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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three patients with the Lesch-Nyhan syndrome were found to have normal delayed hypersensitivity, peripheral-blood T-lymphocyte counts, lymphocyte responses to P.H.A., and serum IgM, IgA, and IgE levels. However, the percentages of B-lymphocytes, IgG levels, serum-isohaemagglutinin titres, and lymphocyte responses to pokeweed mitogen (P.W.M.) were subnormal. These observations suggest that activity of the salvage pathway of purine synthesis catalysed by hypoxanthine-guanine phosphoribosyl transferase (H.G.P.R.T.) is not required for the responses of T-lymphocytes to mitogenic or antigenic stimulation, but may contribute to the proliferation and function of B lymphocytes. The major role of the de-novo pathway of purine synthesis in human lymphocyte responses to mitogenic or antigenic stimulation is shown by the effects of inhibitors of this pathway, including immunosuppressive agents, and by the effects of congenital deficiency or inhibition of adenosine deaminase.
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PMID:Immunological observations on patients with Lesch-Nyhan syndrome, and on the role of de-novo purine synthesis in lymphocyte transformation. 5 61

To delineate the normal function of purine nucleoside phosphorylase and to understand the pathogenesis of the immune dysfunction associated with deficiency of this enzyme, we studied purine metabolism in a patient deficient in purine nucleoside phosphorylase, her erythrocytes and cultured fibroblasts. She exhibited severe hypouricemia and hypouricosuria but excreted excessive amounts of purines in her urine, the major components of which were inosine and guanosine. Her urine also contained deoxyinosine, deoxyguanosine and uric acid 9-N riboside. The patient's erythrocytes but not her cultured fibroblasts contained increased concentrations of phosphoribosylpyrophosphate and inosine. The metabolic abnormalities resembled those in the erythrocytes of patients with the Lesch-Nyhan syndrome. Purine nucleoside phosphorylase is a necessary component of the major, if not the sole, pathway for the conversion of purine nucleosides and nucleotides to uric acid. The increased intracellular concentrations of inosine may, by inhibiting adenosine deaminase, be related to the immunologic dysfunction.
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PMID:Abnormal purine metabolism and purine overproduction in a patient deficient in purine nucleoside phosphorylase. 82 75

This paper reports the detection of five inherited disorders of purine and one of pyrimidine metabolism using intact red blood cells (RBCs) and compares the findings with those from RBC lysate activity. Two different phosphate levels (1 and 18 mmol L-1 Pi) were used to evaluate endogenous PP-ribose-P levels and their generation by PP-ribose-P synthetase. The importance of this dual approach is demonstrated by the following evidence: (a) Six out of eight patients with no detectable hypoxanthine-guanine phosphoribosyltransferase (HGPRT) RBC lysate activity had up to 25% of normal activity in their intact RBCs. Two Lesch-Nyhan patients showed no detectable activity in intact or lysed RBCs. (b) RBC lysates from two heterozygotes for adenosine deaminase (ADA) deficiency also showed no detectable activity, but up to 60% of normal activity using intact RBCs. (c) The existence of an aberrant enzyme in a kindred with a superactive PP-ribose-P synthetase was evident from the fact that intact RBCs failed to respond normally to phosphate activation, despite normal HGPRT and adenine phosphoribosyltransferase (APRT) RBC lysate activity. (d) Raised endogenous PP-ribose-P levels in intact RBCs were demonstrable only in purine nucleoside phosphorylase (PNP) and HGPRT deficiency; levels were normal in APRT deficiency and hereditary oroticaciduria (OPRT/ODC) deficiency. The results indicate that diagnosis from RBC lysate activity alone may be misleading. Intact RBC studies clearly provide a better indication of the functional capacity of the enzyme in vivo. They also show a closer correlation with the clinical phenotype and allow further insight into the associated biochemical abnormalities in some cases.
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PMID:Use of intact erythrocytes in the diagnosis of inherited purine and pyrimidine disorders. 244 57

