | pmid = 925000 | doi-access = free }}</ref> phosphate,<ref name=Jones_1980 /> and ADP.<ref>{{cite journal | vauthors = Chen JJ, Jones ME | title = Effect of 5-phosphoribosyl-a-pyrophosphate on de novo pyrimidine biosynthesis in cultured Ehrlich ascites cells made permeable with dextran sulfate 500 | journal = The Journal of Biological Chemistry | volume = 254 | issue = 8 | pages = 2697–704 | date = Apr 1979 | doi = 10.1016/S0021-9258(17)30128-X | pmid = 218951 | bibcode = 1979JBiCh.254.2697C | doi-access = free }}</ref>

== Mechanism ==

=== OPRTase ===

''P. falciparum'' OPRTase follows a random pathway in OMP synthesis and degradation. [[Transition state]] analyses have used isotopic effects and quantum calculations to reveal a completely dissociated dianionic orotate structure, a ribocation, and a nucleophilic pyrophosphate molecule. Nonetheless, this is unexpected, since most N-ribosyltransferases involve protonated and neutral leaving groups, whereas deprotonated orotate is not a good one in the cationic transition state.<ref name="Zhang, Y. 2010">{{cite journal | vauthors = Zhang Y, Deng H, Schramm VL | title = Leaving group activation and pyrophosphate ionic state at the catalytic site of Plasmodium falciparum orotate phosphoribosyltransferase | journal = Journal of the American Chemical Society | volume = 132 | issue = 47 | pages = 17023–31 | date = Dec 2010 | pmid = 21067187 | doi = 10.1021/ja107806j | pmc=3012390 | bibcode = 2010JAChS.13217023Z }}</ref>

OPRTase, as a member of type I PRTases, has a prominent loop next to its active site. It is flexible in its open state and can hardly be seen in electronic density maps for some OPRTases. For catalysis to occur, a dimer must exist in which a loop from one subunit covers the active site from the other one. In ''Salmonella typhimurium'', a new pair of antiparallel β-sheets is created and five new interatomic contacts are formed in the loop, between the loop and the rest of the protein and between the loop and the ligands.<ref name="Wang, G. P. 2012">{{cite journal | vauthors = Wang GP, Hansen MR, Grubmeyer C | title = Loop residues and catalysis in OMP synthase | journal = Biochemistry | volume = 51 | issue = 22 | pages = 4406–15 | date = Jun 2012 | pmid = 22531099 | doi = 10.1021/bi300082s | pmc=3436960}}</ref>

There are two possibilities as far as the loop movement is concerned: It could move in a rigid manner or it could come from a disordered structure that acquires order. The second scenario seems more likely to occur in OPRTase. There must be an energy balance between the peptide new order and hydrogen bond formation in the loop, between the loop and the rest of the protein, and between the loop and the ligands. There is a 30:1 equilibrium between the close and open structures in the enzyme-Mg-PRPP complex, which suggests that the close conformation is favored.<ref name="Wang, G. P. 2012"/>

Various roles have been proposed to the catalytic loop residues. First of all, there seems to be a correlation between the loop movement and the substrate catalysis positioning. In the biological reaction, a proton transference to the pyrophosphate (PPi) molecule could minimize negative charge accumulation even though the pKa for PPi is 9. Lys26, His105, and Lys103 are candidates for this transference to the α phosphate position. However, it might not be the case, since lateral chains and the metal ion could neutralize some of the negative charge from the produced PPi. Transition-state geometric stabilization could also be gained through loop participation.<ref name="Wang, G. P. 2012"/>

=== ODCase ===

Callahan & Miller (2007) summarize ODCase mechanisms in three proposals. The first one is the substrate carboxyl activation through electrostatic stress. The phosphoryl group binding entails juxtaposition between the carboxylate group and a negatively charged Asp residue (namely Asp91 in ''Saccharomyces cerevisiae''). Repulsion between the negative charges would raise the energy value near the transition state. Nonetheless, crystallographic analyses and the lack of ''S. cerevisiae'' enzyme affinity to substrate analogues where the carboxylate groups is replaced by a cationic substituent have shown some evidence against this theory.<ref name="Callahan, B. P. 2007">{{cite journal | vauthors = Callahan BP, Miller BG | title = OMP decarboxylase--An enigma persists | journal = Bioorganic Chemistry | volume = 35 | issue = 6 | pages = 465–9 | date = Dec 2007 | pmid = 17889251 | doi = 10.1016/j.bioorg.2007.07.004 }}</ref>

