Orotic Acid, More Than Just an Intermediate of Pyrimidine de novo Synthesis

Monika Löffler; Elizabeth A. Carrey; Elke Zameitat

doi:10.1016/j.jgg.2015.04.001

Volume 42 Issue 5

May 2015

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2015 > 42(5): 207-219

PDF( 697 KB)

Orotic Acid, More Than Just an Intermediate of Pyrimidine de novo Synthesis

doi: 10.1016/j.jgg.2015.04.001

a
Institute of Physiological Chemistry, Faculty of Medicine, Philipps University Marburg, 35032 Marburg, Germany
b
UCL Institute of Child Health, University College London, London WC1N 1EH, United Kingdom

More Information

Corresponding author: E-mail address: loeffler@staff.uni-marburg.de (Monika Löffler)
Received Date: 2014-10-30
Accepted Date: 2015-04-09
Rev Recd Date: 2015-04-04

Available Online: 2015-04-18

Publish Date: 2015-05-20

Abstract

Abstract

It is timely to consider the many facets of the small molecule orotic acid (OA), which is well-known as an essential intermediate of pyrimidine de novo synthesis. In addition, it can be taken up by erythrocytes and hepatocytes for conversion into uridine and for use in the pyrimidine recycling pathway. We discuss the link between dietary orotate and fatty liver in rats, and the potential for the alleviation of neonatal hyperbilirubinaemia. We address the development of orotate derivatives for application as anti-pyrimidine drugs, and of complexes with metal ions and organic cations to assist therapies of metabolic syndromes. Recent genetic data link human Miller syndrome to defects in the dihydroorotate dehydrogenase (DHODH) gene, hence to depleted orotate production. Another defect in pyrimidine biosynthesis, the orotic aciduria arising in humans and cattle with a deficiency of UMP synthase (UMPS), has different symptoms. More recent work leads us to conclude that OA may have a role in regulating gene transcription.
- Orotic acid,
- Pyrimidines,
- Orotic aciduria,
- Miller syndrome,
- Gene defects

The authors are retired.

FullText(HTML)

References(132)

