Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of endogenously produced and exogenously added benzene metabolites on the nuclear DNA synthetic activity were investigated using a culture system of mouse bone marrow cells. Effects of the metabolites were evaluated by a 30-min incorporation of [3H]thymidine into DNA following a 30-min interaction with the cells in McCoy's 5a medium with 10% fetal calf serum. Phenol and muconic acid did not inhibit nuclear DNA synthesis. However, catechol, 1,2,4-benzenetriol, hydroquinone, and p-benzoquinone were able to inhibit 52, 64, 79, and 98% of the nuclear DNA synthetic activity, respectively, at 24 microM. In a cell-free DNA synthetic system, catechol and hydroquinone did not inhibit the incorporation of [3H]thymidine triphosphate into DNA up to 24 microM but 1,2,4-benzenetriol and p-benzoquinone did. The effect of the latter two benzene metabolites was completely blocked in the presence of 1,4-dithiothreitol (1 mM) in the cell-free assay system. Furthermore, when DNA polymerase alpha, which requires a sulfhydryl (SH) group as an active site, was replaced by DNA polymerase I, which does not require an SH group for its catalytic activity, p-benzoquinone and 1,2,4-benzenetriol were unable to inhibit DNA synthesis. Thus, the data imply that p-benzoquinone and 1,2,4-benzenetriol inhibited DNA polymerase alpha, consequently resulting in inhibition of DNA synthesis in both cellular and cell-free DNA synthetic systems. The present study identifies catechol, hydroquinone, p-benzoquinone, and 1,2,4-benzenetriol as toxic benzene metabolites in bone marrow cells and also suggests that their inhibitory action on DNA synthesis is mediated by mechanism(s) other than that involving DNA damage as a primary cause.
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PMID:Inhibitory effect of benzene metabolites on nuclear DNA synthesis in bone marrow cells. 292 30

Activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) in the organic extract of the Red Sea sponge Toxiclona toxius was traced by us to five novel natural compounds, namely toxiusol [1], shaagrockol B [3], shaagrockol C [4], toxicol A [6], all of which are sulfated hexaprenoid hydroquinones, and toxicol B [7], the p-hydroquinone derivative of compound 6. The hydrolysis of the two sulfated compounds 1 and 4 yielded the corresponding hydroquinones designated as compounds 2 and 5, and further oxidation of compound 7 afforded the corresponding p-quinone derivative, compound 8. All compounds exhibited inhibitory activity of both DNA polymerizing functions of HIV-1 RT but failed to inhibit the RT-associated ribonuclease H activity. Toxiusol [1] was found to be the most potent inhibitor of the RNA-dependent DNA polymerase function (with 50% inhibition obtained at 1.5 microM and 95% inhibition at 4.6 microM), whereas the DNA-dependent DNA polymerase was significantly less sensitive to the inhibitor (with 50% inhibition achieved at 6.6 microM and 95% inhibition only at 41.6 microM). The fact that compound 1 discriminates between the two DNA polymerase activities of the RT offers new prospects for developing potent and highly specific anti-RT compounds, since the RNA-dependent DNA polymerase activity of RT is the only unique function that is not expressed at significant levels in uninfected mammalian cells.
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PMID:Hexaprenoid hydroquinones, novel inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. 751 Jul 86

Toxiusol, a natural product isolated from the Red Sea sponge Toxiclona toxius, has been shown to be a potent inhibitor of various viral reverse transcriptases (RT) [i.e., of human immunodeficiency virus (HIV-1), equine infectious anemia virus, and murine leukemia virus] and cellular DNA polymerases (i.e., of DNA polymerases alpha and beta and Escherichia coli DNA polymerase I). A thorough investigation of the mode of inhibition was conducted with HIV-1 RT-associated DNA polymerase activity. The inhibition is unaffected by the nature of template-primer used. The inhibitory active site of toxiusol is attributable to the polar moieties at the benzene ring. The presence of either sulfate groups in the natural lead compound or hydroxyl groups in the corresponding hydroquinone is critical, because both compounds are equally effective at low micromolar concentrations. Conversely, the presence of acetyl groups in the same position in the derivative toxiusol diacetate lowers significantly or abolishes the inhibitory activity. Toxiusol binds the HIV-1 RT irreversibly and in a noncompetitive way with high affinity (Ki = 1.2 microM), probably through polar groups. The replacement with acetyl moieties in the analog toxiusol diacetate hampers the binding of the inhibitor to the enzyme (Ki increases to about 26 microM). Still, the compound binds irreversibly, probably through its hydrophobic structure skeleton. Toxiusol diacetate loses its ability to inhibit the first step in the DNA polymerization process (that is, the formation of the DNA-enzyme complex as measured by a gel retardation assay), which contributes to its poor inhibitory capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of inhibition of HIV reverse transcriptase by toxiusol, a novel general inhibitor of retroviral and cellular DNA polymerases. 753 6

Halenaquinol sulfate, a p-hydroquinone sulfate obtained from a marine sponge, inhibited the activity of eukaryotic DNA polymerases in varying degrees; the Ki values for DNA polymerases, alpha, beta, delta and epsilon were 1.3, 80, 17.5 and 2.0 microM, respectively, whereas it was less effective against E. coli DNA polymerase I. The inhibition occurred competitively with each of dATP and dTTP, but non-competitively with dCTP, dGTP and the template DNA. Thus, halenaquinol sulfate is demonstrated to be a potential inhibitor of DNA polymerases alpha and epsilon, and be a useful tool for analyzing the dNTP binding sites of DNA polymerases.
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PMID:Differential inhibition of eukaryotic DNA polymerases by halenaquinol sulfate, a p-hydroquinone sulfate obtained from a marine sponge. 807 May 73

Estrogen administration to rodents results in various types of DNA damage and ultimately leads to tumors in estrogen-responsive tissues. Yet these hormones have been classified as nonmutagenic, because they did not induce mutations in classical bacterial and mammalian mutation assays. In this review, we have discussed the induction by estrogens of DNA and chromosomal damage and of gene mutations, because the classical assays were designed to uncover mutations only at one specific locus and could not have detected other types of mutations or changes in other genes. Various types of estrogen-induced DNA damage include: (a) direct covalent binding of estrogen quinone metabolites to DNA; (b) enhancement of endogenous DNA adducts by chronic estrogen exposure of rodents; (c) free radical generation by metabolic redox cycling between quinone and hydroquinone forms of estrogens and free radical damage to DNA such as strand breakage, 8-hydroxylation of purine bases of DNA and lipid hydroperoxide-mediated DNA modification. Two different types of chromosomal damage have also been induced by estrogen in vivo and in cells in culture such as numerical chromosomal changes and also structural chromosomal aberrations. Gene mutations have been induced in several cell types in culture either by the parent estrogen or by reactive estrogen quinone metabolites. Furthermore, in estrogen-induced kidney tumors in hamsters, several mutations have been observed in the DNA polymerase beta gene mRNA. Estradiol also induces microsatellite instability in these kidney tumors and in premalignant kidney exposed to estradiol. Although this work is still ongoing, it can be concluded that estrogens are complete carcinogens capable of tumor initiation by mutation potentially in critical genes. The hormonal effects of estrogens may complete the development of tumors.
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PMID:Estrogen, DNA damage and mutations. 1006 54