Purine Metabolism Information
Many organisms have metabolic pathways to synthesize and break down purines.
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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.
GMP
- IMP dehydrogenase converts IMP into XMP
- GMP synthase converts XMP into GMP
- GMP reductase converts GMP back into IMP
AMP
- adenylosuccinate synthase converts IMP to adenylosuccinate
- adenylosuccinate lyase converts adenylosuccinate into AMP
- AMP deaminase converts AMP back into IMP
Degradation
Purines are metabolised by several enzymes:
Guanine
- A nuclease frees the nucleotide
- A nucleotidase creates guanosine
- Purine nucleoside phosphorylase converts guanosine to guanine
- Guanase converts guanine to xanthine
- Xanthine oxidase (a form of xanthine oxidoreductase) catalyzes the oxidation of xanthine to uric acid
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 catalyzes the biotransformation of hypoxanthine to xanthine
- Xanthine oxidoreductase acts upon xanthine to create uric acid
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.)
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.
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.
Mycophenolate mofetil is an immunosuppressant drug used to prevent rejection in organ transplantation; it inhibits purine synthesis by blocking inositol monophsophate dehydrogenase. Also Methotrexate indirectly inhibits purine synthesis by blocking the metabolism of folic acid (it is an inhibitor of the Dihydrofolate reductase).
Allopurinol is a drug that 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.
External links
- The Medical Biochemistry Page
- Purine metabolism - Reference pathway
- PUMPA: Purine Metabolic Patients’ Association
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Categories: Purines
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