Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Pyrimidine Metabolism
Mus musculus
Category:
Metabolite Pathway
Sub-Category:
Metabolic
Created: 2018-01-21
Last Updated: 2019-09-15
A group of heterocyclic aromatic organic compound, pyrimidines are similar in structure to benzene and pyridine and count the nucleic acids cytosine, thymine, and uracil as structural derivatives. The following pathway illustrates a many pyrimidine-associated processes such as nucleotide biosynthesis, degradation, and salvage. This pathway depicts a number of pyrimidine-related processes such as nucleotide biosynthesis, degradation, and salvage. For pyrimidine nucleotide biosynthesis, carbamoyl phosphate derived from the action of carbamoyl phosphate synthetase II (CPS-II) on glutamine and bicarbonate is converted into carbamoyl aspartate by aspartate transcarbamoylase, ATCase. Dihydroorotic acid is subsequently generated by the action of carbamoyl aspartate dehydrogenase on carbamoyl aspartate. Dihydroorotate dehydrogenase then converts dihydroorotic acid to orotic acid. From this point, orotate phosphoribosyltransferase incorporates phosphoribosyl pyrophosphate into (PRPP) to produce orotidine monophosphate. Orotidine-5’-phosphate carboxylase subsequently converts orotidine monophosphate into uridine monophosphate (UMP). UMP is further phosphorylated twice to form UTP; the first instance by uridylate kinase and the second instance by ubiquitous nucleoside diphosphate kinase. UTP moves into the CTP synthesis pathway with the action of CTP synthase which aminates the molecule.
The uridine nucleotides are also feedstock for the de novo thymine nucleotides synthesis pathway. DeoxyUMP which is derived from UDP or CDP metabolism is transformed by the action of thymidylate synthase into deoxyTMP of which the methyl group is sourced from N5,N10-methylene THF. THF is subsequently regenerated from DHF via dihydrofolate reductase (DHFR) which is essential for the continuation of thymidylate synthase activity. Serine hydroxymethyl transferase then acts on THF to regenerate N5,N10-THF.
Pyrimidine synthesis is a comparatively simpler process than purine synthesis due to a couple of factors; pyrimidine ring structure is assembled as a free base rather being derived from PRPP and there is no branch in the pyrimidine synthesis pathway as opposed to the purine synthesis pathway. For thymidine, the action of thymidine kinase on it (or alternatively deoxyuridine) plays an important role in what is referred to as the salvage pathway to dTTP synthesis. However to form dTMP, the action of thymine phosphorylase and thymidine kinase is required. For deoxycytidine, deoxycytidine kinase is required (deoxycytidine also acts on deoxyadenosine and deoxyguanosine). For uracil, UMP can be formed by the action of uridine phosphorylase and uridine kinase on uracil. Pyrimidine catabolism ultimately results in the formation of the waste products of urea, H2O, and CO2. The product of cytosine breakdown, uracil, can be broken down to N-carbamoyl-β-alanine which can be catabolized into β-alanine. The product of thymine breakdown is β-aminoisobutyrate. The transamination of α-ketoglutarate to glutamate requires both of these breakdown products (β-alanine and β-aminoisobutyrate) to act as amine group donors. The products of this transamination can move through a further reaction that produces malonyl-CoA or methylmalonyl-CoA, a precursor for succinyl-CoA which is used in the Krebs cycle.
References
Pyrimidine Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, Bult CJ, Agarwala R, Cherry JL, DiCuccio M, Hlavina W, Kapustin Y, Meric P, Maglott D, Birtle Z, Marques AC, Graves T, Zhou S, Teague B, Potamousis K, Churas C, Place M, Herschleb J, Runnheim R, Forrest D, Amos-Landgraf J, Schwartz DC, Cheng Z, Lindblad-Toh K, Eichler EE, Ponting CP: Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 2009 May 5;7(5):e1000112. doi: 10.1371/journal.pbio.1000112. Epub 2009 May 26.
Pubmed: 19468303
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.
Pubmed: 15489334
Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villen J, Haas W, Sowa ME, Gygi SP: A tissue-specific atlas of mouse protein phosphorylation and expression. Cell. 2010 Dec 23;143(7):1174-89. doi: 10.1016/j.cell.2010.12.001.
Pubmed: 21183079
Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y: The transcriptional landscape of the mammalian genome. Science. 2005 Sep 2;309(5740):1559-63. doi: 10.1126/science.1112014.
Pubmed: 16141072
Lee CG, O'Brien WE: A unique member of the thymidylate kinase family that is induced during macrophage activation. J Immunol. 1995 Jun 1;154(11):6094-102.
Pubmed: 7751651
Mehus JG, Deloukas P, Lambeth DO: NME6: a new member of the nm23/nucleoside diphosphate kinase gene family located on human chromosome 3p21.3. Hum Genet. 1999 Jun;104(6):454-9. doi: 10.1007/s004390050987.
Pubmed: 10453732
Burgis NE, Cunningham RP: Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase. J Biol Chem. 2007 Feb 9;282(6):3531-8. doi: 10.1074/jbc.M608708200. Epub 2006 Nov 6.
Pubmed: 17090528
This pathway was propagated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0000046
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings