Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic pathways of pterin de novo synthesis, interconversion and salvage which lead to the tetrahydrobiopterin cofactor of phenylalanine 4-monooxygenase, tyrosine 2-monooxygenase and tryptophan 5-monooxygenase are reviewed and data on the enzymes which catalyze the individual steps are presented. Analogies drawn between the inborn errors of tetrahydrobiopterin production and the Lesch-Nyhan syndrome, in which purine salvage is deficient, are used as a basis for the hypothesis that the neurological manifestations of the Lesch-Nyhan syndrome are due to neurotransmitter imbalance which stems from an imbalance of the aromatic amino acid monooxygenase activities which are themselves due to impaired pterin biosynthesis. The latter arises because, in the absence of the hypoxanthine phosphoribosyltransferase catalyzed purine salvage pathway, the supply of GTP for the GTP cyclohydrolase reaction, which is the first reaction on the pterin de novo synthesis pathway, is reduced. It is proposed that the different aromatic amino acid monooxygenases are differentially affected by this constrained pterin production. The activities of those most directly related to the quantal production of the cerebral neurotransmitters dopamine, norepinephrine and 5-hydroxytryptamine are affected whereas liver phenylalanine 4-monooxygenase activity is not overtly impaired. The results of different lines of research which support this concept are cited, as is direct evidence for a selective reduction of dopamine production in the basal ganglia of patients with the Lesch-Nyhan syndrome. It is proposed that lack of GMP for functions, other than its role in pterin de novo synthesis, accounts for the features of the Lesch-Nyhan syndrome which do not occur when only tetrahydrobiopterin production is deficient as in the inborn errors of tetrahydrobiopterin synthesis.
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PMID:Defects of tetrahydrobiopterin synthesis and their possible relationship to a disorder of purine metabolism (the Lesch-Nyhan syndrome). 286 76

We have examined several aspects of neurotransmitter function in the brains of mice carrying a deletion mutation in the gene encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). During the first 6 weeks of postnatal development, dopamine levels in whole-brain extracts from the mutant mice (HPRT-) failed to increase at rates comparable to normal animals, resulting in 40% lower dopamine levels throughout adulthood. Regional analysis in adult animals showed the caudoputamen to be the most severely affected region, with dopamine deficits of 48-64%. Dopamine levels in other regions were normal or less severely affected. The decrease in dopamine was accompanied by a decrease in tyrosine hydroxylase (TH) activity, the rate-limiting step in dopamine synthesis. Kinetic analysis of TH extracted from the caudoputamen of normal and HPRT- mice demonstrated a 45% decrease in Vmax with an increased affinity for the tetrahydropterin cofactor in the mutants. Labeling of midbrain dopamine neurons using TH immunohistochemistry revealed no obvious deficits in the number of midbrain dopamine neurons, but quantitative autoradiographic studies revealed significant reductions in the binding of 3H-N-[1-(2-benzo(beta)thiophenyl)cyclohexyl]piperidine (3H-BTCP) to dopamine uptake sites in the forebrain of the mutants. In contrast to these abnormalities of the dopamine systems in the mutant mice, other neurotransmitter systems appeared relatively unaffected. Norepinephrine, 5-HT, tryptophan hydroxylase, and glutamic acid decarboxylase were present at normal levels in the brains of the mutants. ChAT activity was slightly lower than normal in the caudoputamen of the mutant animals, but was normal in all other brain regions examined. These results indicate that HPRT deficiency is associated with a relatively specific deficit in basal ganglia dopamine systems that emerges during the first 2 months of postnatal development.
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PMID:Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. 750 65

Many cancer patients receiving chemotherapy experience fatigue, disturbed circadian rhythms, anorexia and a variety of dyspeptic symptoms including nausea. There is no animal model for this 'chemotherapy-related malaise' so we investigated the behavioural and molecular effects of a potent chemotherapeutic agent, cisplatin (CP, 6 mg/kg, i.p.) in rats. Dark-phase horizontal locomotor activity declined post-CP reaching a nadir on day 3 (P < 0.001), before recovering after 7 days. CP's effect was most marked in the late part (05.00-07.00) of the dark-phase. Food intake reached a nadir (P > 0.001) at 2 days, coincident with an increase in gastric contents (cisplatin 9.04+/-0.8 vs. saline 2.32+/-0.3 g; P < 0.001). No changes occurred in hypothalamic mRNA expression for AGRP, NPY, HCRT, CRH, IL-1, IL-6, TNFalpha, ABCG1, SLC6A4, PPIA and HPRT mRNA but tryptophan hydroxylase (TPH) mRNA was decreased (47%, P < 0.05) at day 21 post-CP. This shows that despite marked behavioural effects of cisplatin, only a discrete change (TPH) was found in hypothalamic mRNA expression and that occurred when the animals' behaviour had recovered. Findings are discussed in relation to the neuropharmacology of chemotherapy-induced malaise.
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PMID:Behavioural and hypothalamic molecular effects of the anti-cancer agent cisplatin in the rat: A model of chemotherapy-related malaise? 1644 63