Hypoxanthine-guanine-phosphoribosyltransferase

P5. Patel, P. I., Caskey, C. T., and Chinault, C. A., Fine structure of the human hypoxanthine guanine phosphoribosyltransferase gene. Mol. Cell. Biol. 6,393-403 (1986),... 

The free bases of the purines can be salvaged to spare de novo synthesis. The only hard thing is remembering what the names stand for. HGPRTase is hypoxanthine-guanine phosphoribosyltransferase, and it makes both IMP and GMP. A separate enzyme exists for the salvage of adenine. The salvage pathways are included in Fig. 19-1. 

Puig, J. G., Torres, R. J., Mateos, E A. et al. The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. Medicine (Baltimore) 80 102-112,2001. 

EphR erythropoietin-producing hepatocellular receptor HGPRT hypoxanthine-guanine phosphoribosyltransferase... 

Deficiencies of adenosine deaminase and hypoxanthine-guanine phosphoribosyltransferase or a low activity of thymi-dylate synthase are responsible for clinical disorders. 

Lesch-Nyhan syndrome A deficiency of hypoxanthine-guanine phosphoribosyltransferase results in accumulation of purine bases (Chapter 10). This causes a marked increase in the plasma level of uric acid, and hence can give rise to gout, but it also causes a severe neurological disorder, known as Lesch-Nyhan syndrome, the symptoms of which include... 

HGPRT Hypoxanthine guanine phosphoribosyltransferase MES 2- (N-Morpholino) ethanesulfonic acid... 

Lipopolysaccharide 3-alpha-galactosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase. 

The following reactions are catalyzed by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). 

Ullman B, Allen . Hypoxanthine-guanine phosphoribosyltransferase in trypanosomatids a rational target for antiparasitic chemotherapy. In Boothroyd J, ed. Molecular Approaches to Parasitology. New York Wiley-Liss, Inc., 1995 123-141. 

Table 7.1.4 Concentration range of purine and pyrimidine metabolites in urine (pmol/mmol creatinine) from patients. ADA Adenosine deaminase, APRT adenine phosphoribosyltransferase, ASA adenylosuccinate lyase, DHP dihydropyrimidinase, DPD dihydropyrimidine dehydrogenase, HGPRT hypoxanthine-guanine phosphoribosyltransferase, PNP purine nucleoside phosphorylase, TP thymidine phosphorylase, UMPS uridine monophosphate synthase, / -UP fi-ureidopropionase... 

The activity of hypoxanthine-guanine phosphoribosyltransferase, adenine phos-phoribosyltransferase, adenosine deaminase, and purine nucleoside phosphorylase can be determined in dried blood spots using an HPLC-linked assay [3]. 

A condition known as Lesch-Nyhan syndrome is one of the primary causes of gout. An X-linked recessive trait occurring in males, this condition involves a tremendous overproduction of uric acid due to a deficiency of one of the enzymes involved in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Other abnormalites lead to mental retardation and aggressive behavior. An obvious symptom of the condition is self-mutilation. 

Knaap, A.G.A.C. Langebroek, P.B. (1985) Assays for the induction of gene mutations at the thymidine kinase locus and the hypoxanthine guanine phosphoribosyltransferase locus in L5178Y mouse lymphoma cells in culture. Prog. Mutat. Res., 5, 531-536... 

Free guanine and hypo xanthine (the deamination product of adenine Fig. 22-45) are salvaged in the same way by hypoxanthine-guanine phosphoribosyltransferase. A similar salvage pathway exists for pyrimidine bases in microorganisms, and possibly in mammals. 

TA genetic lack of hypoxanthine-guanine phosphoribosyltransferase activity, seen almost exclusively in male children, results in a bizarre set of symptoms called Lesch-Nyhan syndrome. Children with this genetic disorder, which becomes manifest by the age of 2 years, are sometimes poorly coordinated and mentally retarded. In addition, they are extremely hostile and show compulsive self-destructive tendencies they mutilate themselves by biting off their fingers, toes, and lips. 

This is an X-linked, recessive, inherited disorder associated with a virtually complete deficiency of hypoxanthine-guanine phosphoribosyltransferase and, therefore, the inability to salvage hypoxanthine or guanine. 

Purines that result from the normal turnover of cellular nucleic acids can be reconverted into nucleoside triphosphates and used by the body. Thus, they are "salvaged" instead of being degraded to uric acid. PRPP is the source of the ribose-phosphate, and the reactions are catalyzed by adenine phosphoribosyltransferase, and hypoxanthine-guanine phosphoribosyltransferase (HPRT). 

In mammals specific enzymes for converting purine bases to nucleotides are present in many organs, and in heart muscle this may be the main source of purine nucleotides. The most important of these enzymes is hypoxanthine-guanine phosphoribosyltransferase, which catalyzes the formation of IMP from hypoxanthine and GMP from guanine ... 

The role of hypoxanthine-guanine phosphoribosyltransferase in purine salvage has been confirmed by the abnormally high excretion of purines (as uric acid) in humans who lack hypoxanthine-guanine phosphoribosyltransferase. Studies of purine metabolism in cultures of cells from patients with this hereditary disorder also support this conclusion. 

Besides this salvage role, hypoxanthine-guanine phosphoribosyltransferase is probably important also for the transfer of purines from liver to other tissues. Purine biosynthesis de novo is especially active in the liver, and extrahe-patic cells that have a low capacity for the synthesis of purines de novo, such as erythrocytes and bone marrow cells, depend on uptake of hypoxanthine and xanthine from the... 

Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP in many tissues, by a reaction similar to that of hypoxanthine-guanine phosphoribosyltransferase, but is quite distinct from the latter. It plays a minor role in purine salvage since adenine is not a significant product of purine nucleotide catabolism (see below). The function of this enzyme seems to be to scavenge small amounts of adenine that are produced during intestinal digestion of nucleic acids or in the metabolism of 5 -deoxy-5 -methylthioadenosine, a product of polyamine synthesis. 

Mechanism of overproduction of purine nucleotides in the congenital deficiency of hypoxanthine-guanine phosphoribosyltransferase. The loss of the transferase prevents the recycling of hypoxanthine and guanine. This increases uric acid production as well as the de novo synthesis of purine nucleotides. 

In some diseases, excessive amounts of purines are produced in the body, leading to accumulation of urate. Patients with Lesch-Nyhan syndrome lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HG-PRTase). Children born with this disorder are mentally retarded and prone to self-mutilation. They produce excessive amounts of purines due to accumulation of P-Rib-PP which stimulates the first enzyme of the pathway, amido PRTase (Fig. 15-16). The excess purines are degraded via the reactions... 

Figure 9.98 HPLC elution profiles of an incubation mixture to study hypoxanthine/ guanine phosphoribosyltransferase. The reaction was initiated by the addition of the enzyme mixture, and aliquots were injected onto the HPLC column at 10-minute intervals as indicated on the z axis. The solid peaks represent hypoxanthine, which decreases with time, while the hatched peaks describe the formation of IMP. (From Jahngen and Rossomando, 1984.)...

The enzyme hypoxanthine/guanine phosphoribosyltransferase (HG-PRTase) is an example of an enzyme activity that can utilize either of two substrates. In this case, both hypoxanthine and guanine can be acceptors of the phosphate donated by phosphoribosyl pyrophosphate (PRibPP). Since it is possible to separate hypoxanthine from guanine and the IMP from GMP, it is possible to study the utilization of one substrate in the presence of the other, a condition that parallels that expected in a cell. 

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