Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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 disease (LND) is a rare, X-linked genetic disorder that involves the nearly complete absence of an enzyme (hypoxanthine-guanine phosphoribosyltransferase, or HPRT) that is essential for purine salvage. In addition to hyperuricemia, all patients with classic LND suffer from movement disorder and compulsive self-injury, and most have mental retardation. Patients with partial HPRT deficiency (variants) always have hyperuricemia and often have neurologic abnormalities, but do not self-injure and usually are described as having normal intelligence. Here we compare 15 patients with LND to 9 variants and 13 normal adolescents and adults. Testing revealed unambiguous and qualitatively similar cognitive deficits in both patient groups. The variants produced scores that were intermediate between those of patients with LND and normal participants on nearly every cognitive measure. We discuss these findings in terms of what is known about the neuropathology of LND.
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PMID:Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency. 1177 23

Few data exist on somatic mutation in the epithelial cell lineages that play a central role in human biology and disease. To delineate the "landscape" of somatic mutation in a human epithelial cell lineage, we determined the frequency and molecular nature of somatic mutations occurring in vivo in the X-linked HPRT gene of kidney tubular epithelial cells. Kidney epithelial mutants were frequent (range 0.5 to 4.2 x 10(-4)) and contained a high proportion of unreported HPRT base substitutions, -1-bp deletions and multiple mutations. This spectrum of somatic mutation differed from HPRT mutations identified in human peripheral blood T lymphocytes and from germ-line HPRT mutations identified in Lesch-Nyhan syndrome or hyperuricemia patients. Our results indicate that DNA damage and mutagenesis may have unusual or mechanistically interesting features in kidney tubular epithelium, and that somatic mutation may play a more important role in human kidney disease than has been previously appreciated.
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PMID:The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage. 1181 56

The literature on the pathogenesis of hyperuricemia have been limited to the discussion of metabolic syndromes associated with risk factors for atherosclerosis and hyperuricemia and the genetics of the juvenile form of hyperuricemic nephropathies. A few new mutations in the hypoxanthine-guanine phosphoribosyltransferase gene, which result in Lesch-Nyhan syndrome, have been described. In addition, some new insight has been gained in the renal handling of uric acid by the human kidney.
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PMID:Pathogenesis of hyperuricemia: recent advances. 1201 Jun 14

Lesch-Nyhan syndrome (LNS) is an X-linked hereditary disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase. Patients with this syndrome are characterized by hyperuricemia, self-mutilation, developmental retardation, and movement disorders such as spasticity and dystonia. The authors performed bilateral chronic stimulation of the globus pallidus internus for control of dystonic movements in a 19-year-old man with LNS. His self-mutilating behavior unexpectedly disappeared after chronic stimulation. This is the first case of LNS that has been successfully treated with deep brain stimulation. The findings indicate that neurobehavioral features of this syndrome are either mediated in the basal ganglia pathways or secondary to the dystonia.
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PMID:Disappearance of self-mutilating behavior in a patient with lesch-nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus. Case report. 1259 32

Various enzyme defects in the metabolic pathways of purines and pyrimidines are known, which result in different diseases occurring in children. They mainly affect kidney function, central nervous system, immunological and blood system. For example, complete deficiency of HPRT (hypoxanthine-guanine-phosphoribosyl-transferase) causes the Lesch Nyhan syndrome, which is characterized by hyperuricemia, mental retardation, choreoathetosis and compulsive self-mutilation. XDH deficiency (xanthine-dehydrogenase) causes in arthropathia and myopathia. For screening for these and other enzyme defects, urinary purine and pyrimidine excretion is considered a simple diagnostic tool. The purpose of the present study was to establish a reverse phase HPLC screening method for urinary purines and pyrimidines and to establish age related reference ranges in children for the urinary excretion of orotic acid, uracile, pseudouridine, uric acid, hypoxanthine, xanthine, thymine, 7-methylguanine, inosine, guanosine and adenosine.
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PMID:Purine and pyrimidine metabolites in children's urine. 1292 81

Hypoxanthine phosphoribosyl transferase (HPRT, also known as HGPRT) is an often-used genetic marker in eukaryotic cells. The gene is conserved from bacteria to human, with retained catalytic activity, although substrate specificity may have changed, and the enzyme is essential in malaria-causing protozoans. Inherited mutations in the human HPRT1 gene result in three different phenotypes: Lesch-Nyhan syndrome (LNS or LND), LND variants, and HPRT-related hyperuricemia (HRH). In cultured cells, loss of HPRT activity gives rise to 6-thioguanine (6-TG) resistance. In general, cells from LND patients are also 6-TG resistant, whereas cells from HRH patients are not, with some interesting exceptions. Using modeling methods, we have studied the correlation between the mutable and nonmutated amino acid residues on one hand, and sequence conservation and predicted phenotypic effects on the other hand. Our results demonstrate that most of the mutations are explainable by the predicted effect on protein structure and function. They are also consistent with sequence conservation. Moreover, the mutational profiles of TG-resistant cells and LND overlap to a great extent, while most of the mutations in HRH are unique to that condition. We have also noticed a strong correlation between mutations in the tetramer interfaces and observed phenotypes, suggesting a functional role for a tetramer transition during catalysis.
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PMID:Structural and functional analysis of mutations at the human hypoxanthine phosphoribosyl transferase (HPRT1) locus. 1514 65

