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|
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 184.108.40.206) 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 220.127.116.11). As stated in [Fox81] this step can also be catalyzed by non-specific phosphatases such as EC 18.104.22.168 (not shown). AMP is deaminated to IMP (EC 22.214.171.124). Ribonucleosides are converted to purine bases and α-D-ribose-1-phosphate by phosphorolysis catalyzed by purine nucleoside phosphorylase (EC 126.96.36.199). adenosine is deaminated to inosine (EC 188.8.131.52), and guanine is deaminated to xanthine (EC 184.108.40.206). hypoxanthine is converted to xanthine, which is then converted to urate by the same enzyme, xanthine oxidoreductase (xanthine dehydrogenase EC 220.127.116.11, xanthine oxidase EC 18.104.22.168). 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 22.214.171.124 (reviewed in [Hunsucker05]). xanthosine, in addition to guanosine and inosine, is also a substrate for phosphorolysis by purine nucleoside phosphorylase EC 126.96.36.199 [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].
Variants: pseudouridine degradation, purine deoxyribonucleosides degradation I, purine deoxyribonucleosides degradation II, purine nucleobases degradation I (anaerobic), purine nucleobases degradation II (anaerobic), purine nucleotides degradation I (plants), purine ribonucleosides degradation
Unification Links: KEGG:map00230
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