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MetaCyc Pathway: purine nucleotides degradation II (aerobic)

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: purine nucleotides catabolism

Superclasses: Degradation/Utilization/Assimilation Nucleosides and Nucleotides Degradation Purine Nucleotides Degradation
Superpathways

Some taxa known to possess this pathway include ? : Bos taurus , Escherichia coli K-12 substr. MG1655 Inferred from experiment [Xi00], Gallus gallus , Homo sapiens , Mus musculus , Oryctolagus cuniculus , Rattus norvegicus

Expected Taxonomic Range: Archaea , Bacteria , Opisthokonta

Summary:
General Background

This pathway depicts the degradation of purine nucleotides to purine nucleosides, purine bases, and urate. Further degradation is shown in the pathway llink. Purine degradation plays an important role in nitrogen metabolism in most organisms. The pathway in vertebrates is discussed below. Fungi, bacteria and archaea can utilize some of the intermediates in this pathway and the linked pathway as sole sources of nitrogen, or nitrogen and carbon ([Pope09, Schultz01, DeMoll93] and reviewed in [Vogels76].

In Escherichia coli exogenous purine nucleosides and purine bases are converted to nucleotides via salvage pathways. Although all of the enzymes of the pathway shown here are present in this organism, aerobic purine degradation is incomplete and does not progress past (S)-(+)-allantoin or allantoate formation, and this catabolism does not suffice as a source of nitrogen under aerobic growth conditions [Xi00]. However, (S)-(+)-allantoin can be degraded anaerobically [Cusa99]. See pathways purine ribonucleosides degradation, purine deoxyribonucleosides degradation I and allantoin degradation IV (anaerobic).

The pathways of biosynthesis and degradation of mammalian purine and pyrimidine bases, nucleosides and nucleotides were elucidated in the 1950s and 1960s. Much work in the 1970s and 1980s focused on inborn errors of purine metabolism, although the regulation of purine nucleotide synthesis and the metabolism of purine bases and nucleosides were also studied. More recent work on purine and pyrimidine metabolism using genomics, proteiomics and metabolomics is likely to impact several areas of clinical research including studies of a possible role for high levels of soluble urate in cardiovascular diseases; the development of purine and pyrimidine analogs for the chemotherapy of cancer and autoimmune diseases as well for antiviral and antiparasitic drugs; and the development of urate-lowering drugs for the treatment of gout. Reviewed in [Becker08] and [Nyhan05].

About This Pathway

In mammals both purine ribonucleotide and purine deoxyribonucleotide monophosphates are degraded similarly using a final common pathway. The degradation reactions of purine ribonucleotide monophosphates are shown here as in [Fox81, Simoni07, Alexiou92] and [Pauly00]. Purine degradation in higher plants is very similar. However, plants contain an enzyme, guanosine deaminase (EC 3.5.4.15) that is not present in vertebrates [Roberts03]. The plant pathway is shown in purine nucleotides degradation I (plants).

Related pathways of eukaryotic purine de novo biosynthesis and purine salvage (reutilization) are shown in pathways superpathway of purine nucleotides de novo biosynthesis I, adenosine nucleotides degradation II and xanthine and xanthosine salvage. Rodent studues have demonstrated the catabolism of dietary purines by epithelial cells lining the gastrointestinal tract. These cells coexpress key purine catabolic enzymes [Witte91] .

The first step in degradation involves hydrolysis of purine ribonucleotides to ribonucleosides by 5'-nucleotidase (EC 3.1.3.5). As stated in [Fox81] this step can also be catalyzed by non-specific phosphatases such as EC 3.1.3.2 (not shown). AMP is deaminated to IMP (EC 3.5.4.6). Ribonucleosides are converted to purine bases and α-D-ribose-1-phosphate by phosphorolysis catalyzed by purine nucleoside phosphorylase (EC 2.4.2.1). adenosine is deaminated to inosine (EC 3.5.4.4), and guanine is deaminated to xanthine (EC 3.5.4.3). hypoxanthine is converted to xanthine, which is then converted to urate by the same enzyme, xanthine oxidoreductase (xanthine dehydrogenase EC 1.17.1.4, xanthine oxidase EC 1.17.3.2). This is the rate-limiting enzyme in the pathway. Reviewed in [Fox81, Okamoto08] and [George09]).