Lesch-Nyhan syndrome (LNS) is a rare X-recessive disorder that leads to virtually complete deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Partial HPRT deficiency results in uric acid overproduction with subsequent hyperuricemia, nephrolithiasis, renal failure and gouty arthritis. In contrast, at complete HPRT deficiency, besides overproduction of uric acid neurological problems appear including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The cause for the uric acid overproduction has been clarified, but the connection between the enzyme deficiency and the neurological manifestations in LNS remains unclear. A hypothesis, which explains this relation, is proposed in the paper. The hypothesis has several important points most substantial of which is the accelerated biosynthesis of semiessential amino acid histidine that against the background of accelerated purine de novo biosynthesis results in 5-aminoimidazole-4-carboxamideribotide (AICAR) and histamine accumulation. The histamine and AICAR were determined to be the compounds that cause the neurobehavioral symptoms of LNS for several reasons. First, in the basal ganglia a balance between the direct (activating) and the indirect (inhibiting) pathways arising on the basis of the antagonistic and reciprocal dopamine-adenosine interactions normally exists. This balance can tonically regulate smooth voluntary movements and the activity of the thalamus, which, in turn, processes the afferent sensorimotor signals from the whole body to the all areas of the cerebral cortex and is concerned to modulate mental development and bring sensory information into awareness. Second, histamine is known to induce a selective damage in dopaminergic neurons inhibiting the direct dopaminergic pathway, which could lead to muscular rigidity, and slowness in initiating movements as well as tremor that are characteristic of Parkinsonism in LNS. Third, AICAribosid (AICAR breakdown product) is a potent adenosine A2a receptor antagonist inhibiting the indirect dopamine-adenosinergic pathway and, therefore, could be responsible for the choreoathetosis, dystonia and ballismus found in LNS. The excitatory-inhibitory disbalance in the basal ganglia could result in inadequate modification of the thalamus activity with subsequent mental retardation and symptoms that include the patients not being aware for their own bodies that could give rise to self-mutilation. Finally, a possibility for the creation of a new animal model that could exactly match the human LNS is proposed in the paper.
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PMID:The biochemical basis of the neurobehavioral abnormalities in the Lesch-Nyhan syndrome: a hypothesis. 1519 65

Mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior. Mutations in the same gene also cause less severe clinical phenotypes with only some portions of the full syndrome. A large database of 271 mutations associated with both full and partial clinical phenotypes was recently compiled. Since the original database was assembled, 31 additional mutations have been identified, bringing the new total to 302. The results demonstrate a very heterogeneous collection of mutations for both LND and its partial syndromes. The differences between LND and the partial phenotypes cannot be explained by differences in the locations of mutations, but the partial phenotypes are more likely to have mutations predicted to allow some residual enzyme function. The reasons for some apparent exceptions to this proposal are addressed.
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PMID:The spectrum of mutations causing HPRT deficiency: an update. 1557 Dec 20

In human neuroblastoma cell lines (LAN5, SHEP and IMR32), mycophenolic acid (MPA) at concentrations (10(-7)-10(-6) M) readily attainable during immunosuppressive therapy with mycophenolate mofetil (Cellcept), induces guanine nucleotide depletion leading to cell cycle arrest and apoptosis through a p53 mediated pathway (up-regulation of p53, p21 and bax and down-regulation of bcl-2 and survivin). MPA-induced apoptosis is also associated to a marked decrease of p27 protein. In the same cell lines MPA, at lower concentrations (50 nM), corresponding to the plasma levels of the active free drug during Cellcept therapy, induces differentiation toward the neuronal phenotype by causing a partial chronic guanine nucleotide depletion. MPA-induced differentiation is not associated to p27 accumulation as occurs using retinoic acid. At a fixed concentration of MPA a higher percentage of apoptotic or differentiated cells is obtained when non dialysed serum substitutes for the dialysed one, due to the higher hypoxanthine concentration in the former (about 10 microM) leading to competition on HPRT-mediated salvage of guanine. At hypoxanthine or oxypurinol concentrations higher than 1 microM (up to 100 microM) no further enhancement of MPA effects was obtained, in agreement with the recently described safety of the allopurinol-mycophenolate mofetil combination in the treatment of hyperuricemia of kidney transplant recipients. The apoptotic effects of MPA do not appear to be significantly increased by the UDP-glucuronosyltransferase inhibitor niflumic acid.
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PMID:Potential role of mycophenolate mofetil in the management of neuroblastoma patients. 1557 Dec 95

The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki' values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 muM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout.
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PMID:Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. 1569 61


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