Purine metabolism

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Many organisms have metabolic pathways to synthesize and break down purines.

Contents 1 Synthesis 1.1 GMP 1.2 AMP 2 Degradation 2.1 Guanine 2.2 Adenine 3 Salvage 4 Disorders 5 Pharmacotherapy 6 External links

[edit] Synthesis

Purines are biologically synthesized as nucleotides (bases attached to ribose 5-phosphate). The committed step is amidophosphoribosyltransferase.

Both adenine and guanine are derived from the nucleotide inosine monophosphate (IMP), which is synthesised on a pre-existing ribose-phosphate through a complex pathway using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate ions transferred from the coenzyme tetrahydrofolate.

[edit] GMP

• IMP dehydrogenase converts IMP into XMP
• GMP synthase converts XMP into GMP
• GMP reductase converts GMP back into IMP

[edit] AMP

• adenylosuccinate synthase converts IMP to adenylosuccinate
• adenylosuccinate lyase converts adenylosuccinate into AMP
• AMP deaminase converts AMP back into IMP

[edit] Degradation

Purines are metabolised by several enzymes:

[edit] Guanine

• A nuclease frees the nucleotide
• A nucleotidase creates guanosine
• Purine nucleoside phosphorylase converts guanosine to guanine
• Guanase converts guanine to xanthine
• Xanthine oxidase converts xanthine to uric acid

[edit] Adenine

• A nuclease frees the nucleotide
  • A nucleotidase creates adenosine, then adenosine deaminase creates inosine
  • Alternatively, AMP deaminase creates inosinic acid, then a nucleotidase creates inosine
• Purine nucleoside phosphorylase acts upon inosine to create hypoxanthine
• Xanthine oxidoreductase acts upon hypoxanthine to create xanthine
• Xanthine oxidoreductase acts upon xanthine to create uric acid

[edit] Salvage

Purines from turnover of nucleic acids (or from food) can also be salvaged and reused in new nucleotides.

• The enzyme adenine phosphoribosyltransferase (APRT) salvages adenine.
• The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) salvages guanine and hypoxanthine. (Genetic deficiency of HGPRT causes Lesch-Nyhan syndrome.)

[edit] Disorders

When a defective gene causes gaps to appear in the metabolic recycling process for purines and pyrimidines, these chemicals are not metabolised properly, and adults or children can suffer from any one of twenty-eight hereditary disorders, possibly some more as yet unknown. Symptoms can include gout, anaemia, autism, epilepsy, delayed development, deafness, compulsive self-biting, kidney failure or stones, or loss of immunity.

[edit] Pharmacotherapy

Modulation of purine metabolism has pharmacotherapeutic value.

Purine synthesis inhibitors inhibit the proliferation of cells, especially leukocytes. These inhibitors include azathioprine, an immunosuppressant used in organ transplantation, autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease such as Crohn's disease and ulcerative colitis.

Allopurinol is a drug which inhibits the enzyme xanthine oxidoreductase and thus lowers the level of uric acid in the body. This may be useful in the treatment of gout, which is a disease caused by excess uric acid forming crystals in joints.

[edit] External links

• The Medical Biochemistry Page
• Purine metabolism - Reference pathway
• PUMPA: Purine Metabolic Patients’ Association

v • d • e Metabolism (Catabolism, Anabolism) General Metabolic pathway · Metabolic network · Cellular respiration (Anaerobic/Aerobic) Specific paths Protein metabolism Protein synthesis · Amino acid synthesis · Catabolism Nucleotide metabolism: Purine metabolism  · Nucleotide salvage · Pyrimidine metabolism Carbohydrate metabolism Anabolism Gluconeogenesis · Glycogenesis · Photosynthesis (Carbon fixation) Carbohydrate catabolism Glycolysis · Glycogenolysis · Fermentation (ABE, Ethanol, Lactic acid)  · Cellular respiration · Xylose metabolism Other Pentose phosphate pathway Lipid metabolism Fatty acid metabolism Fatty acid degradation (Lipolysis, Beta oxidation) · Fatty acid synthesis Other Eicosanoid metabolism · Sphingolipid metabolism · Steroid metabolism Other Metal metabolism (Iron metabolism) · Ethanol metabolism

v • d • e Metabolism: amino acid metabolism - nucleotide enzymes Purine metabolism Anabolism R5P->IMP: Ribose-phosphate diphosphokinase - Amidophosphoribosyltransferase - Phosphoribosylglycinamide formyltransferase - AIR synthetase (FGAM cyclase) - Phosphoribosylaminoimidazole carboxylase - Phosphoribosylaminoimidazolesuccinocarboxamide synthase - IMP synthase IMP->AMP: Adenylosuccinate synthase - Adenylosuccinate lyase - reverse (AMP deaminase) IMP->GMP: IMP dehydrogenase - GMP synthase - reverse (GMP reductase) Nucleotide salvage Hypoxanthine-guanine phosphoribosyltransferase - Adenine phosphoribosyltransferase Catabolism Adenosine deaminase - Purine nucleoside phosphorylase - Guanine deaminase - Xanthine oxidase - Urate oxidase Pyrimidine metabolism Anabolism CAD (Carbamoyl phosphate synthase II, Aspartate carbamoyltransferase, Dihydroorotase) Dihydroorotate dehydrogenase - Orotidine 5'-phosphate decarboxylase/Uridine monophosphate synthetase CTP synthase Catabolism Dihydropyrimidine dehydrogenase - Dihydropyrimidinase/DPYS - Beta-ureidopropionase/UPB1 Deoxyribonucleotides Ribonucleotide reductase - Nucleoside-diphosphate kinase - DCMP deaminase - Thymidylate synthase - Dihydrofolate reductase see also disorders, intermediates

v • d • e Nucleotide metabolic intermediates Purine metabolism Anabolism R5P→IMP: R5P · PRPP · PRA · GAR · FGAR · FGAM · AIR · CAIR · SAICAR · AICAR · FAICAR IMP→AMP: Adenylosuccinate IMP→GMP: Xanthosine monophosphate Catabolism Hypoxanthine · Xanthine · Uric acid · 5-Hydroxyisourate Pyrimidine metabolism Anabolism Carbamoyl phosphate · Carbamoyl aspartic acid · 4,5-Dihydroorotic acid · Orotic acid · Orotidine 5'-monophosphate · Uridine monophosphate Catabolism uracil: Dihydrouracil · 3-Ureidopropionic acid · β-Alanine thymine: Dihydrothymine · β-Ureidoisobutyric acid · 3-Aminoisobutyric acid see also enzymes, disorders

v • d • e Inborn error of purine-pyrimidine metabolism (E79, 277.2) Purine metabolism Anabolism Adenylosuccinate lyase deficiency - Myoadenylate deaminase deficiency Nucleotide salvage Lesch-Nyhan syndrome/Hyperuricemia - Adenine phosphoribosyltransferase deficiency Catabolism Adenosine deaminase deficiency - Purine nucleoside phosphorylase deficiency - Xanthinuria - Gout Pyrimidine metabolism Anabolism Orotic aciduria Catabolism Dihydropyrimidine dehydrogenase deficiency see also nucleotide metabolism, intermediates