Also shown in this pathway is the degradation of XMP, an intermediate in the biosynthesis of GMP from IMP (see pathway superpathway of purine nucleotides de novo biosynthesis I). XMP degradation is included in some pathway diagrams [Alexiou92, Voet04]. XMP has been shown to be a substrate for 5'-nucleotidase EC 3.1.3.5 (reviewed in [Hunsucker05]). xanthosine, in addition to guanosine and inosine, is also a substrate for phosphorolysis by purine nucleoside phosphorylase EC 2.4.2.1 [Stoychev02] and reviewed in [Kulikowska04]. Unlike the prokaryotic purine nucleoside phosphorylase, adenosine is not a natural substrate for mammalian purine nucleoside phosphorylase (in [Stoychev02]).

The end product of purine catabolism depends upon the taxon of the organism in question. urate is the end product in humans, hominoid primates (i.e. chimpanzees, gorillas), new world monkeys, birds and reptiles. Higher primates contain a mutational inactivation of the liver enzyme uricase and cannot produce allantoin. allantoin is produced in non-primate mammals and old world monkeys, which produce uricase (see linked pathway urate degradation to allantoin I). Other organisms can also produce and further catabolize allantoin (see the pathway link in urate degradation to allantoin I and subsequent links). In [Johnson09] and in [Anzai05].

In humans, urate in blood enters the kidney but most is reabsorbed by a renal urate reabsorption system. Only approximately 10% is excreted. Kidney urate transporting systems are still under investigation. Both urate and allantoin are found in the urine of species that produce them (reviewed in [Anzai05]).

Abnormalities of the human pathway occur as a result of enzyme deficiencies, enzyme overactivities, and increased turnover of nucleic acids due to certain disorders. Conditions resulting in increased degradation of ATP, or decreased synthesis of ATP, also affect purine nucleotide degradation. After purine nucleotide dephosphorylation, the salvage (reutilization) reactions may be a major regulatory mechanism (reviewed in [Fox81]) (see pathways adenosine nucleotides degradation II and xanthine and xanthosine salvage). The enzymes of the pathway occur in a variety of mammalian tissues. In mice the highest levels of purine catabolic enzymes have been found in the proximal small intestine [Mohamedali93].

Subpathways: adenosine nucleotides degradation II , guanosine nucleotides degradation III , urate biosynthesis/inosine 5'-phosphate degradation

Variants: pseudouridine degradation , purine deoxyribonucleosides degradation , purine deoxyribonucleosides degradation I , purine nucleobases degradation I (anaerobic) , purine nucleobases degradation II (anaerobic) , purine nucleotides degradation I (plants) , purine ribonucleosides degradation

Unification Links: KEGG:map00230

Credits:
Created 09-Oct-2009 by Fulcher CA , SRI International


References

Alexiou92: Alexiou M, Leese HJ (1992). "Purine utilisation, de novo synthesis and degradation in mouse preimplantation embryos." Development 114(1);185-92. PMID: 1576959

Anzai05: Anzai N, Enomoto A, Endou H (2005). "Renal urate handling: clinical relevance of recent advances." Curr Rheumatol Rep 7(3);227-34. PMID: 15919000

Becker08: Becker MA, Sabina RL (2008). "PP07: new approaches, new knowledge, new challenges in human purine and pyrimidine metabolism." Nucleosides Nucleotides Nucleic Acids 27(6);547-53. PMID: 18600501

Cusa99: Cusa E, Obradors N, Baldoma L, Badia J, Aguilar J (1999). "Genetic analysis of a chromosomal region containing genes required for assimilation of allantoin nitrogen and linked glyoxylate metabolism in Escherichia coli." J Bacteriol 1999;181(24);7479-84. PMID: 10601204

DeMoll93: DeMoll E, Auffenberg T (1993). "Purine metabolism in Methanococcus vannielii." J Bacteriol 175(18);5754-61. PMID: 8376322

Fox81: Fox IH (1981). "Metabolic basis for disorders of purine nucleotide degradation." Metabolism 30(6);616-34. PMID: 6262603

George09: George J, Struthers AD (2009). "Role of urate, xanthine oxidase and the effects of allopurinol in vascular oxidative stress." Vasc Health Risk Manag 5(1);265-72. PMID: 19436671

Hunsucker05: Hunsucker SA, Mitchell BS, Spychala J (2005). "The 5'-nucleotidases as regulators of nucleotide and drug metabolism." Pharmacol Ther 107(1);1-30. PMID: 15963349

Johnson09: Johnson RJ, Sautin YY, Oliver WJ, Roncal C, Mu W, Gabriela Sanchez-Lozada L, Rodriguez-Iturbe B, Nakagawa T, Benner SA (2009). "Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?." J Comp Physiol B 179(1);67-76. PMID: 18649082

