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)

Cultured fibroblasts with hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency exhibited acceleration of purine synthesis de novo, absence of salvage IMP synthesis from hypoxanthine, but normal total IMP synthesis. Cells with phosphoribosylpyrophosphate synthetase superactivity exhibited acceleration of both de novo and salvage IMP synthesis and increased total IMP synthesis. The study of mutant cells furnished evidence that in normal as well as mutant cells, GMP and AMP are not converted to each other in significant amounts and that these nucleotides are not degraded by nucleotidases. Purine nucleotide degradation in fibroblasts occurs mainly by dephosphorylation of IMP. In HGPRT-containing cells, salvage IMP synthesis from preformed and exogenously supplied hypoxanthine is the main source for IMP production.
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PMID:Characterization of purine nucleotide metabolism in cultured fibroblasts with deficiency of hypoxanthine-guanine phosphoribosyltransferase and with superactivity of phosphoribosylpyrophosphate synthetase. 625 15

A purine nucleotide (inosinate) cycle is demonstrated with human lymphoblasts. The lymphoblast requires approximately 50 nmol of purine/10(6) cell increment. When the inosinate cycle is interrupted by the genetic, severe deficiency of either or both purine nucleoside phosphorylase (PNP) or hypoxanthine phosphoribosyltransferase (HPRT), purine accumulates in the culture medium as inosine, guanosine, deoxyinosine, and deoxyguanosine (PNP deficiency or PNP, HPRT deficiency) or hypoxanthine and guanine (HPRT deficiency). This accumulation represents an additional 25 to 32 nmol of purine which must be synthesized per 10(6) cell increment. PNP-deficient lymphoblasts have PPRibP contents characteristic of normal lymphoblasts, about 20 to 25 pmol/10(6) cells. HPRT-deficient lymphoblasts have four times higher PPRibP contents. The lymphoblast deficient for both PNP and HPRT has only a marginal elevation of PPRibP content, 1.5 times normal values. The elevated PPRibP content of HPRT-deficient cells reflects the efficient, unilateral reutilization of the ribose moiety of purine ribonucleotides and is not a cause of purine overproduction. Purine overproduction characterizing PNP-deficient lymphoblasts appears similar to overproduction from deficiency of HPRT, i.e. a break in the inosinate cycle rather than overactive de novo purine synthesis.
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PMID:Purine nucleotide reutilization by human lymphoblast lines with aberrations of the inosinate cycle. 642 40

Purine enzyme activities are usually assayed by radiochemical procedures and often TLC is part of the separation method. In screening patients with rheumatic diseases, these procedures have shown disadvantages like a relatively large coefficient of variation (C.V.) and time-instability. We describe a non-radiochemical reversed-phase HPLC micro-method with UV detection for measurement of activities of purine 5'-nucleotidase (5'NT; EC 3.1.3.5), purine nucleoside phosphorylase (PNP; EC 2.4.2.1) and hypoxanthine guanine phosphoribosyltransferase (HGPRT; EC 2.4.2.8) in human peripheral blood mononuclear cells (PBMC). The HPLC procedure is compared with the radiochemical TLC procedure by testing both with a 5'NT and a PNP assay. Reproducibility is tested with 14 healthy controls in each procedure. Short-term and long-term time-stability is tested by comparing enzyme activities measured immediately after preparation of the PBMC (week 0) with those found after freezing and storage at -20 degrees C for a maximum of 10 weeks. The HPLC procedure is preferable to the radiochemical TLC procedure because it shows significantly better reproducibility and better time-stability and in addition is non-radiochemical and less time-consuming.
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PMID:Purine enzyme activities in peripheral blood mononuclear cells: comparison of a new non-radiochemical high-performance liquid chromatography procedure and a radiochemical thin-layer chromatography procedure. 765 19

