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:3.1.21.1 (DNase)
7,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We found a novel inhibitor specific to eukaryotic DNA polymerase epsilon(pol epsilon) from plant cultured cells, Nicotina tabacum L. The compound (compound 1) was a dipeptide alcohol, L-homoserylaminoethanol. The 50% inhibition of pol epsilon activity by the compound was 43.6 microg/mL, and it had almost no effect on the activities of the other eukaryotic DNA polymerases such as alpha, beta, gamma and delta, prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human telomerase, human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase, human DNA topoisomerase I and II, T4 polynucleotide kinase and bovine deoxyribonuclease I. Kinetic studies showed that inhibition of pol epsilon by the compound was non-competitive with respect to both template-primer DNA and nucleotide substrate. We succeeded in chemically synthesizing the stereoisomers, L-homoserylaminoethanol and D-homoserylaminoethanol, and found both were effective to the same extent. The IC(50) values of L- and D-homoserylaminoethanols for pol epsilon were 42.0 and 41.5 microg/mL, respectively. This represents the second discovery of a pol epsilon-specific inhibitor, and the first report on a water-soluble peptide-like compound as the inhibitor, which is required in biochemical studies of pol epsilon.
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PMID:L-Homoserylaminoethanol, a novel dipeptide alcohol inhibitor of eukaryotic DNA polymerase from a plant cultured cells, Nicotina tabacum L. 1498 Jun 8

Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostane-type triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC(50) = 4.6 microM), while the compound moderately inhibited the activities of DNA polymerases alpha, beta, gamma, delta, epsilon, eta, iota, kappa and lambda only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC(50) = 37.5 microM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (alpha-like polymerase) or II (beta-like polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type-1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T 7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonuclease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II-preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD(50) values were 63.6 and 38.4 microM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.
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PMID:A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane-type triterpene acids from Poria cocos. 1507 95

We reported previously that a novel dipeptide alcohol, l-homoserylaminoethanol (Hse-Gly-ol), is a selective inhibitor of eukaryotic DNA polymerase epsilon (pol epsilon) [Bioorg. Med. Chem.2004, 12, 957-962]. The discovery suggests that the dipeptide structure could be a chemical frame for a DNA polymerase inhibitor. Therefore, we chemically synthesized 27 different species of dipeptide alcohols, and tested this inhibitory capability. Compound 6 (l-aspartylaminoethanol, Asp-Gly-ol) was found to be the strongest pol alpha inhibitor. Compound 6 did not influence the activities of other replicative DNA polymerases such as delta and epsilon, and had no effect on the activities of prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. The inhibitory effect of compound 6 on pol alpha was dose-dependent, and 50% inhibition was observed at a concentration of 33.5 microM. Compound 6-induced inhibition of pol alpha activity was non-competitive with both the DNA template-primer and the dNTP substrate. This is the first report on a water-soluble pol alpha-specific inhibitor, sought for precise biochemical studies of pol alpha. The relationships between the structures of dipeptide alcohols and the inhibition of eukaryotic DNA polymerases are discussed.
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PMID:Dipeptide alcohol-based inhibitors of eukaryotic DNA polymerase alpha. 1572 71

Bronchiectasis is associated with heterogeneous predisposing conditions that cause abnormal dilatation and persistent inflammation in the bronchial tree and lung parenchyma. The disease remains a common cause of significant morbidity and mortality, especially when associated with hereditary disorders such as cystic fibrosis, ciliary dyskinesia, and immunodeficiency states. Recent investigations have focused on the inflammatory mediators involved in the pathogenesis of bronchiectasis. High-resolution computed tomography is now the diagnostic modality of choice and may also contribute to clinical management. Computed tomography and high-resolution computed tomography have identified bronchiectasis in individuals with HIV and alpha-1-antitrypsin deficiency. Early identification of predisposing disorders and aggressive management of symptoms has already been demonstrated by prolonged survival and decreased morbidity in cystic fibrosis patients, and similar management may benefit other populations with bronchiectasis. New treatments such as recombinant human DNase have been shown to improve pulmonary function and quality of life in cystic fibrosis patients and may prove useful in other chronic inflammatory lung disease.
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PMID:An update on bronchiectasis. 1578 1