References

[1]	Ahmed, A.A., Porter, G.A., McCarthy, R.D. Isolation, quantification, and biosynthetic origin of orotic acid in milk J. Dairy Sci., 61 (1978),pp. 39-43
[2]	Akiho, H., Iwai, A., Katoh-Sudoh, M. et al. Post-ischaemic treatment with orotic acid prevented neuronal injury in gerbil brain ischaemia Neuroreport, 8 (1997),pp. 607-610
[3]	Akiho, H., Iwai, A., Katoh-Sudoh, M. et al. Neuroprotective effect of Y-39558, orotic acid ethylester, in gerbil forebrain ischemia Jpn. J. Pharmacol., 76 (1998),pp. 441-444
[4]	Akiho, H., Iwai, A., Tsukamoto, S. et al. Neuro-protective effect of YM-39558 in focal cerebral ischemia in cats Neuropharmacology, 37 (1998),pp. 159-168
[5]	Akalin, A.S., Gönc, S. The determination of orotic acid in ruminant milk using HPLC Milchwissenschaft, 51 (1996),pp. 554-556
[6]	Alonso, E., Rubio, V. Orotic aciduria due to arginine deprivation: changes in the levels of carbamoyl phosphate and of other urea cycle intermediates in mouse liver J. Nutr., 119 (1989),pp. 1188-1195
[7]	Angeletti, P.C., Engler, J.A. Adenovirus preterminal protein binds to the CAD enzyme at active sites of viral DNA replication on the nuclear matrix J. Virol., 72 (1998),pp. 2896-2904
[8]	Bach, I., Kumberger, O., Schmidbaur, H. Synthesis and crystal structure of lithium orotate (−1) monohydrate and magnesium bis [orotate(−1)] octahydrate Chem. Ber., 123 (1990),pp. 2267-2271
[9]	Bachstez, M. Über die Konstitution der Orotsäure Berichte der Chemie, 63 (1930),pp. 1000-1007
[10]	Ballard, E., Johnson, T.B. Synthesis of derivatives of pyrimidine-5-carboxylic acid J. Am. Chem. Soc., 64 (1942),pp. 795-796
[11]	Balasubramaniam, S., Duley, J.A., Christodoulou, J. Inborn errors of pyrimidine metabolism: clinical update and therapy J. Inherit. Metab. Dis., 37 (2014),pp. 687-698
[12]	Bernstein, B.A., Richardson, T., Amundson, C.H. Inhibition of cholesterol biosynthesis and acetyl-coenzyme A synthetase by bovine milk and orotic acid J. Dairy Sci., 60 (1977),pp. 1846-1853
[13]	Biscaro, G., Belloni, E. About a new compound of the milk Annuario della Soc. Chimica di Milano, 11 (1905),p. 15
[14]	Blázquéz, L.C., Flores, J.r., Jara, F.V. et al. Determination of orotic acid (Vitamin B13) in milk by differential pulse polarography (DPP) Fresenius J. Anal. Chem., 338 (1990),pp. 80-81
[15]	Boguslawski, W., Wrobel, J. An inhibitor of sterol biosynthesis in cow's milk Nature, 247 (1974),pp. 210-211
[16]	Bonham, J.R., Guthrie, P., Downing, M. et al. The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease J. Inherit. Metab. Dis., 22 (1999),pp. 174-184
[17]	Brosnan, M.E., Brosnan, J.T. Orotic acid excretion and arginine metabolism J. Nutr., 137 (2007),pp. 1656S-1661S
[18]	Brusilow, A.W., Hauser, E. Simple method of measurement of orotic acid and orotidine in urine J. Chromatogr., 493 (1989),pp. 388-391
[19]	Buang, Y. Dietary adenine alleviates fatty liver induced by orotic acid Indo. J. Chem., 10 (2010),pp. 363-369
[20]	Butour, J.L., Wimmer, S., Wimmer, F. et al. Chem. Biol. Interact., 104 (1997),pp. 165-178
[21]	Cansev, M. Uridine and cytidine in the brain: their transport and utilization Brain Res. Rev., 52 (2006),pp. 390-397
[22]	Carpenter, K.H., Potter, M., Hammond, J.W. et al. Benign persistent orotic aciduria and the possibility of misdiagnosis of ornithine carbamoly transferase deficiency J. Inherit. Metab. Dis., 20 (1997),pp. 354-358
[23]	Carrey, E.A., Dietz, C., Glubb, D.M. et al. Reproduction, 123 (2002),pp. 757-768
[24]	Christopherson, R.I., Jones, M.E. The overall synthesis of L-5,6-dihydroorotate by multienzymatic protein pyr1-3 from hamster cells. Kinetic studies, substrate channeling, and the effects of inhibitors J. Biol. Chem., 255 (1980),pp. 11381-11395