Soon American researchers are expected to request approval for human gene therapy trials in individuals suffering from Lesch-Nyhan syndrome or ADA (adenosine deaminase) deficiency. Walters, who chairs the Working Group on Human Gene Therapy of the National Institutes of Health's Recombinant DNA Advisory Committee, summarizes the ethical dilemmas raised by these new genetic techniques. He addresses the issues of risk assessment, selection of patients, informed consent, and confidentiality, and reviews the framework for ethical evaluation of human gene therapy that has been developed in the United States. Walters also comments on genetic screening for late-onset disorders, the lack of commercial interest in gene therapy, the future possibility of altering human germlines, and the economics of genetic therapy.
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PMID:The ethics of human gene therapy. 345 68

The prenatal detection of hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) deficiency, the Lesch-Nyhan syndrome, during the first trimester of an affected pregnancy through the use of chorionic villus sampling is reported. Quantitation of reaction products formed by villus cell extracts from exogenous hypoxanthine-8-[14C] or adenine-8-[14C] is used in diagnosis. We report the diagnosis of Lesch-Nyhan syndrome using a chorionic villus specimen and confirmation of that diagnosis. In addition, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), enzymes deficient in inherited immune disorders, are detected in chorionic villus samples. These heritable disorders also appear amenable to early prenatal diagnosis.
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PMID:First trimester diagnosis of Lesch-Nyhan syndrome: applications to other disorders of purine metabolism. 392 83

Rats ingesting high doses of caffeine reproduce the self-destructive behaviour observed in the Lesch-Nyhan syndrome. This syndrome includes a deficit in hypoxanthine-guanine phosphoribosyltransferase. We have observed, however, that the activity of hypoxanthine-guanine phosphoribosyltransferase increases in direct proportion to the concentration of caffeine found in rat brain. It appears, therefore, that the caffeine model is not a true model for the Lesch-Nyhan syndrome, or alternatively, that the deficit in hypoxanthine-guanine phosphoribosyltransferase is coincidental and not a main key to the multifarious aspects of the syndrome, particularly the self-mutilation. The possibility that levels of dopamine are increased in the caffeine model are discussed as a basis for the destructive behaviour. We have found also that ingestion of large amounts of caffeine increases the activities in rat brain of adenosine deaminase, purine nucleoside phosphorylase, aspartate carbamoyl-transferase, dihydroorotase, and dihydroorotate oxidase.
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PMID:Lesch-Nyhan syndrome, caffeine model: increase of purine and pyrimidine enzymes in rat brain. 614 65

The effects of Mycoplasma pneumoniae on host cell metabolism were studied by using two types of host cells, MRC-5 human lung fibroblasts, a normal cell line, and Lesch-Nyhan fibroblasts, a cell line deficient in hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8). The susceptibilities of the two cell types were determined by infecting the cells with M. pneumoniae at different multiplicities of infection (MOI). Our data indicate that the Lesch-Nyhan cells were four times more susceptible to damage by M. pneumoniae than the MRC-5 cells. The effects of different MOIs (10 and 50) on de novo purine synthesis. DNA synthesis, and the development of a cytopathic effect were determined. In both cell types, the higher MOI inhibited de novo purine synthesis to a greater extent than the lower MOI. This correlated closely with the cytopathic effect which developed in the monolayers (i.e., the more the inhibition of de novo purine synthesis, the greater the cytopathic effect which developed). In the Lesch-Nyhan cells, DNA synthesis was completely inhibited by the high MOI, whereas in the MRC-5 cells, DNA synthesis was stimulated by the high MOI. In the MRC-5 cells infected with M. pneumoniae, purine salvage activity increased, as indicated by an increase in adenosine deaminase (EC 3.5.4.4) activity. These data indicate that M. pneumoniae alters host cell metabolism, particularly the nucleic acid metabolic pathways. This may explain in part the mechanism of pathogenesis of M. pneumoniae infection.
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PMID:De novo purine synthesis, purine salvage, and DNA synthesis in normal and Lesch-Nyhan fibroblasts infected with Mycoplasma pneumoniae. 640 90