OMP protonation on O4 or O2 before decarboxylation, which entails and ylide formation on N1, has also been considered. Proton donor absence near O4 or O2 in crystallographic structures is evidence against it along with the ylide generation exclusion as a limiting step in 15N experiments. Moreover, doubts have aroused as to protonated intermediate viability due to electronic stabilizers absence. As a consequence, bond rupture between C6 and C7 due to protonation of the former going through a carbanion state has been proposed.<ref name="Callahan, B. P. 2007"/>

Finally, catalysis might take place by simple electrostatic attraction. C6 carbanion formation would create dipole interactions with a cationic Lys from the active site. This does not explain the velocity increase when compared with the uncatalyzed process.<ref name="Callahan, B. P. 2007"/>

== Clinical significance ==

A UMP synthase deficiency can result in a metabolic disorder called [[orotic aciduria]].<ref name="pmid9042911">{{cite journal | vauthors = Suchi M, Mizuno H, Kawai Y, Tsuboi T, Sumi S, Okajima K, Hodgson ME, Ogawa H, Wada Y | title = Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families | journal = American Journal of Human Genetics | volume = 60 | issue = 3 | pages = 525–39 | date = Mar 1997 | pmid = 9042911 | pmc = 1712531 }}</ref>

Deficiency of this enzyme is an inherited [[autosomal recessive]] trait in [[Holstein cattle]], and it will cause death before birth.<ref name="pmid2625493">{{cite journal | vauthors = Shanks RD, Robinson JL | title = Embryonic mortality attributed to inherited deficiency of uridine monophosphate synthase | journal = Journal of Dairy Science | volume = 72 | issue = 11 | pages = 3035–9 | date = Nov 1989 | pmid = 2625493 | doi = 10.3168/jds.S0022-0302(89)79456-X | doi-access = free }}</ref>

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.<ref>{{cite thesis | vauthors = Merry A | year = 2007 | title = Characterisation and Identification of a Radiation Sensitive Mutant in ''Caenorhabditis elegans''. | publisher = University of Bristol | type = Ph.D. | url = http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441381 }}</ref>

== Pharmacological importance ==

UMPS and its two separate domains, ODCase and OPRTase, have been shown to be essential to viability in parasites from the Chromoalveolata taxon such as ''L. donovani'' or ''P. falciparum''.<ref name="French, JB. 2011"/><ref name="Krungkrai, S. R. 2004">{{cite journal | vauthors = Krungkrai SR, Aoki S, Palacpac NM, Sato D, Mitamura T, Krungkrai J, Horii T | title = Human malaria parasite orotate phosphoribosyltransferase: functional expression, characterization of kinetic reaction mechanism and inhibition profile | journal = Molecular and Biochemical Parasitology | volume = 134 | issue = 2 | pages = 245–55 | date = Apr 2004 | pmid = 15003844 | doi = 10.1016/j.molbiopara.2003.12.006 }}</ref> Since UMPS, ODCase and OPRTase are different between organisms, research on species-specific inhibitors has been performed.<ref name="Zhang, Y. 2010"/><ref name="Krungkrai, S. R. 2004"/>

== Inhibition ==

=== OPRTase ===

Studies on OPRTase inhibition are based on substrate analogues. In ''[[Mycobacterium tuberculosis]]'', two of the most promising inhibitors are 2,6-dihydroxipyridine-4-carboxylic acid and 3-benzylidene-2,6-dioxo-1,2,3,6-tetrahydropyridine-4-carboxylic acid. Union enthalpy and enthropy from the latter correspond to high-affinity ligands. Properties such as lipophilicity, solubility, permeability, and equilibrium constants are under study.<ref>{{cite journal | vauthors = Breda A, Machado P, Rosado LA, Souto AA, Santos DS, Basso LA | title = Pyrimidin-2(1H)-ones based inhibitors of Mycobacterium tuberculosis orotate phosphoribosyltransferase | journal = European Journal of Medicinal Chemistry | volume = 54 | pages = 113–22 | date = Aug 2012 | pmid = 22608674 | doi = 10.1016/j.ejmech.2012.04.031 }}</ref>

Selenilation products have also been used. Abdo ''et al.'' (2010) performed reactions on 2-ethoxiethanselenic acid using electron-rich aromatic substrates to produce (2-ethoxiethyl)seleno ethers. These are able to become aryl-selenilated products such as the 5-uridinyl family, which has shown inhibition at submicromolar concentrations in ''P. falciparum'' and ''H. sapiens''.<ref>{{cite journal | vauthors = Abdo M, Zhang Y, Schramm VL, Knapp S | title = Electrophilic aromatic selenylation: new OPRT inhibitors | journal = Organic Letters | volume = 12 | issue = 13 | pages = 2982–5 | date = Jul 2010 | pmid = 20521773 | doi = 10.1021/ol1010032 | pmc=2906230}}</ref>