We reported previously that a novel dipeptide alcohol, L-homoserylaminoethanol (Hse-Gly-ol), is a selective inhibitor of eukaryotic DNA polymerase epsilon (pol epsilon). The discovery suggests that the dipeptide structure could be a chemical frame for a DNA polymerase inhibitor. Therefore, we chemically synthesized 14 different species of dipeptide alcohols and their derivatives, and tested this inhibitory capability. The mercapto group in the dipeptide alcohol was found to be important, and compound 4 (L-cysteinylaminoethanol, Cys-Gly-ol) was the strongest pol alpha inhibitor. Compound 4 did not influence the activities of other replicative DNA polymerases such as delta and epsilon, and had no effect on the activities of prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human immunodeficiency virus type-1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. The inhibitory effect of compound 4 on pol alpha was dose-dependent, and 50% inhibition was observed at a concentration of 14.8 microM. Compound 4-induced inhibition of pol alpha activity was non-competitive with both the DNA template-primer and the nucleotide substrate. The relationships between the structures of dipeptide alcohol and the inhibition of eukaryotic DNA polymerases are discussed.
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PMID:Inhibitory effect of dipeptide alcohol derivatives containing mercapto group on eukaryotic DNA polymerase alpha. 1614

We previously reported that a phenolic compound, curcumin (diferuloylmethane), was a selective inhibitor of DNA polymerase lambda (pol lambda) in vitro [Y. Mizushina, M. Hirota, C. Murakami, T. Ishidoh, S. Kamisuki, N. Shimazaki, M. Takemura, M. Perpelescu, M. Suzuki, H. Yoshida, F. Sugawara, O. Koiwai, K. Sakaguchi, Some anti-chronic inflammatory compounds are DNA polymerase lambda-specific inhibitors, Biochem. Pharmacol. 66 (2003) 1935-1944.]. We also found that monoacetylcurcumin ([1E,4Z,6E]-7-(4''-acetoxy-3''-methoxyphenyl)-5-hydroxy-1-(4'-hydroxy-3'-methoxyphenyl)hepta-1,4,6-trien-3-on), a chemically synthesized derivative of curcumin, was a stronger pol lambda inhibitor than curcumin, achieving 50% inhibition at a concentration of 3.9microM. Monoacetylcurcumin did not influence the activities of replicative pols such as alpha, delta, and epsilon, and showed no effect even on the activity of pol beta, the three-dimensional structure of which is thought to be highly similar to that of pol lambda. The compound-induced inhibition of pol lambda activity was non-competitive with respect to both the DNA template-primer and the dNTP substrate. Monoacetylcurcumin did not inhibit the activity of the C-terminal catalytic domain of pol lambda including the pol beta-like core, in which the BRCT motif was deleted. The compound did not influence the activities of prokaryotic pols or other mammalian DNA metabolizing enzymes such as calf primase of pol alpha, calf terminal deoxynucleotidyl transferase, human telomerase, human immunodeficiency virus type-1 reverse transcriptase, T7 RNA polymerase, T4 polynucleotide kinase, and bovine deoxyribonuclease I. Therefore, we concluded that monoacetylcurcumin is a selective inhibitor of pol lambda and could be used as a chromatographic ligand to purify pol lambda. We then made a monoacetylcurcumin-conjugated column with epoxy-activated Sepharose 6B. In the column, pol lambda of full length was selectively adsorbed and eluted.
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PMID:Monoacetylcurcumin: a new inhibitor of eukaryotic DNA polymerase lambda and a new ligand for inhibitor-affinity chromatography. 1623 65

Coenzyme Q (CoQ) is an isoprenoid quinine that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. CoQ having shorter isoprenoid chains, especially CoQ1 and CoQ2, selectively inhibited the in vitro activity of eukaryotic DNA polymerase (pol) gamma, which is a mitochondrial pol. These compounds did not influence the activities of nuclear DNA replicative pols such as alpha, delta and epsilon, and nuclear DNA repair-related pols such as beta, eta, iota, kappa and lambda. CoQ also inhibited DNA topoisomerase II (topo II) activity, although the enzymatic characteristics, including modes of action, amino acid sequences and three-dimensional structures, were markedly different from those of pol gamma. These compounds did not inhibit the activities of procaryotic pols such as Escherichia coli pol I, and other DNA metabolic enzymes such as human immunodeficiency virus reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. CoQ1, which has the shortest isoprenoid chains, had the strongest inhibitory effect on pol gamma and topo II activities among CoQ1-CoQ10, with 50% inhibitory concentration (IC50) values of 12.2 and 15.5 microM, respectively. CoQ1 could prevent the growth of human promyelocytic leukemia cells, HL-60, and the 50% lethal dose (LD50) value was 14.0 microM. The cells were halted at S phase and G1 phase in the cell cycle, and suppressed mitochondrial proliferation. From these results, the relationship between the inhibition of pol gamma/topo II and cancer cell growth by CoQ is discussed.
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PMID:Inhibitory effect of coenzyme Q on eukaryotic DNA polymerase gamma and DNA topoisomerase II activities on the growth of a human cancer cell line. 1686 5