A number of genetically determined enzyme defects leading to disturbances of purine metabolism can prenatally be monitored, and heterozygote detection is possible in several cases. In severe hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency, associated with a neurological disease known as the Lesch-Nyhan Syndrome, rapid prenatal diagnosis can be performed by means of a simple quantitative radiochemical enzyme assay at the single cell level. In this X-linked recessive disease, the female heterozygotes can be detected by using cultured skin fibroblasts, but alternatively single hair root enzymes can directly be assayed. Two other genetic purine enzyme defects lead to deranged immune function: in adenosine deaminase (ADA) deficiency both T- and B-lymphocyte function are severely impaired. In purine nucleoside phosphorylase (PNP) deficiency, only certain T-cell abnormalities have been observed, with apparently normal B-cell function. Both diseases are transmitted as autosomal recessive traits. Prenatal diagnosis is possible, e.g. by means of the above mentioned microtechniques. Heterozygote detection can be done using blood cells or cultured fibroblasts. Microchemical methods offer the possibility to perform enzyme characterisation even when a very limited amount of material is available. In the case of HGPRT, ADA, and PNP, for a substrate affinity curve and pH optimum curve a few hundred cells are sufficient. These and other possibilities illustrate the general usefulness of simple microtechniques in clinical enzymology.
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PMID:Inherited purine enzyme deficiencies: prenatal diagnosis and heterozygote detection. 640 79

Defects in X-linked phosphoribosylpyrophosphate synthetase 1 (PRPS1) manifest as follows: (1) PRS-I enzyme "superactivity" (gain-of-function mutations affecting allosteric regions); (2) PRS-I overexpression (which may be linked to miRNA mutation); (3) severe PRS-I deficiency/Arts syndrome (missense mutations producing loss-of-function); (4) moderate PRS-I deficiency/Charcot-Marie-Tooth disease-5 (less severe loss-of-function mutations); and (5) mild PRS-I deficiency/Deafness-2 (mutations producing slight destabilization). Similar to Lesch-Nyhan disease, PRPS1-related disorders arise from phosphoribosyl-pyrophosphate (PRPP)-dependent nucleotide "depletion" of purine nucleotides (e.g., ATP, GTP). S-adenosylmethionine (SAMe) appears to partially alleviate purine depletion via a PRPP-independent path. Synthesis of pyrimidine nucleotides is PRPP dependent, with uridine monophosphate synthase deficiency producing pyrimidine nucleotide depletion. But pyrimidine salvage from uridine does not require PRPP, and this nucleoside is transported freely to pyrimidine-depleted tissues. Regulation of nicotinamide nucleotides is less clear; synthesis from pyridine nucleobases is PRPP dependent. Nucleotide "depletion" contrasts with nucleotide "toxicity," exemplified by the purine disorders adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiencies or by pyrimidine nucleotidase deficiency. These are characterized by the accumulation of one or more abnormal nucleotides such as succinyl- or deoxy-nucleotides or their metabolites, which interrupt other nucleotide or related pathways or are toxic to specific cell types. Theoretically, purine toxicity disorders would not be ameliorated by SAMe therapy, and this was confirmed for one adenylosuccinate lyase-deficient child. Nucleotide defects may also be seen as an aspect of mitochondrial disease, with SAMe-based mitochondrial therapy perhaps meriting further investigation.
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PMID:The PRPP synthetase spectrum: what does it demonstrate about nucleotide syndromes? 2213 67

The purines are a group of molecules used by all cells for many vital biochemical processes including energy-requiring enzymatic reactions, cofactor-requiring reactions, synthesis of DNA or RNA, signaling pathways within and between cells, and other processes. Defects in some of the enzymes of purine metabolism are known to be associated with specific clinical disorders, and neurological problems may be a presenting sign or the predominant clinical problem for several of them. This chapter describes three disorders for which the clinical features and metabolic basis are well characterized. Deficiency of adenylosuccinate-lyase (ADSL) causes psychomotor retardation, epilepsy, and autistic features. Lesch-Nyhan disease is caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and is characterized by hyperuricemia, motor and cognitive disability, and self-injurious behavior. Deficiency of myoadenylate deaminase (mAMPD) is associated with myopathic features. In addition to these disorders, several other disorders are briefly summarized. These include defects of phosphoribosylpyrophosphate synthase, adenosine deaminase (ADA), purine nucleoside phosphorylase (PND), deoxyguanosine kinase (dGK), or IMP dehydrogenase (IMPDH). Each of these disorders provides an unusual window on the unique importance of purine metabolism for function of different parts of the nervous system.
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PMID:Metabolic disorders of purine metabolism affecting the nervous system. 2362 5


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