[25]	Conner, T.W., Rawls, J.M. Biochem. Genet., 20 (1982),pp. 607-619
[26]	Connolly, G.P., Duley, J.A. Uridine and its nucleotides: biological actions, therapeutic potentials Trends Pharmacol. Sci., 20 (1999),pp. 218-225
[27]	Cortes, P., Levin, N.W., Dumler, F. et al. Biochem. J., 182 (1979),pp. 677-686
[28]	Dalbeth, N., Wong, S., Gamble, G.D. et al. Acute effect of milk on serum urate concentration: a randomized control cross-over trail Ann. Rheum. Dis., 69 (2010),pp. 1677-1682
[29]	Durschlag, R.P., Robinson, J.L. Orotic acid-induced metabolic changes in the rat J. Nutr., 110 (1980),pp. 816-821
[30]	Ehle, F.R., Robinson, J.L., Clark, J.H. et al. Effect of amino acid concentration on orotic acid production by bovine mammary tissue J. Dairy Sci., 64 (1981),pp. 2192-2196
[31]	Eisenberg, M., Kirkpatrick, R., Rawls, J. Gene, 124 (1993),pp. 263-267
[32]	European Food Safety Authority Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements EFSA J., 1187 (2009),pp. 1-25
[33]	Evans, D.R., Guy, H.I. Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway J. Biol. Chem., 279 (2004),pp. 33035-33038
[34]	Fabbrizzi, L., Licchelli, M., Mancin, F. et al. Fluorescence sensing of ionic analytes in water: from transition metal ions to vitamin B13 Chem-Eur. J., 8 (2002),pp. 94-101
[35]	Fang, J.X., Uchiumi, T., Yagi, M. et al. Protein instability and functional defects caused by mutations of dihydroorotate dehydrogenase in Miller syndrome patients Biosci. Rep., 32 (2012),pp. 631-639
[36]	Falk, M. Orotsäure Die Pharmazie, 40 (1985),pp. 377-383
[37]	Ferdinandy, P., Fazekas, T., Kádár, E. Effects of orotic acid on ischaemic/reperfused myocardial function and glycogen content in isolated working rat hearts Pharmacol. Res., 37 (1998),pp. 111-114
[38]	Ferrari, V., Giordano, G., Cracco, A.T. et al. Determination of urinary orotate excretion by high-performance liquid chromatography J. Chromatogr., 497 (1989),pp. 101-107
[39]	Fico, M.E., Motyl, T., Milner, J.A. Species comparison of the influence of ammonia on orotic acid and urea biosynthesis in liver J. Nutr., 114 (1984),pp. 613-621
[40]	Fukushima, R., Kanamori, S., Hirashiba, M. et al. Teratogenicity study of the dihydroorotate dehydrogenase inhibitor and protein tyrosine kinase inhibitor leflunomide in mice Reprod. Toxicol., 24 (2007),pp. 310-316
[41]	Fukushima, R., Kanamori, S., Hirashiba, M. et al. Inhibiting the teratogenicity of the immunosuppressant leflunomide in mice by supplementation of exogenous uridine Toxicol. Sci., 108 (2009),pp. 419-426
[42]	Geiss, K.R., Stergiou, N., Neuenfeldt, H.U. et al. Effects of magnesium orotate on exercise tolerance in patients with coronary heart disease Cardiovasc. Drug Ther., 12 (1998),pp. 153-156
[43]	Gerlach, J., Löffler, M., Schäfer, M.K.H. Nucleos. Nucleot. Nucl., 30 (2011),pp. 1147-1154
[44]	Gil, A., Sànchez-Medina, F. Acid-soluble nucleotides of cow's, goat's and sheep's milk at different stages of lactation J. Dairy Res., 48 (1981),pp. 35-44
[45]	Gilissen, C., Hoischen, A., Brunner, H.G. et al. Unlocking Mendelian disease using exome sequencing Genome Biol., 12 (2011),pp. 228-238
[46]	Griffin, J.L., Bonney, S.A., Mann, C. et al. An integrated reverse functional genomic and metabolic approach to understanding orotic acid-induced fatty liver Physiol. Genomics, 17 (2004),pp. 140-149
[47]	Grisham, C.M., Garrett, R.H., Garrett, R.
[48]	Häberle, J., Rubio, V.
[49]	Hallanger, L.E., Laakso, J.W., Schultze, M.O. Orotic acid in milk J. Biol. Chem., 202 (1953),pp. 83-89
[50]	Harley, E.H., Sacks, S., Berman, P. et al. Source and fate of circulating pyrimidines Adv. Exp. Med. Biol., 195PtA (1986),pp. 109-113
