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)

Nuclear magnetic relaxation rate measurements have been performed on the protons and phosphorus atoms of phosphoribosyl 1-pyrophosphate (PRibPP) in the presence and absence of paramagnetic chromium(III), cobalt(II), and manganese(II) ions. The longitudinal relaxation rates were then used to calculate interatomic distances between the magnetic nuclei and these paramagnetic probes, from which was devised a conformation of the PRibPP-metal ion complex in solution. Thereafter, the experiments were accomplished in the presence of Mn(II) and a series of orotate phosphoribosyltransferase (OPRTase) and hypoxanthine/guanine phosphoribosyltransferase (HGPRTase) concentrations, and from these data were estimated the distances between Mn(II) and the PRibPP nuclei at the active sites of these two enzymes from yeast. Comparisons between the Mn(II)-PRibPP conformation in solution and this structure at the active sites of OPRTase and HGPRTase revealed that the metal ion remained coordinated with the pyrophosphate group of PRibPP in all instances, whereas the overall distances between the ribose ring and Mn(II) at the enzyme active sites were approximately 1 A further from the metal ion. Model building studies also revealed that the 5'-phosphate group of PRibPP is positioned directly over the ribose ring in solution and at the OPRTase and HGPRTase active sites and may protect the 1'-carbon of PRibPP against on-line displacements of pyrophosphate under these conditions, where the PRibPP-to-Mn(II) concentration ratio is greater than 2000.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Orotate phosphoribosyltransferase and hypoxanthine/guanine phosphoribosyltransferase from yeast: nuclear magnetic relaxation studies of the structures of enzyme-bound phosphoribosyl 1-pyrophosphate. 243 58

Proteose peptone-induced peritoneal macrophages from CBA/J (H-2k) mice have been fused to a hypoxanthine phosphoribosyltransferase-negative variant of the P388D1 (H-2d) murine macrophage cell line. Six hybrid clones were isolated following HAT selection and further characterized. Five of the six clones express class I antigens of both parental haplotypes by microelisa and by flow cytometric analysis. Class II antigen expression of both haplotypes was apparent following a 72-hr incubation of the hybrids with concanavalin A-stimulated rat spleen cell supernatant. However, I-Ad was expressed in all hybrids to a greater extent than I-Ak. Three clones with the highest level of I-Ak expression, E5, C2, and C4, were capable of antigen presentation to the I-Ak-restricted T-cell line, D10.G4.1. LPS induction of the hybrids resulted in a 2- to 15-fold increase in the amount of IL-1 produced relative to the P388D1 parent. Finally, in distinction to P388D1, all hybrids demonstrated increased Fc-mediated erythrophagocytosis of chromium-labeled antibody-coated erythrocytes. These murine macrophage hybrids appear stable and should serve as useful models in understanding the regulation of macrophage function.
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PMID:Establishment and characterization of murine macrophage hybrids. 349 85

The interaction of multiple carcinogens on human cells has not been extensively examined. This study reports the results of experiments in which normal human fibroblasts were exposed to both benzo[a]pyrene diolepoxide (BPDE) and potassium dichromate. The effect of four different treatment protocols on the cloning ability of the cells and the mutant frequency of the HPRT gene was determined. The combined treatment of both carcinogens caused a slightly greater than additive decrease in the cloning ability of the cells when compared to cells treated with the individual carcinogens. The result was the same regardless of the treatment protocol used in the experiment. The results of the mutant frequency experiments, however, varied dramatically with the protocol employed. The mutant frequency in cells which were simultaneously treated with both carcinogens was dramatically reduced from the mutant frequency found when cells were treated with BPDE alone. This antagonistic effect was not present when cells were either pretreated with potassium dichromate prior to BPDE or incubated with potassium dichromate following BPDE treatment. The observed antagonistic effect was the result of oxidative stress produced by chromium since it was completely or nearly completely reversed by the addition of either vitamin E or catalase to the cultures.
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PMID:Chromium can reduce the mutagenic effects of benzo[a]pyrene diolepoxide in normal human fibroblasts via an oxidative stress mechanism. 972 58

The cellular response to multiple carcinogen treatment has not been extensively studied, even though the effect of individual carcinogens is, in many cases, well known. We have previously shown that potassium dichromate can protect normal human fibroblasts from the mutagenic effects of benzo[a]pyrene diolepoxide (BPDE), and that this effect may be via an oxidative stress mechanism [Tesfai et al. (1998) Mutat Res 416:159-168]. Here, we extend our previous work by showing that nickel subsulfide can produce the some effect. Normal human fibroblasts, preincubated with nickel subsulfide for 46 hr followed by a coincubation of nickel subsulfide and BPDE for 2 hr, showed a dramatic reduction in the mutant frequency of the hypoxanthine (guanine)phosphoribosyl-transferase (HPRT) gene when compared to cells treated only with BPDE. The preincubation period with nickel subsulfide was necessary to see the antagonistic effect, since it was not observed if the cells were simply incubated with both carcinogens for 2 hr. The extent of the antagonistic effect was nickel subsulfide dose-dependent and also appeared to be species-specific, since the effect was not observed when Chinese hamster fibroblasts were tested. Finally, the antagonistic effect of the nickel subsulfide was eliminated by vitamin E, suggesting that production of reactive oxygen species by the nickel may be required. This data, along with our previous work, suggest that the antagonistic effect we observe is not chromium-specific, and that it could be species-specific.
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PMID:Nickel subsulfide is similar to potassium dichromate in protecting normal human fibroblasts from the mutagenic effects of benzo[a]pyrene diolepoxide. 1033 23

Chromium picolinate (CrPic, Chromax) is a dietary supplement that is stable and more bioavailable than other commercially available forms of chromium. Chromium supplementation is known to enhance the action of insulin, particularly in insulin resistance and type 2 diabetes mellitus. A previous study reported that CrPic produced increases in mutations of the hypoxanthine phosphoribosyltransferase (Hprt) gene in Chinese hamster ovary (CHO) cell mutation tests. This study, however, evaluated CrPic produced by the testing laboratory and used an atypical 48 h exposure period for this test system. The current study evaluated the mutagenic potential of the most widely utilized commercial form of CrPic in CHO/Hprt mutation tests following International Conference on Harmonisation (ICH) Guidelines (+/-S9 metabolic activation with a 5h exposure) in addition to repeating the test with a 48 h exposure period -S9 activation. CrPic was suspended in dimethyl sulfoxide (DMSO) up to a concentration of 50 mg/mL; exposures were conducted under conditions in which precipitate was not evident and under conditions in which some precipitate of CrPic was visually evident in the cell culture medium at the highest concentrations (500 microg/mL). The concentrations evaluated for mutagenicity ranged from 15.6 to 500 microg/mL (+S9 and -S9) for the 5 h exposure and 31.3-500 microg/mL for the 48 h exposure (-S9). Only a slight degree of cytotoxicity was seen in the standard tests up to the limit of solubility in the medium. Toxicity, i.e., cloning efficiency < or =50% of the solvent control, but no mutagenic increases were observed at 500 microg/mL following a 48 h exposure period. The results of these studies showed that CrPic was non-mutagenic in two independent CHO/Hprt assays and in an assay using a 48 h exposure period.
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PMID:Lack of mutagenicity of chromium picolinate in the hypoxanthine phosphoribosyltransferase gene mutation assay in Chinese hamster ovary cells. 1588 52

Certain hexavalent chromium [Cr(VI)] compounds are human lung carcinogens. Although much is known about Cr-induced DNA damage, very little is known about mechanisms of Cr(VI) mutagenesis and the role that DNA repair plays in this process. Our goal was to investigate the role of excision repair (ER) pathways in Cr(VI)-mediated mutagenesis in mammalian cells. Repair-proficient Chinese hamster ovary cells (AA8), nucleotide excision repair (NER)-deficient (UV-5) and base excision repair (BER)-inhibited cells were treated with Cr(VI) and monitored for forward mutation frequency at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus. BER was inhibited using methoxyamine hydrochloride (Mx), which binds to apurinic/apyrimidinic sites generated during BER. Notably, we found that both NER-deficient (UV-5 and UV-41) and BER-inhibited (AA8 + Mx) cells displayed attenuated Cr(VI) mutagenesis. To determine whether this was unique to Cr(VI), we included the alkylating agent, methylmethane sulfonate (MMS) and ultraviolet (UV) radiation (260 nm) in our studies. Similar to Cr(VI), UV-5 cells exhibited a marked attenuation of MMS mutagenesis, but were hypermutagenic following UV exposure. Moreover, UV-5 cells expressing human xeroderma pigmentosum complementation group D displayed similar sensitivity to Cr(VI) and MMS-induced mutagenesis as AA8 controls, indicating that the genetic loss of NER was responsible for attenuated mutagenesis. Interestingly, Cr(VI)-induced clastogenesis was also attenuated in NER-deficient and BER-inhibited cells. Taken together, our results suggest that NER and BER are required for Cr(VI) and MMS-induced genomic instability. We postulate that, in the absence of ER, DNA damage is channeled into an error-free system of DNA repair or damage tolerance.
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PMID:Excision repair is required for genotoxin-induced mutagenesis in mammalian cells. 1833 48

Inappropriate survival signaling after DNA damage may facilitate clonal expansion of genetically compromised cells, and it is known that protein tyrosine phosphatase (PTP) inhibitors activate key survival pathways. In this study we employed the genotoxicant, hexavalent chromium [Cr(VI)], which is a well-documented carcinogen of occupational and environmental concern. Cr(VI) induces a complex array of DNA damage, including DNA double strand breaks (DSBs). We recently reported that PTP inhibition bypassed cell cycle arrest and abrogated Cr(VI)-induced clonogenic lethality. Notably, PTP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of DNA damage may lead to genomic instability (GIN), via cell cycle checkpoint bypass. The aim of the present study was to determine the effect of PTP inhibition on DNA DSB formation and chromosomal integrity after Cr(VI) exposure. Diploid human lung fibroblasts were treated with Cr(VI) in the presence or absence of the PTP inhibitor, sodium orthovanadate, for up to 24h, and cells were analyzed for DNA DSBs and chromosomal damage. Cr(VI) treatment induced a rapid increase in DNA DSBs, and a significant increase in total chromosomal damage (chromatid breaks and gaps) after 24h. In sharp contrast, PTP inhibition abrogated both DNA DSBs and chromosomal damage after Cr(VI) treatment. In summary, PTP inhibition in the face of Cr(VI) genotoxic stress decreases chromosomal instability (CIN) but increases mutagenesis, which we postulate to be a result of error-prone DNA repair.
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PMID:Protein tyrosine phosphatase (PTP) inhibition enhances chromosomal stability after genotoxic stress: decreased chromosomal instability (CIN) at the expense of enhanced genomic instability (GIN)? 2258 56

Hexavalent chromium (Cr[VI]) is associated with occupational lung cancer and poses a significant public health concern. When exposed to Cr[VI], cells rapidly internalize this compound and metabolize it to Cr[III]. Byproducts of Cr[VI] metabolism include unstable Cr[V] and Cr[IV] intermediates that are believed to be directly responsible for the genotoxicity and carcinogenicity caused by Cr[VI] exposure; however, the carcinogenic potential of the Cr intermediates and the mechanisms of Cr-induced carcinogenesis remain to be further defined. Utilizing synthetic Cr[IV] and Cr[V] compounds, we demonstrate here that Cr[IV] or Cr[V] exposure induces DNA double-strand breaks; however, of the two compounds, mammalian cells only respond to Cr[V]-induced DNA damage. Exposure to Cr[V], but not Cr[IV], results in initiation of cell cycle checkpoints and activates the ATM kinase, a critical regulator of the DNA damage response. Furthermore, cells exposed to Cr[IV] have significantly increased mutation frequencies in the HPRT gene compared to cells exposed to Cr[V], indicating that Cr[IV] possesses a higher mutagenic potential than Cr[V]. We also find that MLH1, a critical mismatch repair (MMR) protein, is required for activation of the G2/M cell cycle checkpoint in response to Cr[VI] exposure and to limit Cr-induced mutagenesis. Our results provide evidence for Cr[IV] as the ultimate mutagenic intermediate produced during Cr[VI] metabolism and indicate that functional MMR is crucial in the cellular response to chromium exposure.
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PMID:DNA mismatch repair protein Mlh1 is required for tetravalent chromium intermediate-induced DNA damage. 2913 97

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