This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: uracil degradation (reductive)
|Superclasses:||Degradation/Utilization/Assimilation → Nucleosides and Nucleotides Degradation → Pyrimidine Nucleotides Degradation → Pyrimidine Nucleobases Degradation|
Some taxa known to possess this pathway include : Acidovorax facilis , Arabidopsis thaliana col , Brevibacillus agri , Burkholderia cepacia , Escherichia coli B , Lachancea kluyveri , Limonium latifolium , Pseudomonas aeruginosa , Pseudomonas putida , Pseudomonas stutzeri , Ralstonia pickettii , Rattus norvegicus , Salmonella enterica enterica serovar Typhimurium , Triticum aestivum , Zea mays
Pyrimidine nucleotides can be catabolized through three different pathways. The best characterized is the reductive pathway (this pathway and uracil degradation I (reductive)) in which the pyrimidine nucleotides are reduced to a β amino acid, CO2 and ammonia. The pathway is found in mammals, plants, some fungi and microorganisms [Fritzson57, Campbell57, Evans61, Tsai65, Gojkovic00]. The oxidative pathway (see uracil degradation II (oxidative)) is only found in a few bacterial species and has not been characterized nearly as well. In it uracil is converted to urea and malonate via barbiturate [Hayaishi52, Lara52]. A third pathway, known as the Rut pathway, was discovered much later in Escherichia coli and other bacteria (see uracil degradation III) [Loh06]. That pathway starts with opening of the pyrimidine ring, and forms 3-hydroxypropanoate from uracil, with concomitant production of CO2 and ammonia.
About This Pathway
Some bacterial species are known to catabolize pyrimidines via a reductive pathway leading to the production of β-amino acids. The reductive pathway has been observed in various microorganisms including Clostridium uracilicum [Campbell57, Campbell57a], Acidovorax facilis [Kramer69], Escherichia coli B [Patel87], Pseudomonas aeruginosa [Kim91a], Ralstonia pickettii [West94], Pseudomonas stutzeri [Xu92], Pseudomonas putida [West01], Burkholderia cepacia [West97], Salmonella enterica enterica serovar Typhimurium [West85] and Brevibacillus agri [Kao03].
The reductive pathway of thymine is essentially the same in mammalian tissues [Fink52, Fritzson57]. The product of the pathway, (R)-3-amino-2-methylpropanoate, is is a non-protein amino acid [Solem74]. The stereoisomer of this compound, (S)-3-amino-2-methylpropanoate, is produced via the degradation of L-valine (see L-valine degradation I). While the (S) isomer is reabsorbed into the plasma, the (R) isomer is eliminated in urine [Solem74, vanGennip81].
The pathway proceeds in three sequential enzymatic steps. The first enzyme is (NADP)-dependent dihydropyrimidine dehydrogenase (EC 184.108.40.206), which catalyzes the reversible reduction of both uracil and thymine to 5,6-dihydrouracil and 5,6-dihydrothymine, respectively. The second enzyme, dihydropyrimidinase (EC 220.127.116.11) performs reversible hydrolytic ring-opening of 5,6-dihydrouracil and 5,6-dihydrothymine to 3-ureidopropanoate and (R)-3-ureido-isobutyrate, respectively. Finally, 3-amino-isobutyrate synthase / β-alanine synthase (EC 18.104.22.168) catalyzes the irreversible hydrolysis of 3-ureidopropanoate and (R)-3-ureido-isobutyrate to β-alanine and 3-amino-isobutyrate, respectively, in a reaction that produces ammonium and carbon dioxide.
Campbell57: Campbell LL (1957). "Reductive degradation of pyrimidines. I. The isolation and characterization of a uracil fermenting bacterium, Clostridium uracilicum nov. spec." J Bacteriol 73(2);220-4. PMID: 13416173
Duhaze03: Duhaze C., Gagneul D., Leport L., Larher F.R., Bouchereau A. "Uracil as one of the multiple sources of β-alanine in Limonium latifolium, a halotolerant β-alanine betaine accumulating Plumbaginaceae." Plant Physiol. Biochem. (2003) 41 : 993-998.
