 | This article includes a list ofgeneral references, butit lacks sufficient correspondinginline citations. Please help toimprove this article byintroducing more precise citations.(July 2014) (Learn how and when to remove this message) |
Purine metabolism refers to themetabolic pathways to synthesize and break downpurines that are present in many organisms.
Purines are biologically synthesized asnucleotides and in particular as ribotides, i.e. bases attached toribose 5-phosphate. Bothadenine andguanine are derived from the nucleotideinosine monophosphate (IMP), which is the first compound in the pathway to have a completely formed purine ring system.
Inosine monophosphate is synthesized on a pre-existing ribose-phosphate through a complex pathway (as shown in the figure on the right). The source of thecarbon andnitrogen atoms of the purine ring, 5 and 4 respectively, come from multiple sources. The amino acidglycine contributes all its carbon (2) and nitrogen (1) atoms, with additional nitrogen atoms from glutamine (2) andaspartic acid (1), and additional carbon atoms fromformyl groups (2), which are transferred from thecoenzymetetrahydrofolate as10-formyltetrahydrofolate, and a carbon atom frombicarbonate (1). Formyl groups build carbon-2 and carbon-8 in the purine ring system, which are the ones acting as bridges between two nitrogen atoms.
A key regulatory step is the production of 5-phospho-α-D-ribosyl 1-pyrophosphate (PRPP) byribose-phosphate diphosphokinase, which is activated byinorganic phosphate and inactivated by purine ribonucleotides. It is not the committed step to purine synthesis because PRPP is also used in pyrimidine synthesis and salvage pathways.
The first committed step is the reaction of PRPP,glutamine and water to5'-phosphoribosylamine (PRA),glutamate, andpyrophosphate - catalyzed byamidophosphoribosyltransferase, which is activated by PRPP and inhibited byAMP,GMP andIMP.
In the second step reactPRA,glycine and ATP to createGAR, ADP, and pyrophosphate - catalyzed byphosphoribosylamine—glycine ligase (GAR synthetase). Due to the chemical lability of PRA, which has a half-life of 38 seconds at PH 7.5 and 37 °C, researchers have suggested that the compound is channeled from amidophosphoribosyltransferase to GAR synthetasein vivo.[1]
Steps 3 through 10 are catalyzed by the following enzymes:
3.phosphoribosylglycinamide formyltransferase.
4.phosphoribosylformylglycinamidine synthase.
5.AIR synthetase (FGAM cyclase).
6.phosphoribosylaminoimidazole carboxylase.
7.phosphoribosylaminoimidazolesuccinocarboxamide synthase.
The products AICAR and fumarate move on to two different pathways. AICAR serves as the reactant for the ninth step, while fumarate is transported to the citric acid cycle which can then skip the carbon dioxide evolution steps to produce malate. The conversion of fumarate to malate is catalyzed by fumarase. In this way, fumarate connects purine synthesis to the citric acid cycle.[2]
9.phosphoribosylaminoimidazolecarboxamide formyltransferase.
10.Inosine monophosphate synthase.
Ineukaryotes the second, third, and fifth step are catalyzed bytrifunctional purine biosynthetic protein adenosine-3, which is encoded by the GART gene.
Both ninth and tenth step are accomplished by a single protein named Bifunctional purine biosynthesis protein PURH, encoded by the ATIC gene.
Purines are metabolised by severalenzymes:
The formation of 5'-phosphoribosylamine from glutamine and PRPP catalysed by PRPP amino transferase is the regulation point for purine synthesis. The enzyme is an allosteric enzyme, so it can be converted from IMP, GMP and AMP in high concentration binds the enzyme to exerts inhibition while PRPP is in large amount binds to the enzyme which causes activation. So IMP, GMP and AMP are inhibitors while PRPP is an activator. Between the formation of 5'-phosphoribosyl, aminoimidazole and IMP, there is no known regulation step.
Purines from turnover of cellular nucleic acids (or from food) can also be salvaged and reused in new nucleotides.
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 includegout, anaemia, epilepsy, delayed development, deafness, compulsive self-biting, kidney failure or stones, or loss of immunity.
Purine metabolism can have imbalances that can arise from harmful nucleotide triphosphates incorporating into DNA and RNA which further lead to genetic disturbances and mutations, and as a result, give rise to several types of diseases. Some of the diseases are:
Modulation of purine metabolism has pharmacotherapeutic value.
Purine synthesis inhibitors inhibit the proliferation of cells, especiallyleukocytes. These inhibitors includeazathioprine, an immunosuppressant used inorgan transplantation,autoimmune disease such asrheumatoid arthritis or inflammatory bowel disease such asCrohn's disease andulcerative colitis.
Mycophenolate mofetil is an immunosuppressant drug used to prevent rejection in organ transplantation; it inhibits purine synthesis by blocking inosine monophosphate dehydrogenase (IMPDH).[5]Methotrexate also indirectly inhibits purine synthesis by blocking the metabolism offolic acid (it is an inhibitor of thedihydrofolate 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.
In order to understand howlife arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausibleprebiotic conditions. Nam et al.[6] demonstrated the direct condensation of purine and pyrimidine nucleobases with ribose to give ribonucleosides in aqueous microdroplets, a key step leading to RNA formation. Also, a plausible prebiotic process for synthesizing purine ribonucleosides was presented by Becker et al.[7]
Organisms in all three domains of life,eukaryotes,bacteria andarchaea, are able to carry outde novobiosynthesis of purines. This ability reflects the essentiality of purines for life. The biochemical pathway of synthesis is very similar in eukaryotes and bacterial species, but is more variable among archaeal species.[8] A nearly complete, or complete, set of genes required for purine biosynthesis was determined to be present in 58 of the 65 archaeal species studied.[8] However, also identified were seven archaeal species with entirely, or nearly entirely, absent purine encoding genes. Apparently the archaeal species unable to synthesize purines are able to acquire exogenous purines for growth.,[8] and are thus similar to purine mutants of eukaryotes, e.g. purine mutants of theAscomycete fungusNeurospora crassa,[9] that also require exogenous purines for growth.