Tiazofurin and ribavirin are clinically used inhibitors of IMP dehydrogenase (DH), binding to the NAD and IMP sites, respectively, of the target enzyme. In patients with chronic granulocytic leukemia in blast crisis, daily tiazofurin infusions decreased the high IMP DH activity in blast cells and resulted in 77% response (G. Weber. In: R. A. Harkness et al., Purine and Pyrimidine Metabolism in Man, Vol. VII, Part B, pp. 287-292, 1991). However, patients relapsed in a few weeks with emergence of high IMP DH activity (G. Tricot et al., Int. J. Cell Cloning, 8: 161-170, 1990). The present study showed that the tiazofurin-induced depression of IMP DH activity in rat bone marrow can be maintained by ribavirin injection. Tiazofurin (150 mg/kg, i.p., once a day for 2 days) decreased IMP DH activity to 10% and ribavirin (250 mg/kg, i.p., once a day for the subsequent 3 days) maintained the enzymic activity at 20 to 30% of control values. In control rats where no ribavirin was given, IMP DH activity of the tiazofurin-treated rats rapidly returned to the range of untreated animals. The decrease of IMP DH activity (t1/2 = 2.6 h) sharply preceded that of the bone marrow cellularity (t1/2 = 17.4 h). In addition to the target enzyme, IMP DH, tiazofurin also decreased activities of the guanylate metabolic enzymes, guanine phosphoribosyltransferase and GMP reductase, and the pyrimidine salvage enzymes, deoxycytidine and thymidine kinases with t1/2 of 2.6, 4.7, 6.0, 3.4, and 6.5 h, respectively. In cycloheximide-treated rats, where much of protein biosynthesis was blocked, the t1/2(8) of these five enzymes in bone marrow were shorter, 1.6, 4.3, 3.0, 0.6, and 0.8 h, respectively. Thus, the impact of tiazofurin in the bone marrow entails a decrease in the activity of the target enzyme, IMP DH, and also of other enzymes in purine and pyrimidine biosynthesis as a result of the enzyme half-lives shortened by this drug. These novel observations should assist in achieving better protection and recovery of bone marrow during and after chemotherapy.
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PMID:Sequential impact of tiazofurin and ribavirin on the enzymic program of the bone marrow. 790 99

Purine metabolism was studied in the obligate intracellular bacterium Chlamydia psittaci AA Mp in the wild type and a variety of mutant host cell lines with well-defined deficiencies in purine metabolism. C. psittaci AA Mp cannot synthesize purines de novo, as assessed by its inability to incorporate exogenous glycine into nucleic acid purines. C. psittaci AA Mp can take ATP and GTP, but not dATP or dGTP, directly from the host cell. Exogenous hypoxanthine and inosine were not utilized by the parasite. In contrast, exogenous adenine, adenosine, and guanine were directly salvaged by C. psittaci AA Mp. Crude extract prepared from highly purified C. psittaci AA Mp reticulate bodies contained adenine and guanine but no hypoxanthine phosphoribosyltransferase activity. Adenosine kinase activity was detected, but guanosine kinase activity was not. There was no competition for incorporation into nucleic acid between adenine and guanine, and high-performance liquid chromatography profiles of radiolabelled nucleic acid nucleobases indicated that adenine, adenosine, and deoxyadenosine were incorporated only into adenine and that guanine, guanosine, and deoxyguanosine were incorporated only into guanine. Thus, there is no interconversion of nucleotides. Deoxyadenosine and deoxyguanosine were cleaved to adenine and guanine before being utilized, and purine (deoxy)nucleoside phosphorylase activity was present in reticulate body extract.
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PMID:Purine metabolism by intracellular Chlamydia psittaci. 833 25

The present study was conducted in order to clarify the role of the glia in brain purine metabolism. This, in connection with the clarification of the etiology of the neurological manifestations associated with some of the inborn errors of purine metabolism in man. Purine nucleotide content, the capacity for de novo and salvage purine synthesis and the activity of several enzymes of purine nucleotide degradation, were assayed in primary cultures of rat astroglia in relation to culture age. The capacity of the intact cells to produce purine nucleotides de novo exhibited a marked decrease with the culture age, but the activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), catalyzing salvage nucleotide synthesis, increased. Aging was also associated with a marked increase in the activity of the degradation enzymes AMP deaminase, purine nucleoside phosphorylase (PNP) and guanine deaminase (guanase). The activity of adenosine deaminase and of AMP-5'-nucleotidase, increased markedly during the first 17 days in culture, but decreased thereafter. The results indicate that purine nucleotide metabolism in the cultured astroglia is changing with aging to allow the cells to maintain their nucleotide pool by reutilization of preformed hypoxanthine, rather than by de-novo production of new purines. Aging is also associated with increased capacity for operation of the adenine nucleotide cycle, contributing to the homeostasis of adenine nucleotides and to the energy charge of the cells. In principle, the age-related alterations in purine metabolism in the astroglia resemble those occurring in the maturating neurons, except for the capacity to produce purines de novo, which exhibited inverse trends in the two tissues. However, in comparison to the neurons, the cultured astroglia possess the capacity for a more intensive metabolism of purine nucleotides.
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PMID:Developmental changes in purine nucleotide metabolism in cultured rat astroglia. 877 Jun 61