Gojkovic00: Gojkovic Z, Jahnke K, Schnackerz KD, Piskur J (2000). "PYD2 encodes 5,6-dihydropyrimidine amidohydrolase, which participates in a novel fungal catabolic pathway." J Mol Biol 295(4);1073-87. PMID: 10656811
Kramer69: Kramer J, Kaltwasser H (1969). "[Utilization of pyrimidine derivatives by Hydrogenomonas facilis. I. Intermediates and enzymes of cytosine degradation]." Arch Mikrobiol 68(3);227-35. PMID: 4986615
Loh06: Loh KD, Gyaneshwar P, Markenscoff Papadimitriou E, Fong R, Kim KS, Parales R, Zhou Z, Inwood W, Kustu S (2006). "A previously undescribed pathway for pyrimidine catabolism." Proc Natl Acad Sci U S A 103(13);5114-9. PMID: 16540542
vanGennip81: van Gennip AH, Kamerling JP, de Bree PK, Wadman SK (1981). "Linear relationship between the R- and S-enantiomers of a beta-aminoisobutyric acid in human urine." Clin Chim Acta 116(3);261-7. PMID: 6945923
Hamajima98: Hamajima N, Kouwaki M, Vreken P, Matsuda K, Sumi S, Imaeda M, Ohba S, Kidouchi K, Nonaka M, Sasaki M, Tamaki N, Endo Y, De Abreu R, Rotteveel J, van Kuilenburg A, van Gennip A, Togari H, Wada Y (1998). "Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene." Am J Hum Genet 63(3);717-26. PMID: 9718352
Kikugawa94: Kikugawa M, Kaneko M, Fujimoto-Sakata S, Maeda M, Kawasaki K, Takagi T, Tamaki N (1994). "Purification, characterization and inhibition of dihydropyrimidinase from rat liver." Eur J Biochem 219(1-2);393-9. PMID: 8307005
Kim76: Kim BD, Keenen S, Bodnar JK, Sander EG (1976). "Role of enzymatically catalyzed 5-iodo-5,6-dihydrouracil ring hydrolysis on the dehalogenation of 5-iodouracil." J Biol Chem 251(22);6909-14. PMID: 993199
Kimura98: Kimura M, Sakata SF, Matoba Y, Matsuda K, Kontani Y, Kaneko M, Tamaki N (1998). "Cloning of rat dihydropyrimidine dehydrogenase and correlation of its mRNA increase in the rat liver with age." J Nutr Sci Vitaminol (Tokyo) 44(4);537-46. PMID: 9819714
Lu93: Lu ZH, Zhang R, Diasio RB (1993). "Comparison of dihydropyrimidine dehydrogenase from human, rat, pig and cow liver. Biochemical and immunological properties." Biochem Pharmacol 46(5);945-52. PMID: 8373446
Matsuda96: Matsuda K, Sakata S, Kaneko M, Hamajima N, Nonaka M, Sasaki M, Tamaki N (1996). "Molecular cloning and sequencing of a cDNA encoding dihydropyrimidinase from the rat liver." Biochim Biophys Acta 1307(2);140-4. PMID: 8679696
Matthews87: Matthews MM, Traut TW (1987). "Regulation of N-carbamoyl-beta-alanine amidohydrolase, the terminal enzyme in pyrimidine catabolism, by ligand-induced change in polymerization." J Biol Chem 262(15);7232-7. PMID: 3108250
Van04: Van Kuilenburg AB, Stroomer AE, Van Lenthe H, Abeling NG, Van Gennip AH (2004). "New insights in dihydropyrimidine dehydrogenase deficiency: a pivotal role for beta-aminoisobutyric acid?." Biochem J 379(Pt 1);119-24. PMID: 14705962
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