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Pathway Description
Metabolism and Physiological Effects of Orotic acid
Homo sapiens
Metabolic Pathway
Created: 2021-10-20
Last Updated: 2023-10-25
Orotic acid (orotate) is classified as a pyrimidinemonocarboxylic acid. Most urinary orotic acid is synthesized in the body, where it arises as an intermediate in the pathway for the synthesis of pyrimidine nucleotides. It originates from l-glutamine, which is obtained from protein sources such as red meat and eggs in the diet. L-glutamine is metabolized to orotate in the liver. L-glutamine is first converted to carbamoyl phosphate then to N-Carbamoyl-L-aspartate and finally to dihydroorotate by the CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). Dihydroorotate is converted to orotate in the mitochondria of the cell via the enzyme dihydroorotate dehydrogenase. Orotate can enter the bloodstream where it exerts detrimental effects on other systems. A build up of orotate in the body leads to acidosis which can have detrimental effects on other systems in the body causing renal failure, neurotoxicity, endothelial dysfunction and hypertension.
References
Metabolism and Physiological Effects of Orotic acid References
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Pubmed: 25601987
Fonteh, Aliah L. (2018) "Orotic Aciduria," Fidei et Veritatis: The Liberty University Journal of Graduate Research: Vol. 2 : Iss. 1 , Article 1.
Available at: https://digitalcommons.liberty.edu/fidei_et_veritatis/vol2/iss1/1
Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M: KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2021 Jan 8;49(D1):D545-D551. doi: 10.1093/nar/gkaa970.
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Pubmed: 29140435
Kekuda R, Prasad PD, Fei YJ, Torres-Zamorano V, Sinha S, Yang-Feng TL, Leibach FH, Ganapathy V: Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter Bo from a human placental choriocarcinoma cell line. J Biol Chem. 1996 Aug 2;271(31):18657-61. doi: 10.1074/jbc.271.31.18657.
Pubmed: 8702519
Rasko JE, Battini JL, Gottschalk RJ, Mazo I, Miller AD: The RD114/simian type D retrovirus receptor is a neutral amino acid transporter. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2129-34. doi: 10.1073/pnas.96.5.2129.
Pubmed: 10051606
Tailor CS, Nouri A, Zhao Y, Takeuchi Y, Kabat D: A sodium-dependent neutral-amino-acid transporter mediates infections of feline and baboon endogenous retroviruses and simian type D retroviruses. J Virol. 1999 May;73(5):4470-4.
Pubmed: 10196349
Davidson JN, Rao GN, Niswander L, Andreano C, Tamer C, Chen KC: Organization and nucleotide sequence of the 3' end of the human CAD gene. DNA Cell Biol. 1990 Nov;9(9):667-76. doi: 10.1089/dna.1990.9.667.
Pubmed: 1979741
Sigoillot FD, Kotsis DH, Serre V, Sigoillot SM, Evans DR, Guy HI: Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD. J Biol Chem. 2005 Jul 8;280(27):25611-20. doi: 10.1074/jbc.M504581200. Epub 2005 May 12.
Pubmed: 15890648
Iwahana H, Fujimura M, Ii S, Kondo M, Moritani M, Takahashi Y, Yamaoka T, Yoshimoto K, Itakura M: Molecular cloning of a human cDNA encoding a trifunctional enzyme of carbamoyl-phosphate synthetase-aspartate transcarbamoylase-dihydroorotase in de Novo pyrimidine synthesis. Biochem Biophys Res Commun. 1996 Feb 6;219(1):249-55. doi: 10.1006/bbrc.1996.0213.
Pubmed: 8619816
Baumgartner R, Walloschek M, Kralik M, Gotschlich A, Tasler S, Mies J, Leban J: Dual binding mode of a novel series of DHODH inhibitors. J Med Chem. 2006 Feb 23;49(4):1239-47. doi: 10.1021/jm0506975.
Pubmed: 16480261
Minet M, Dufour ME, Lacroute F: Cloning and sequencing of a human cDNA coding for dihydroorotate dehydrogenase by complementation of the corresponding yeast mutant. Gene. 1992 Nov 16;121(2):393-6. doi: 10.1016/0378-1119(92)90150-n.
Pubmed: 1446837
Copeland RA, Davis JP, Dowling RL, Lombardo D, Murphy KB, Patterson TA: Recombinant human dihydroorotate dehydrogenase: expression, purification, and characterization of a catalytically functional truncated enzyme. Arch Biochem Biophys. 1995 Oct 20;323(1):79-86. doi: 10.1006/abbi.1995.0012.
Pubmed: 7487077
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