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Pathway Description
Pyrimidine Metabolism
Bos taurus
Category:
Metabolite Pathway
Sub-Category:
Metabolic
Created: 2018-08-10
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
Zimin AV, Delcher AL, Florea L, Kelley DR, Schatz MC, Puiu D, Hanrahan F, Pertea G, Van Tassell CP, Sonstegard TS, Marcais G, Roberts M, Subramanian P, Yorke JA, Salzberg SL: A whole-genome assembly of the domestic cow, Bos taurus. Genome Biol. 2009;10(4):R42. doi: 10.1186/gb-2009-10-4-r42. Epub 2009 Apr 24.
Pubmed: 19393038
Harhay GP, Sonstegard TS, Keele JW, Heaton MP, Clawson ML, Snelling WM, Wiedmann RT, Van Tassell CP, Smith TP: Characterization of 954 bovine full-CDS cDNA sequences. BMC Genomics. 2005 Nov 23;6:166. doi: 10.1186/1471-2164-6-166.
Pubmed: 16305752
Hines V, Keys LD 3rd, Johnston M: Purification and properties of the bovine liver mitochondrial dihydroorotate dehydrogenase. J Biol Chem. 1986 Aug 25;261(24):11386-92.
Pubmed: 3733756
Hines V, Johnston M: Analysis of the kinetic mechanism of the bovine liver mitochondrial dihydroorotate dehydrogenase. Biochemistry. 1989 Feb 7;28(3):1222-6. doi: 10.1021/bi00429a040.
Pubmed: 2540819
Yamada M, Shahjahan M, Tanabe T, Kishi F, Nakazawa A: Cloning and characterization of cDNA for mitochondrial GTP:AMP phosphotransferase of bovine liver. J Biol Chem. 1989 Nov 15;264(32):19192-9.
Pubmed: 2478555
Wieland B, Tomasselli AG, Noda LH, Frank R, Schulz GE: The amino acid sequence of GTP:AMP phosphotransferase from beef-heart mitochondria. Extensive homology with cytosolic adenylate kinase. Eur J Biochem. 1984 Sep 3;143(2):331-9. doi: 10.1111/j.1432-1033.1984.tb08376.x.
Pubmed: 6088234
Tomasselli AG, Frank R, Schiltz E: The complete primary structure of GTP:AMP phosphotransferase from beef heart mitochondria. FEBS Lett. 1986 Jul 7;202(2):303-8. doi: 10.1016/0014-5793(86)80706-2.
Pubmed: 3013690
Allegrini S, Pesi R, Tozzi MG, Fiol CJ, Johnson RB, Eriksson S: Bovine cytosolic IMP/GMP-specific 5'-nucleotidase: cloning and expression of active enzyme in Escherichia coli. Biochem J. 1997 Dec 1;328 ( Pt 2):483-7. doi: 10.1042/bj3280483.
Pubmed: 9371705
Albin N, Johnson MR, Diasio RB: cDNA cloning of bovine liver dihydropyrimidine dehydrogenase. DNA Seq. 1996;6(4):243-50.
Pubmed: 8912928
Porter DJ, Chestnut WG, Taylor LC, Merrill BM, Spector T: Inactivation of dihydropyrimidine dehydrogenase by 5-iodouracil. J Biol Chem. 1991 Oct 25;266(30):19988-94.
Pubmed: 1939061
Arimura N, Inagaki N, Chihara K, Menager C, Nakamura N, Amano M, Iwamatsu A, Goshima Y, Kaibuchi K: Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem. 2000 Aug 4;275(31):23973-80. doi: 10.1074/jbc.M001032200.
Pubmed: 10818093
Rahajeng J, Giridharan SS, Naslavsky N, Caplan S: Collapsin response mediator protein-2 (Crmp2) regulates trafficking by linking endocytic regulatory proteins to dynein motors. J Biol Chem. 2010 Oct 15;285(42):31918-22. doi: 10.1074/jbc.C110.166066. Epub 2010 Aug 27.
Pubmed: 20801876
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
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