Kulikowska04: Kulikowska E, Kierdaszuk B, Shugar D (2004). "Xanthine, xanthosine and its nucleotides: solution structures of neutral and ionic forms, and relevance to substrate properties in various enzyme systems and metabolic pathways." Acta Biochim Pol 51(2);493-531. PMID: 15218545

Mohamedali93: Mohamedali KA, Guicherit OM, Kellems RE, Rudolph FB (1993). "The highest levels of purine catabolic enzymes in mice are present in the proximal small intestine." J Biol Chem 268(31);23728-33. PMID: 8226898

Nyhan05: Nyhan WL (2005). "Disorders of purine and pyrimidine metabolism." Mol Genet Metab 86(1-2);25-33. PMID: 16176880

Okamoto08: Okamoto K, Eger BT, Pai EF, Nishino T (2008). "Mammalian xanthine oxidoreductase - mechanism of transition from xanthine dehydrogenase to xanthine oxidase." FEBS J 275(13);3278-89. PMID: 18513323

Pauly00: Pauly DF, Pepine CJ (2000). "D-Ribose as a supplement for cardiac energy metabolism." J Cardiovasc Pharmacol Ther 5(4);249-58. PMID: 11150394

Pope09: Pope SD, Chen LL, Stewart V (2009). "Purine utilization by Klebsiella oxytoca M5al: genes for ring-oxidizing and -opening enzymes." J Bacteriol 191(3);1006-17. PMID: 19060149

Roberts03: Roberts EL (2003). "Guanosine deaminase in human serum and tissue extracts--a reappraisal of the products." Br J Biomed Sci 60(4);197-203. PMID: 14725335

Schultz01: Schultz AC, Nygaard P, Saxild HH (2001). "Functional analysis of 14 genes that constitute the purine catabolic pathway in Bacillus subtilis and evidence for a novel regulon controlled by the PucR transcription activator." J Bacteriol 183(11);3293-302. PMID: 11344136

Simoni07: Simoni RE, Gomes LN, Scalco FB, Oliveira CP, Aquino Neto FR, de Oliveira ML (2007). "Uric acid changes in urine and plasma: an effective tool in screening for purine inborn errors of metabolism and other pathological conditions." J Inherit Metab Dis 30(3);295-309. PMID: 17520339

Stoychev02: Stoychev G, Kierdaszuk B, Shugar D (2002). "Xanthosine and xanthine. Substrate properties with purine nucleoside phosphorylases, and relevance to other enzyme systems." Eur J Biochem 269(16);4048-57. PMID: 12180982

Voet04: Voet D, Voet JG (2004). "Biochemistry, 3rd Edition." John Wiley & Sons Inc.

Vogels76: Vogels GD, Van der Drift C (1976). "Degradation of purines and pyrimidines by microorganisms." Bacteriol Rev 40(2);403-68. PMID: 786256

Witte91: Witte DP, Wiginton DA, Hutton JJ, Aronow BJ (1991). "Coordinate developmental regulation of purine catabolic enzyme expression in gastrointestinal and postimplantation reproductive tracts." J Cell Biol 115(1);179-90. PMID: 1918135

Xi00: Xi H, Schneider BL, Reitzer L (2000). "Purine catabolism in Escherichia coli and function of xanthine dehydrogenase in purine salvage." J Bacteriol 182(19);5332-41. PMID: 10986234

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

Ahmad68: Ahmad SI, Barth PT, Pritchard RH (1968). "Properties of a mutant of Escherichia coli lacking purine nucleoside phosphorylase." Biochim Biophys Acta 161(2);581-3. PMID: 4875425

AlvesPereira08: Alves-Pereira I, Canales J, Cabezas A, Cordero PM, Costas MJ, Cameselle JC (2008). "CDP-alcohol hydrolase, a very efficient activity of the 5'-nucleotidase/UDP-sugar hydrolase encoded by the ushA gene of Yersinia intermedia and Escherichia coli." J Bacteriol 190(18);6153-61. PMID: 18641143

Amaya02: Amaya Y, Kawamoto S, Kashima Y, Okamoto K, Nishino T (2002). "Purification and characterization of multiple forms of rat liver xanthine oxidoreductase expressed in baculovirus-insect cell system." J Biochem 132(4);597-606. PMID: 12359075