=== ODCase ===

ODCase inhibitors also come from substrate analogues such as modifications on the OMP or UMP rings. In ''H. sapiens'', ODCase has been inhibited by halide compounds derived from UMP (e.g., 5-FUMP, 5-BrUMP, 5-IUMP, and 6-IUMP.)<ref>{{cite journal | vauthors = Wittmann JG, Heinrich D, Gasow K, Frey A, Diederichsen U, Rudolph MG | title = Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design | journal = Structure | volume = 16 | issue = 1 | pages = 82–92 | date = Jan 2008 | pmid = 18184586 | doi = 10.1016/j.str.2007.10.020 | doi-access = free }}</ref>

In ''Methanobacterium thermoautotrophicum'', a different strategy has been applied, modifying weak interacting ligands as cytidine-5’-monophosphate, which derivates into barbiturate ribonucleoside-5’-monophosphate, xantosine-5’-monophosphate.<ref>{{cite journal | vauthors = Wu N, Pai EF | title = Crystal structures of inhibitor complexes reveal an alternate binding mode in orotidine-5'-monophosphate decarboxylase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 31 | pages = 28080–7 | date = Aug 2002 | pmid = 12011084 | doi = 10.1074/jbc.m202362200 | doi-access = free }}</ref> ''P. falciparum'' ODCase has been successfully inhibited by modifications on cytidine-5’-monophosphate N3 and N4.<ref>{{cite journal | vauthors = Purohit MK, Poduch E, Wei LW, Crandall IE, To T, Kain KC, Pai EF, Kotra LP | title = Novel cytidine-based orotidine-5'-monophosphate decarboxylase inhibitors with an unusual twist | journal = Journal of Medicinal Chemistry | volume = 55 | issue = 22 | pages = 9988–97 | date = Nov 2012 | pmid = 22991951 | doi = 10.1021/jm301176r }}</ref>

== Interactive pathway map ==
{{FluoropyrimidineActivity WP1601|highlight=Uridine_monophosphate_synth
ase}}

==See also==
* [[Orotidine 5'-phosphate decarboxylase]]
* [[Orotate phosphoribosyltransferase]]