[51]	Hayek-Ouassini, M., Henseling, J., Löffler, M. Separation of N-carbamoyl aspartate and L-dihydroorotate from serum with high-performance liquid chromatography with fluorimetric detection Chromatographia, 55 (2002),pp. 411-415
[52]	Heidelberger, C. Fluorinated pyrimidines Prog. Nucleic Acid Res. Mol. Biol., 4 (1965),pp. 1-50
[53]	Hinkel, G.H., Le Petit, G. Untersuchungen über die enterale Resorption der Orotsäure bei Neugeborenen Padiatr. Grenzgeb., 12 (1973),pp. 63-69
[54]	Hitchings, G.H., Elion, G.B., VanderWerff, H. et al. Pyrimidine derivatives as antagonists of pteroylglutamic acid J. Biol. Chem., 174 (1948),pp. 765-766
[55]	Hong, E.S., Kim, E.K., Kang, S.M. et al. Effect of carnitine-orotate complex on glucose metabolism and fatty liver: a double-blind, placebo-controlled study J. Gastroen. Hepatol., 29 (2014),pp. 1449-1457
[56]	Itzhaki, S. Regulation of uracil utilization for RNA synthesis in Ehrlich ascites tumor cells by glucose metabolism Life Sci., 11 (1972),pp. 649-655
[57]	Indyk, H.E., Woollard, D.C. Determination of orotic acid, uric acid, and creatinine in milk by liquid chromatography J. AOAC Int., 87 (2004),pp. 116-122
[58]	Jacobs, C., Sweetman, L., Nyhan, W.L. et al. Stable isotope dilution analysis of orotic acid and uracil in amniotic fluid Clin. Chim. Acta, 143 (1984),pp. 123-133
[59]	Javaid, Z.Z., el Kouni, M.H., Iltzsch, M.H. Biochem. Pharmacol., 58 (1999),pp. 1457-1465
[60]	Jeevanadam, M., Shoemaker, J.D., Horowitz, G.D. et al. Orotic acid excretion during starvation and refeeding in normal men Metabolism, 34 (1985),pp. 325-329
[61]	Jensen, K.F., Björnberg, O. Evolutionary and functional families of dihydroorotate dehydrogenase Path Pyrimidines, 6 (1998),pp. 20-28
[62]	Jones, M.E. Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis Ann. Rev. Biochem., 49 (1980),pp. 253-279
[63]	Jung, E.J., Kwon, S.W., Jung, B.H. et al. Role of the AMPK/SREBP-1 pathway in development of orotic acid-induced fatty liver J. Lipid Res., 52 (2011),pp. 1617-1625
[64]	Kaneti, J.J., Golovinsky, E.V. Quantitative relationships between the electronic structure and biological activity of some analogues of orotic acid Chem. Biol. Interact., 3 (1971),pp. 421-428
[65]	Karatas, F. An investigation of orotic acid levels in the breastmilk of smoking and non-smoking mothers Eur. J. Clin. Nutr., 56 (2002),pp. 958-960
[66]	Kelley, W.N., Greene, M.L., Fox, I.H. et al. Effects of orotic acid on purine and lipoprotein metabolism in man Metabolism, 19 (1979),pp. 1025-1035
[67]	Keppler, D., Holstege, A.
[68]	Kesner, L., Aronson, F.L., Silverman, M. et al. Determination of orotic and dihydroorotic acids in biological fluids and tissues Clin. Chem., 21 (1975),pp. 353-355
[69]	Kinoshita, S., Tanaka, K., 1963. Method for producing orotic acid by fermentation process. US Patent 3086917.
[70]	Kinoshita, F., Kondoh, T., Komori, K. et al. Miller syndrome with novel dihydroorotate dehydrogenase gene mutations Pediatr. Int., 53 (2011),pp. 587-591
[71]	Kintzel, H.W., Hinkel, G.K., Schwarze, R. The decrease in the serum bilirubin level in premature infants by orotic acid Acta Paediatr. Scand., 60 (1971),pp. 1-5
[72]	Kozhevnikova, E.N., van der Knaap, J.A., Pindyurin, A.V. et al. Metabolic enzyme IMPDH is also a transcription factor regulated by cellular state Mol. Cell, 47 (2012),pp. 133-139
[73]	Kumberger, O., Riede, J., Schmidbaur, H. Preparation and crystal structure of calcium and zinc orotate(2-)hydrates Chem. Ber., 124 (1991),pp. 2739-2742
[74]	Larson, B.L., Hegarty, H.M. Orotic acid in milks of various species and commercial dairy products J. Dairy Sci., 62 (1979),pp. 1641-1644
[75]	Latzel, K.
[76]	Levitte, S., Selesky, R., King, B. et al. FEBS J., 277 (2010),pp. 1420-1439