Factors controlling relative flux rates of the de novo and salvage pathways of purine nucleotide biosynthesis during animal cell growth are not fully understood. To examine the relative role of each pathway for cell growth, three cell lines including CHO K1 (a wild-type Chinese hamster ovary fibroblast cell line), CHO ade -A (an auxotrophic cell line deficient of amidophosphoribosyltransferase (ATase), a presumed rate-limiting enzyme of the de novo pathway), and CHO ade -A transfected with human ATase cDNA (-A+hATase) resulting in 30-350% of the ATase activity of CHO K1, were cultured in purine-rich or purine-free media. Based on the enzyme activities of ATase and hypoxanthine phosphoribosyltransferase, the metabolic rate of the de novo and salvage pathways, the rate of cell growth (growth rate) in three cell lines under various culture conditions, and the effect of hypoxanthine infusion on the metabolic rate of the de novo pathway in rat liver, we concluded the following. 1) In -A+hATase transfectants, ATase activity limits the rate of the de novo pathway, which is closely linked with the growth rate. 2) Purine nucleotides are synthesized preferentially by the salvage pathway as long as hypoxanthine, the most essential source of purine salvage, can be utilized, which was confirmed in rat liver in vivo by hypoxanthine infusion. The preferential usage of the salvage pathway results in sparing the energy expenditure required for de novo synthesis. 3) The regulatory capacity of the de novo pathway (about 200%) was larger than that of the salvage pathway (about 20%) with constant hypoxanthine phosphoribosyltransferase activity.
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PMID:Amidophosphoribosyltransferase limits the rate of cell growth-linked de novo purine biosynthesis in the presence of constant capacity of salvage purine biosynthesis. 921 23

Purine and pyridine metabolism were studied in ten Lesch-Nyhan patients, with virtually no hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity in erythrocytes. Increased NAD erythrocyte concentrations were found in all patients. Raised activities of two enzymes catalysing NAD synthesis from nicotinic acid (nicotinic acid phosphoribosyltransferase: NAPRT, and NAD synthetase: NADs) was found in erythrocyte lysates from all patients. The two enzymes had normal apparent Km for their substrates and increased Vmax. The rate of synthesis of pyridine nucleotides from nicotinic acid by intact erythrocytes in vitro was also increased in most patients. These findings suggest that raised NAD concentrations in HPRT- erythrocytes are due to enhanced synthesis as a result of increased enzyme activities.
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PMID:Hypoxanthine-guanine phosphoribosyltransferase deficiency and erythrocyte synthesis of pyridine coenzymes. 1040 7

We recently showed that an increased supply of purine nucleotides increased the growth rate of cultured fibroblasts. To understand the mechanism of the growth rate regulation, CHO K1 (a wild type of Chinese hamster ovary fibroblast cell line) and CHO ade (-)A (a cell line deficient in amidophosphoribosyltransferase, a rate-limiting enzyme of the de novo pathway) were cultured under various conditions. Moreover, a defective de novo pathway in CHO ade (-)A cells was exogenously restored by 5-amino-4-imidazole-carboxamide riboside, a precursor of the de novo pathway. The following parameters were determined: the growth rate of CHO fibroblasts, the metabolic rate of the de novo pathway, the enzyme activities of amidophosphoribosyltransferase and hypoxanthine phosphoribosyltransferase, the content of intracellular nucleotides, and the duration of each cell-cycle phase. We concluded the following: (i) Purine de novo synthesis, rather than purine salvage synthesis or pyrimidine synthesis, limits the growth rate. (ii) Purine nucleotides are synthesized preferentially by the salvage pathway as long as hypoxanthine is available for energy conservation. (iii) The GTP content depends on the intracellular ATP content. (iv) Biosynthesis of purine nucleotides increases the growth rate mainly through ATP production and promotion of the G(1)/S transition.
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PMID:The rate of cell growth is regulated by purine biosynthesis via ATP production and G(1) to S phase transition. 1087 58

Purine phosphoribosyltransferase activities in normal and experimental hyperkeratotic epidermis of guinea pig skin were demonstrated quantitatively by a new microassay method. The ratio of HGPRTase with hypoxanthine as a substrate to APRTase activity in normal and hyperkeratotic epidermis was found to be 0.94 and 0.60, respectively. The HGPRTase and APRTase activities expressed as micromoles per gram wet weight per min. were increased in experimental hyperkeratotic epidermis and it is suggested that the salvage pathway for purine nucleotide biosynthesis is activated in experimental hyperkeratotic epidermis. The pH optimum of these enzymes and their stability in the frozen state were also demonstrated.
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PMID:Purine phosphoribosyltransferase activities in guinea pig epidermis. 1546 43


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