Amaya90: Amaya Y, Yamazaki K, Sato M, Noda K, Nishino T (1990). "Proteolytic conversion of xanthine dehydrogenase from the NAD-dependent type to the O2-dependent type. Amino acid sequence of rat liver xanthine dehydrogenase and identification of the cleavage sites of the enzyme protein during irreversible conversion by trypsin." J Biol Chem 265(24);14170-5. PMID: 2387845

Applebury70: Applebury ML, Johnson BP, Coleman JE (1970). "Phosphate binding to alkaline phosphatase. Metal ion dependence." J Biol Chem 245(19);4968-76. PMID: 4319108

Asai07: Asai R, Matsumura T, Okamoto K, Igarashi K, Pai EF, Nishino T (2007). "Two mutations convert mammalian xanthine oxidoreductase to highly superoxide-productive xanthine oxidase." J Biochem 141(4);525-34. PMID: 17301076

Bennett03: Bennett EM, Li C, Allan PW, Parker WB, Ealick SE (2003). "Structural basis for substrate specificity of Escherichia coli purine nucleoside phosphorylase." J Biol Chem 278(47);47110-8. PMID: 12937174

Bennett03a: Bennett EM, Anand R, Allan PW, Hassan AE, Hong JS, Levasseur DN, McPherson DT, Parker WB, Secrist JA, Sorscher EJ, Townes TM, Waud WR, Ealick SE (2003). "Designer gene therapy using an Escherichia coli purine nucleoside phosphorylase/prodrug system." Chem Biol 10(12);1173-81. PMID: 14700625

Berry04a: Berry CE, Hare JM (2004). "Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications." J Physiol 555(Pt 3);589-606. PMID: 14694147

Bertosa14: Bertosa B, Mikleusevic G, Wielgus-Kutrowska B, Narczyk M, Hajnic M, Lescic Asler I, Tomic S, Luic M, Bzowska A (2014). "Homooligomerization is needed for stability: a molecular modelling and solution study of Escherichia coli purine nucleoside phosphorylase." FEBS J 281(7);1860-71. PMID: 24785777

Bezirdzhian86: Bezirdzhian KhO, Kocharian ShM, Akopian ZhI (1986). "[Isolation of the hexameric form of purine nucleoside phosphorylase from E. coli. Comparative study of trimeric and hexameric forms of the enzyme]." Biokhimiia 1986;51(7);1085-92. PMID: 3089333

Bezirdzhian87: Bezirdzhian KhO, Kocharian ShM, Akopian ZhI (1987). "[Hexamere purine nucleoside phosphorylase from Escherichia coli K-12. Kinetic analysis and mechanism of reaction]." Biokhimiia 52(11);1770-6. PMID: 3125860

Bezirdzhian87a: Bezirdzhian KhO, Kocharian ShM, Akopian ZhI (1987). "[Hexameric purine nucleoside phosphorylase II from Escherichia coli K-12. Physico-chemical and catalytic properties and stabilization with substrates]." Biokhimiia 1987;52(10);1624-31. PMID: 3122852

Bianchi03: Bianchi V, Spychala J (2003). "Mammalian 5'-nucleotidases." J Biol Chem 278(47);46195-8. PMID: 12947102

Bideon75: Bideon GM (1975). "Purification and characterization of a cyclic nucleotide-regulated 5'-nucleotidase from potatoe." Biochim Biophys Acta 384(2);443-57. PMID: 235999

Bonthron85: Bonthron DT, Markham AF, Ginsburg D, Orkin SH (1985). "Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency." J Clin Invest 76(2);894-7. PMID: 3839802

Borowiec06: Borowiec A, Lechward K, Tkacz-Stachowska K, Skladanowski AC (2006). "Adenosine as a metabolic regulator of tissue function: production of adenosine by cytoplasmic 5'-nucleotidases." Acta Biochim Pol 53(2);269-78. PMID: 16770441

Bowne02: Bowne SJ, Sullivan LS, Blanton SH, Cepko CL, Blackshaw S, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Daiger SP (2002). "Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa." Hum Mol Genet 11(5);559-68. PMID: 11875050

Boyle88: Boyle JM, Hey Y, Guerts van Kessel A, Fox M (1988). "Assignment of ecto-5'-nucleotidase to human chromosome 6." Hum Genet 81(1);88-92. PMID: 2848759

Bradshaw60: Bradshaw, W.H., Barker, H.A. (1960). "Purification and properties of xanthine dehydrogenase from Clostridium cylindrosporum." J. Biol. Chem. 235(12): 3620-3629.

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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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