==References==
{{reflist|33em}}

== Further reading ==
{{refbegin |33em}}
* {{cite book | vauthors = Suchi M, Harada N, Tsuboi T, Asai K, Okajima K, Wada Y, Takagi Y | chapter = Molecular Cloning of Human UMP Synthase | series = Advances in Experimental Medicine and Biology | date = 1989 | title = Purine and Pyrimidine Metabolism in Man VI | volume = 253A | pages = 511–8 | pmid = 2624233 | doi = 10.1007/978-1-4684-5673-8_83 | isbn = 978-1-4684-5675-2 }}
* {{cite journal | vauthors = Suttle DP, Bugg BY, Winkler JK, Kanalas JJ | title = Molecular cloning and nucleotide sequence for the complete coding region of human UMP synthase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 6 | pages = 1754–8 | date = Mar 1988 | pmid = 3279416 | pmc = 279857 | doi = 10.1073/pnas.85.6.1754 | bibcode = 1988PNAS...85.1754S | doi-access = free }}
* {{cite journal | vauthors = Patterson D, Jones C, Morse H, Rumsby P, Miller Y, Davis R | title = Structural gene coding for multifunctional protein carrying orotate phosphoribosyltransferase and OMP decarboxylase activity is located on long arm of human chromosome 3 | journal = Somatic Cell Genetics | volume = 9 | issue = 3 | pages = 359–74 | date = May 1983 | pmid = 6574608 | doi = 10.1007/BF01539144 | s2cid = 29498380 }}
* {{cite journal | vauthors = McClard RW, Black MJ, Livingstone LR, Jones ME | title = Isolation and initial characterization of the single polypeptide that synthesizes uridine 5'-monophosphate from orotate in Ehrlich ascites carcinoma. Purification by tandem affinity chromatography of uridine-5'-monophosphate synthase | journal = Biochemistry | volume = 19 | issue = 20 | pages = 4699–706 | date = Sep 1980 | pmid = 6893554 | doi = 10.1021/bi00561a024 }}
* {{cite journal | vauthors = Iannuzzi L, Di Meo GP, Ryan AM, Gallagher DS, Ferrara L, Womack JE | title = Localization of uridine monophosphate synthase (UMPS) gene to river buffalo chromosomes by FISH | journal = Chromosome Research | volume = 2 | issue = 3 | pages = 255–6 | date = May 1994 | pmid = 8069469 | doi = 10.1007/BF01553326 | s2cid = 13407149 }}
* {{cite journal | vauthors = Ichikawa W, Uetake H, Shirota Y, Yamada H, Takahashi T, Nihei Z, Sugihara K, Sasaki Y, Hirayama R | title = Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer | journal = British Journal of Cancer | volume = 89 | issue = 8 | pages = 1486–92 | date = Oct 2003 | pmid = 14562021 | pmc = 2394351 | doi = 10.1038/sj.bjc.6601335 }}
* {{cite journal | vauthors = Miyoshi Y, Uemura H, Ishiguro H, Kitamura H, Nomura N, Danenberg PV, Kubota Y | title = Expression of thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyl transferase in prostate cancer | journal = Prostate Cancer and Prostatic Diseases | volume = 8 | issue = 3 | pages = 260–5 | year = 2005 | pmid = 15999119 | doi = 10.1038/sj.pcan.4500817 | doi-access = free }}
* {{cite journal | vauthors = Ochiai T, Sugitani M, Nishimura K, Noguchi H, Okada T, Ouchi M, Yamada M, Kitajima M, Tsuruoka Y, Takahashi Y, Futagawa S | title = Impact of orotate phosphoribosyl transferase activity as a predictor of lymph node metastasis in gastric cancer | journal = Oncology Reports | volume = 14 | issue = 4 | pages = 987–92 | date = Oct 2005 | pmid = 16142362 | doi = 10.3892/or.14.4.987 }}
* {{cite journal | vauthors = Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE | title = A human protein-protein interaction network: a resource for annotating the proteome | journal = Cell | volume = 122 | issue = 6 | pages = 957–68 | date = Sep 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 | hdl = 11858/00-001M-0000-0010-8592-0 | s2cid = 8235923 | hdl-access = free }}
* {{cite journal | vauthors = Kitajima M, Takita N, Hata M, Maeda T, Sakamoto K, Kamano T, Ochiai T | title = The relationship between 5-fluorouracil sensitivity and single nucleotide polymorphisms of the orotate phosphoribosyl transferase gene in colorectal cancer | journal = Oncology Reports | volume = 15 | issue = 1 | pages = 161–5 | date = Jan 2006 | pmid = 16328050 | doi = 10.3892/or.15.1.161 }}
* {{cite journal | vauthors = Ichikawa W, Takahashi T, Suto K, Sasaki Y, Hirayama R | title = Orotate phosphoribosyltransferase gene polymorphism predicts toxicity in patients treated with bolus 5-fluorouracil regimen | journal = Clinical Cancer Research | volume = 12 | issue = 13 | pages = 3928–34 | date = Jul 2006 | pmid = 16818689 | doi = 10.1158/1078-0432.CCR-05-2665 | doi-access = free }}
* {{cite journal | vauthors = Taomoto J, Yoshida K, Wada Y, Tanabe K, Konishi K, Tahara H, Fukushima M | title = Overexpression of the orotate phosphoribosyl-transferase gene enhances the effect of 5-fluorouracil on gastric cancer cell lines | journal = Oncology | volume = 70 | issue = 6 | pages = 458–64 | year = 2007 | pmid = 17237621 | doi = 10.1159/000098873 | s2cid = 8032104 }}
* {{cite journal | vauthors = Nio Y, Toga T, Maruyama R, Fukushima M | title = Expression of orotate phosphoribosyl transferase in human pancreatic cancer: implication for the efficacy of uracil and tegafur-based adjuvant chemotherapy | journal = Oncology Reports | volume = 18 | issue = 1 | pages = 59–64 | date = Jul 2007 | pmid = 17549346 | doi = 10.3892/or.18.1.59 | doi-access = free }}
* {{cite journal | vauthors = Sanada Y, Yoshida K, Ohara M, Tsutani Y | title = Expression of orotate phosphoribosyltransferase (OPRT) in hepatobiliary and pancreatic carcinoma | journal = Pathology & Oncology Research | volume = 13 | issue = 2 | pages = 105–13 | year = 2007 | pmid = 17607371 | doi = 10.1007/BF02893485 | citeseerx = 10.1.1.629.7176 | s2cid = 32129544 }}
* {{cite journal | vauthors = Sakamoto E, Nagase H, Kobunai T, Oie S, Oka T, Fukushima M, Oka T | title = Orotate phosphoribosyltransferase expression level in tumors is a potential determinant of the efficacy of 5-fluorouracil | journal = Biochemical and Biophysical Research Communications | volume = 363 | issue = 1 | pages = 216–22 | date = Nov 2007 | pmid = 17854773 | doi = 10.1016/j.bbrc.2007.08.164 | bibcode = 2007BBRC..363..216S }}
{{refend}}

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