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)

Lesch-Nyhan syndrome is a hereditary disorder of purine metabolism causing overproduction of uric acid and neurological problems including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The syndrome is caused by a defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which converts guanine and hypoxanthine to the nucleotides GMP and IMP. There is evidence that the neurological problems are due to an adverse effect of the HPRT deficiency on the survival and/or development of dopaminergic neurons, specifically. Here we report that HPRT-deficient PC12 mutants that have a normal or near normal dopamine content (55-97% of that of wild-type cells) fail to undergo neuronal differentiation induced by nerve growth factor (NGF) when the de novo pathway of purine synthesis is partially inhibited. However, nerve growth factor-induced differentiation is near normal under these conditions in PC12 HPRT-deficient mutants containing much lower dopamine levels (<8% of that of wild type cells), indicating a neurotoxic effect of the endogenous dopamine in the mutants. The degree of inhibition of the de novo pathway of purine synthesis was the same in both classes of HPRT-deficient mutants. Expression of BCl-2 in a PC12 mutant that has a normal dopamine content allowed partial NGF-induced differentiation suggesting that the apoptotic pathway might be involved in the failure of differentiation when the de novo pathway of purine synthesis is partially inhibited.
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PMID:Impaired differentiation of HPRT-deficient dopaminergic neurons: a possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome. 967 Sep 94

Purines are a class of small organic molecules that are essential for all cells. They play critical roles in neuronal differentiation and function. Their importance is highlighted by several inherited disorders of purine metabolism, such as Lesch-Nyhan disease, which is caused by a deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Despite the known importance of purines in the nervous system, knowledge regarding their metabolism in neurons is limited. In the current studies, purine pools and their metabolism were examined in rat PC6-3 cells, a PC12 pheochromocytoma subclone that undergoes robust differentiation with nerve growth factor. The results were compared with five new independent PC6-3 subclones with defective purine recycling because of different mutations affecting HGprt enzyme activity. The results demonstrate an increase in most purines and in energy state following neuronal differentiation, as well as specific abnormalities when purine recycling is lost. The loss of HGprt-mediated purine recycling also is associated with significant loss of dopamine and related metabolites in the mutant PC6-3 lines, suggesting an important connection between purine and dopamine pathways. These results provide insights into how purine pools and metabolism change with neuronal differentiation, and how specific enzyme defects may cause neuronal dysfunction. Differentiation of dopaminergic PC6-3 cells is accompanied by increased purine pools and energy state. The lack of a functional purine recycling pathway causes purine limitation in both undifferentiated and differentiated cells, as well as profound loss of dopamine content. The results imply an unknown mechanism by which intracellular purine levels regulate dopamine levels.
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PMID:Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling. 2385 90

The importance of specific pathways of purine metabolism for normal brain function is highlighted by several inherited disorders, such as Lesch-Nyhan disease (LND). In this disorder, deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt), causes severe neurological and behavioral abnormalities. Despite many years of research, the mechanisms linking the defect in purine recycling to the neurobehavioral abnormalities remain unclear. In the current studies, an unbiased approach to the identification of potential mechanisms was undertaken by examining changes in protein expression in a model of HGprt deficiency based on the dopaminergic rat PC6-3 line, before and after differentiation with nerve growth factor (NGF). Protein expression profiles of 5 mutant sublines carrying different mutations affecting HGprt enzyme activity were compared to the HGprt-competent parent line using the method of stable isotopic labeling by amino acids in cell culture (SILAC) followed by denaturing gel electrophoresis with liquid chromatography and tandem mass spectrometry (LC-MS/MS) of tryptic digests, and subsequent identification of affected biochemical pathways using the Database for Annotation, Visualization and Integrated Discovery (DAVID) functional annotation chart analysis. The results demonstrate that HGprt deficiency causes broad changes in protein expression that depend on whether the cells are differentiated or not. Several of the pathways identified reflect predictable consequences of defective purine recycling. Other pathways were not anticipated, disclosing previously unknown connections with purine metabolism and novel insights into the pathogenesis of LND.
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PMID:Consequences of impaired purine recycling on the proteome in a cellular model of Lesch-Nyhan disease. 2576 94