Purine phosphoribosyl transferase

The absence of de novo purine nucleotide synthesis in protozoal parasites as well as in the trematode Schistosoma mansoni is reflected in the relative importance of purine phosphoribosyl transferases in many parasite species. 

Act on enzymes indispensable to pare Purine phosphoribosyl transferase sites Protozoa Allopurinol... 

The potential of the purine phosphoribosyl transferases (APRTase, XPRTase, HGPRTase) and AdK as targets for antiparasitic chemotherapy stems from the major role of these enzymes in purine acquisition by the trypanosomatid parasites. However, because of the existence of various alternative purine salvage pathways (Fig. 1), it is conceivable that inhibition of a single enzyme would not kill the parasite. This has been confirmed by elaborate genetic investigation... 

Some very interesting differences can exist between an enzyme in cancerous tissue and the analogous enzyme in normal tissues. For instance, the specific activity of purine phosphoribosyl transferase in mouse tumour cells (Ehrlich ascites) had between 15 and 60 times the activity of that in liver, brain, spleen, heart, or kidneys of the same animal (Murray, 1966). Again, the adenylate kinase of a rat hepatoma was 22 times more strongly inhibited than the analogous enzyme from healthy rat muscle using an ATP analogue P P -his-[8- (ethylthio) adenosine-5 -]pentaphosphate (Kappler et at., 1982). 

STABILIZATION BY PRPP OF CELLULAR PURINE PHOSPHORIBOSYL-TRANSFERASES AGAINST INACTIVATION BY FREEZING AND THA ING. STUDY OF NORMAL AND HYPOXANTHINE-GUANINE PHOSPHORIBOSYL-TRANSFERASE DEFICIENT HUMAN FIBROBLASTS... 

GENETIC CONTROL OF BACTERIAL PURINE PHOSPHORIBOSYL-TRANSFERASES AND AN APPROACH TO GENE ENRICHMENT... 

A systematic study of purine phosphoribosyl transferases has led to the discovery of a deficiency of adenine phosphoribosyl transferase (APRT) in a patient with gout and several members of his family, who were either suffering from gout, hyperuricaemia or were normal. 

Screening the purine phosphoribosyl transferases in patients with gout has demonstrated an adenine phosphoribosyl transferase deficiency in one of them. 

Guanine Phosphoribosyl Transferase. Guanine phosphoribosyl transferase (GPRT) is one of the enzymes of the purine salvage pathway, which is needed by protozoa because they lack the ability to synthesize purine nucleotides. 

Two phosphoribosyl transferases then convert adenine to AMP and hypoxanthine and guanine to IMP or GMP (Figure 34-4). A second salvage mechanism involves phosphoryl transfer from ATP to a purine ri-bonucleoside (PuR) ... 

Most cases of hyperuricemia are due to disturbed uric acid excretion via the kidneys (1). A high-purine diet (e.g., meat) may also have unfavorable effects (2). A rare hereditary disease, Lesch-Nyhan syndrome, results from a defect in hypoxanthine phosphoribosyl-transferase (A, enzyme [1]). The impaired recycling of the purine bases caused by this leads to hyperuricemia and severe neurological disorders. 

Azathioprine [a zah THIO preen] has been the cornerstone of immunosuppressive therapy over the last several decades. It has a nitroimidazoloyl side chain attached to the sulfur of 6-mercap-topurine, which is removed by non-enzymatic reduction in the body by glutathione to yield 6-mercaptopurine (6-MP). The latter is then converted to the corresponding nucleotide, thioinosinic acid (TIMP), by the salvage pathway enzyme, hypoxanthine-gua-nine phosphoribosyl transferase. The immunosuppressant effects of azathioprine are due to this fraudulent nucleotide. (See pp. 380-381 for a discussion of 6-MP s mechanism of action, resistance, pharmacokinetics, and adverse effects.) Because of their rapid proliferation in the immune response, and their dependence on de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. The drug has little effect on suppressing a secondary immune response. 

The salvage pathway does not involve the formation of new heterocyclic bases but permits variation according to demand of the state of the base (B), i.e. whether at the nucleoside (N), or nucleoside mono- (NMP), di- (NDP) or tri- (NTP) phosphate level. The major enzymes and routes available (Scheme 158) all operate with either ribose or 2-deoxyribose derivatives except for the phosphoribosyl transferases. Several enzymes involved in the biosynthesis of purine nucleotides or in interconversion reactions, e.g. adenosine deaminase, have been assayed using a method which is based on the formation of hydrogen peroxide with xanthine oxidase as a coupling enzyme (81CPB426). 

Note PNP = Purine Nucleotide Phosphorylase HGPRT = Hypoxanthine-Guanine Phosphoribosyl Transferase... 

Most of the free purines derived from the breakdown of DNA, RNA, and nucleotides in the diet are catabolized to xanthine and then to uric acid in the gut mucosa. The AMP and GMP biosynthesized in the body can also be bmken down to free purines, such as adenine, guanine, and hypoxanthine. These purines, in contrast to those derived frcim the diet, are largely reused for the synthesis of ATP and GTP- They are first converted back to AMP or GMP in a pathway of reutiliza-lion called the purine salvage pathway. For example, adenine phosphoribosyl-transferase (PRPP) catalyzes the conversion of adenine to AMP. Here, PRPP serves as the source of the phosphoribose group. Pyrophosphate is a product of the reaction. 

Figure 7-21. Salvage of the purine bases guanine, adenine, and hypoxanthine occurs in reactions catalyzed by phosphoribosyl transferases.

Lesch-Nyhan syndrome is caused by a defective hypoxanthine-gua-nine phosphoribosyl transferase (HGPRT). Purine bases cannot be salvaged (i.e., reconverted to nucleotides). The purines are converted to uric acid, which rises in the blood. Mental retardation and self-mutilation are characteristics of the disease. 

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