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MetaCyc Pathway: thymine degradation
Inferred from experiment

Enzyme View:

Pathway diagram: thymine degradation

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/AssimilationNucleosides and Nucleotides DegradationPyrimidine Nucleotides DegradationPyrimidine 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

Expected Taxonomic Range: Bacteria , Lachancea, Mammalia, Viridiplantae

General Background

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 [Kim91], 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, which catalyzes the reversible reduction of both uracil and thymine to 5,6-dihydrouracil and 5,6-dihydrothymine, respectively. The second enzyme, dihydropyrimidinase (EC performs reversible hydrolytic ring-opening of 5,6-dihydrouracil and 5,6-dihydrothymine to 3-ureidopropanoate and (R)-3-ureido-isobutanoate, respectively. Finally, 3-amino-isobutyrate synthase / β-alanine synthase (EC catalyzes the irreversible hydrolysis of 3-ureidopropanoate and (R)-3-ureido-isobutanoate to β-alanine and 3-amino-2-methylpropanoate, respectively, in a reaction that produces ammonium and carbon dioxide.

Created 10-Feb-2010 by Caspi R, SRI International


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

Campbell57a: Campbell LL (1957). "Reductive degradation of pyrimidines. II. Mechanism of uracil degradation by Clostridium uracilicum." J Bacteriol 73(2);225-9. PMID: 13416174

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.

Evans61: Evans WR, Axelrod B (1961). "Pyrimidine metabolism in germinating seedlings." Plant Physiol 36(1);9-13. PMID: 16655478

Fink52: Fink, K, Henderson, RB, Fink, RM (1952). "Aminoisobutyric acid in rat urine following administration of pyrimidines." J Biol Chem 197(1);441-52. PMID: 12981074

Fritzson57: Fritzson P (1957). "The catabolism of C14-labeled uracil, dihydrouracil, and beta-ureidopropionic acid in rat liver slices." J Biol Chem 226(1);223-8. PMID: 13428755

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

Hayaishi52: Hayaishi O, Kornberg A (1952). "Metabolism of cytosine, thymine, uracil, and barbituric acid by bacterial enzymes." J Biol Chem 197(2);717-32. PMID: 12981104

Kao03: Kao CH, Hsu WH (2003). "A gene cluster involved in pyrimidine reductive catabolism from Brevibacillus agri NCHU1002." Biochem Biophys Res Commun 303(3);848-54. PMID: 12670488

Kim91: Kim S, West TP (1991). "Pyrimidine catabolism in Pseudomonas aeruginosa." FEMS Microbiol Lett 61(2-3);175-9. PMID: 1903745

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

Lara52: Lara FJ (1952). "On the decomposition of pyrimidines by bacteria. II. Studies with cell-free enzyme preparations." J Bacteriol 64(2);279-85. PMID: 14955523

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

Patel87: Patel BN, West TP (1987). "Degradation of the pyrimidine bases uracil and thymine by Escherichia coli B." Microbios 49(199);107-13. PMID: 3553866

Solem74: Solem E (1974). "The absolute configuration of beta-aminoisobutyric acid formed by degradation of thymine in man." Clin Chim Acta 53(2);183-90. PMID: 4841987

Tsai65: Tsai CS, Axelrod B (1965). "Catabolism of Pyrimidines in Rape Seedlings." Plant Physiol 40(1);39-44. PMID: 16656066

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

West01: West TP (2001). "Pyrimidine base catabolism in Pseudomonas putida biotype B." Antonie Van Leeuwenhoek 80(2);163-7. PMID: 11759049

West85: West TP, Traut TW, Shanley MS, O'Donovan GA (1985). "A Salmonella typhimurium strain defective in uracil catabolism and beta-alanine synthesis." J Gen Microbiol 131(5);1083-90. PMID: 3926948

West94: West TP (1994). "Pyrimidine ribonucleoside catabolic enzyme activities of Pseudomonas pickettii." Antonie Van Leeuwenhoek 66(4);307-12. PMID: 7710277

West97: West, T.P. (1997). "Reductive catabolism of uracil and thymine by Burkholderia cepacia." Arch. Microbiol. 168:237-239.

Xu92: Xu, G., West, T.P. (1992). "Reductive catabolism of pyrimidine bases by Pseudomonas stutzeri." J. Gen. Microbiol. 138:2459-2463.

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Fritzson60: Fritzson, P (1960). "Properties and assay of dihydrouracil dehydrogenase of rat liver." J Biol Chem 235;719-25. PMID: 13825299

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

KvalnesKrick93: Kvalnes-Krick KL, Traut TW (1993). "Cloning, sequencing, and expression of a cDNA encoding beta-alanine synthase from rat liver." J Biol Chem 268(8);5686-93. PMID: 8449931

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

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

Maguire78: Maguire JH, Dudley KH (1978). "Partial purification and characterization of dihydropyrimidinases from calf and rat liver." Drug Metab Dispos 6(5);601-5. PMID: 30611

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

Sakamoto01: Sakamoto T, Sakata SF, Matsuda K, Horikawa Y, Tamaki N (2001). "Expression and properties of human liver beta-ureidopropionase." J Nutr Sci Vitaminol (Tokyo) 47(2);132-8. PMID: 11508704

Shiotani81: Shiotani T, Weber G (1981). "Purification and properties of dihydrothymine dehydrogenase from rat liver." J Biol Chem 256(1);219-24. PMID: 7451435

Tamaki87: Tamaki N, Mizutani N, Kikugawa M, Fujimoto S, Mizota C (1987). "Purification and properties of beta-ureidopropionase from the rat liver." Eur J Biochem 169(1);21-6. PMID: 3678231

Van04a: 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

Wallach57: Wallach, DP, Grisolia,A S (1957). "The purification and properties of hydropyrimidine hydrase." J Biol Chem 226(1);277-88. PMID: 13428761

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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