[77]	Lewan, L., Petersen, I., Ynger, T. Incorporation of orotic acid into nucleotides and RNA in mouse organs during 60 minutes Hoppe-Seyler's Z. Biol. Chem., 356 (1975),pp. 425-429
[78]	Lieberman, I., Kornberg, A. Enzymatic synthesis and breakdown of a pyrimidine, orotic acid. I. Dihydroorotic dehydrogenase Biochim. Biophys. Acta, 12 (1953),pp. 223-234
[79]	Lipkowitz, M.S. Regulation of uric acid excretion by the kidney Curr. Rheumatol. Rep., 14 (2012),pp. 179-188
[80]	Löffler, M., Carrey, E.A., Zameitat, E.
[81]	Löffler, M., Jöckel, J., Schuster, G. et al. Dihydroorotate-ubiquinone oxidoreductase links mitochondria in the biosynthesis of pyrimidine nucleotides Mol. Cell. Biochem., 174 (1997),pp. 125-129
[82]	Löffler, M., Zameitat, E.
[83]	Manjeshwar, S., Pichiri-Coni, G., Coni, P. et al. Ribonucleotide reductase: a possible target for orotic acid mitoinhibition in normal hepatocytes in primary culture Cancer Lett., 73 (1993),pp. 149-154
[84]	Manjeshwar, S., Rao, P.M., Rajalakshmi, S. et al. Mol. Carcinogen., 24 (1999),pp. 188-196
[85]	Manna, L., Hauge, S.M. A possible relationship of Vitamin B13 to orotic acid J. Biol. Chem., 202 (1953),pp. 91-96
[86]	Mentel, M., Spirek, M., Jorck-Ramberg, D. et al. Transfer of genetic material between pathogenic and food-borne yeasts Appl. Environ. Microbiol., 72 (2006),pp. 5122-5225
[87]	Merry, A., Quiao, M., Hasler, M. et al. Biochem. J., 458 (2014),pp. 343-353
[88]	Mitchell, K.J., Houlahan, M.B. Fed. Proc., 6 (1947),pp. 506-509
[89]	Miura, D., Anzai, N., Jutabha, P. et al. Human urate transporter 1 (hURAT1) mediates the transport of orotate J. Physiol. Sci., 61 (2011),pp. 253-257
[90]	Morin, A., Fritsch, L., Mathieu, J.R.R. et al. Identification of CAD as an androgen receptor interactant and an early marker of prostate tumor recurrence FASEB J., 26 (2012),pp. 460-467
[91]	Motyl, T., Wincenciak, M., Blachowski, S. et al. Metabolic effect of orotic acid in calves J. Vet. Med. A, 40 (1993),pp. 679-689
[92]	Nath, M., Vats, M., Roy, P. Eur. J. Med. Chem., 59 (2013),pp. 310-321
[93]	Ng, S.B., Buckingham, K.J., Lee, C. et al. Exome sequencing identifies a mendelian disorder Nat. Genet., 42 (2010),pp. 30-35
[94]	Nieper, H.A. Die Wirkung von Zink-Orotat Z. Präklin. Geratrie, 6 (1974),pp. 127-131
[95]	Novak, A.F., Hauge, S.M. Isolation of an unidentified growth factor (vitamin B13) in distillers' dried solubles J. Biol. Chem., 174 (1948),pp. 647-651
[96]	Ott, H.W., Dickinson, A.M., van Inderstine, A. et al. Studies related to “vitamin B13” J. Nutr., 64 (1957),pp. 525-531
[97]	O'Sullivan, W.J. Orotic acid Aust. N. Z. J. Med., 3 (1973),pp. 417-423
[98]	Pôrto, L.C., de Castro, C.H., Savergnini, S.S. et al. Improvement of the energy supply and contractile function in normal and ischemic rat hearts by dietary orotic acid Life Sci., 90 (2012),pp. 476-483
[99]	Rathod, O.K., Khatri, A. Synthesis and antiproliferative activity of threo-5-fluoro-l-dihydroorotate J. Biol. Chem., 265 (1990),pp. 14242-14249
[100]	Rainger, J., Bengani, H., Campbell, L. et al. Miller (Genée–Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH Hum. Mol. Genet., 21 (2012),pp. 3969-3983
[101]	Raisonnier, A., Bouma, M.E., Salva, C. et al. Metabolism of orotic acid: lack of orotate phosphoribosyltransferase in rat intestinal mucosa Eur. J. Biochem., 118 (1981),pp. 65-569
[102]	Rao, P.M., Nagamine, Y., Roomi, M.W. et al. Orotic acid, a new promoter for experimental liver carcinogenesis Toxicol. Pathol., 12 (1984),pp. 173-178
[103]	Reichard, P., Lagerkvist, U. The biogenesis of orotic acid in liver slices Acta Chem. Scand., 7 (1953),pp. 1207-1217
[104]	Reiter, S., Löffler, W., Gröbner, W. et al. Urinary oxipurinol-1-riboside excretion and allopurinol-induced orotic aciduria Adv. Exp. Med. Biol., 195A (1986),pp. 453-460