Trichosanthin (TCS) is a type I ribosome-inactivating protein (RIP) possessing multiple pharmacological properties. One of its interesting properties is to inhibit human immunodeficiency virus (HIV) replication but its strong immunogenicity has limited the repeated clinical administration. To map the antigenic determinants and reduce the immunogenicity of TCS, two potential antigenic sites (YFF81-83 and KR173-174) were identified by computer modeling, and then three TCS mutants namely TCS(YFF81-83ACS), TCS(KR173-174CG), and TCS(YFF-KR) were constructed by site-directed mutagenesis. The RI activity and DNase-like activity of the three constructed TCS mutants were similar to natural TCS but with much lower immunogenicity. Results suggested that the two selected sites are all located at or near the antigenic determinants of TCS. In toxicity studies, the LD(50) of the three TCS mutants was not different from natural TCS. These findings would be useful in designing a better therapeutic agent for AIDS.
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PMID:Mapping the antigenic determinants and reducing the immunogenicity of trichosanthin by site-directed mutagenesis. 1697 28

Tetralols 1 and 2, dihydroisocoumarins 3-6, and chromone 7 are natural compounds isolated from cultures of fungi, and their structures were determined by spectroscopic analyses. Compounds 1 and 2 from Nodulisporium sp. are novel tetralols, 1,2,3,4-tetrahydro-5-methoxynaphthalene-1,4-diol (nodulisporol) and 3,4-dihydro-4-hydroxy-8-methoxynaphthalen-1(2H)-one (nodulisporone), respectively. All isolated compounds selectively inhibited the activity of human DNA polymerase lambda (pol lambda), and compound 5 (3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarin) was the strongest inhibitor of pol lambda in the tested compounds with an IC(50) value of 49 microM. New tetralols (1 and 2) are the third and second strongest inhibitors of pol lambda, but did not influence the activities of mammalian pols alpha to kappa, and showed no effect even on the activities of plant pols alpha and beta, prokaryotic pols, and other DNA metabolic enzymes such as calf terminal deoxynucleotidyl transferase, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, and bovine deoxyribonuclease I. The structure-activity relationships of isolated compounds such as novel tetralols, dihydroisocoumarins, and chromone are discussed.
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PMID:Nodulisporol and Nodulisporone, novel specific inhibitors of human DNA polymerase lambda from a fungus, Nodulisporium sp. 1736 59

Talaroflavone (1) and 1-deoxyrubralactone (2) are natural compounds isolated from cultures of a fungal strain derived from sea algae, and their structures were determined by spectroscopic analyses. Compound 2 is a novel rubralactone derivative, 6-hydroxy-8-methoxy-1-methyl-1,2,3a,9b-tetrahydrocyclopenta[c]isochromene-3,5-dione. These compounds selectively inhibited the activities of families X and Y of eukaryotic DNA polymerases (pols), and compound 2 was a stronger inhibitor than compound 1. The IC(50) values of compound 2 on rat pol beta, which is a pol of family X, and human pol kappa, which is a pol of family Y, were 11.9 and 59.8 microM, respectively. On the other hand, compounds 1 and 2 did not influence the activities of the other families of eukaryotic pols, such as family A (i.e., pol gamma) and family B (i.e., pols alpha, delta, and epsilon), and showed no effect even on the activities of plant pols alpha and beta, prokaryotic pols, and other DNA metabolic enzymes, such as calf primase of pol alpha, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, mouse IMP dehydrogenase (type II), human topoisomerase I and II, T4 polynucleotide kinase, and bovine deoxyribonuclease I. This is the first report about the selective inhibitors of families X and Y of eukaryotic pols.
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PMID:1-deoxyrubralactone, a novel specific inhibitor of families X and Y of eukaryotic DNA polymerases from a fungal strain derived from sea algae. 1817 92


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