[105]	Robinson, J.L. Adenine-induced orotic aciduria in rats fed diets with and without orotic acid Nutr. Res., 1 (1981),pp. 253-259
[106]	Robinson, J.L., Dombrowski, D.B. Effects of orotic acid ingestion on urinary and blood parameters in humans Nutr. Res., 3 (1983),pp. 407-415
[107]	Robinson, J.L., Drabik, M.R., Dombrowski, D.B. et al. Consequences of UMP synthase deficiency in cattle Proc. Natl. Acad. Sci. USA, 80 (1983),pp. 321-323
[108]	Rosenfeldt, F.L., Richards, S.M., Lin, Z. et al. Mechanism of cardioprotective effect of orotic acid Cardiovasc. Drug Ther., 12 (1998),pp. 159-170
[109]	Rüthrich, H.L., Wetzel, W., Matthies, H. Memory retention in old rats: improvement by orotic acid Psychopharmacology, 79 (1983),pp. 348-351
[110]	Salerno, C., Celli, P.D.M., Finocchiaro, R. et al. Determination of urinary orotic acid and uracil by capillary zone electrophoresis J. Chromatogr., 734 (1999),pp. 175-178
[111]	Schaefer, C., Schäfer, M.K.H., Löffler, M. Nucleos. Nucleot. Nucl., 29 (2010),pp. 476-481
[112]	Shopova, M.D., Moskova-Simeonova, D. Plant growth regulating activity of orotic acid and its 1-cyclohexyl and 1-phenylderivatives Biol. Plantarum., 43 (2000),pp. 437-439
[113]	Sigoillot, F.D., Kotsis, D.H., Serre, V. et al. Nuclear localisation and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD J. Biol. Chem., 280 (2005),pp. 25611-25620
[114]	Stephens, W.
[115]	Tiemeyer, W., Stohrer, M., Giesecke, D. Metabolites of nucleic acids in bovine milk J. Dairy Sci., 67 (1984),pp. 723-728
[116]	Traut, T.W. Physiological concentrations of purines and pyrimidines Mol. Cell. Biochem., 140 (1994),pp. 1-22
[117]	Traut, T.W., Jones, M.E. Uracil metabolism – UMP synthesis from orotic acid or uridine and conversion to ß-alanin: enzymes and cDNA Prog. Nucleic Acid Res. Mol. Biol., 53 (1996),pp. 1-78
[118]	Uddin, M., Altmann, G.G., Leblond, C.P. J. Cell Biol., 98 (1984),pp. 1619-1629
[119]	Van der Knaap, J.A., Kozhevnikova, E.N., Langenberg, K. et al. Regulation of ecdysteroid target genes Mol. Cell. Biol., 30 (2010),pp. 736-744
[120]	Van Kuilenburg, A., van Lenthe, H., Löffler, M. et al. Clin. Chem., 50 (2004),pp. 2117-2124
[121]	Vazzoler, G., Bassani, N., Menin, A. Treatment of hyperbilirubinemia in the newborn with orotic acid Minerva Pediatr., 26 (1974),pp. 1046-1048
[122]	Visek, W. Nitrogen-stimulated orotic acid synthesis and nucleotide imbalance Cancer Res., 152 (1992),pp. 2082-2084
[123]	Voet, D., Voet, J.G.
[124]	Von Kügelen, I. Pharmacological profiles of cloned mammalian P2Y-receptor subtypes Pharmacol. Therapeut., 110 (2006),pp. 414-432
[125]	Wang, Y.M., Hu, X.Q., Xue, Y. et al. Study on possible mechanism of orotic acid-induced fatty liver in rats Nutrition, 27 (2011),pp. 571-575
[126]	Webster, D.R., Becroft, D.M., van Gennip, A.H. et al.
[127]	Weed, L.L., Edmonds, M., Wilson, D.W. Conversion of radioactive orotic acid into pyrimidine nucleotides of nucleic acid by slices of rat liver P. Soc. Expt. Biol. Med., 75 (1950),pp. 192-193
[128]	Wellington, M., Kabir, M.A., Rutschenko, E. Mycologia, 98 (2006),pp. 393-398
[129]	Wevers, R.A., Engelke, U.F.H., Moolenaar, S.H. et al. Clin. Chem., 45 (1999),pp. 539-548
[130]	White, R.M., Cech, J., Ratanasirintrawoot, S. et al. DHODH modulates transcriptional elongation in the neural crest and melanoma Nature, 471 (2011),pp. 518-522
[131]	Willer, G.B., Lee, V.M., Gregg, R.G. et al. Genetics, 170 (2005),pp. 1827-1837
[132]	Wohlhueter, R.M., McIvor, R.S., Plagemann, P.G.W. Facilitated transport of uracil and 5-fluorouracil and permeation of orotic acid into cultured mammalian cells J. Cell. Physiol., 104 (1980),pp. 309-319