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)

Epolactaene (compound 1), a neuritogenic compound found in human neuroblastoma cells, was found to show anti-inflammatory activity in vivo in this study. DNA polymerases and DNA topoisomerase II (topo II) were some of the major molecular targets of compound 1. Since the agent seems to be a potential pharmaceutical medicine, we synthesized derivatives chemically and obtained seven compounds, 1 to 7 to screen clinically more efficient epolactaene derivatives. A comparison of its structural derivatives revealed that the long alkyl side chain seemed to have an important role in the inhibitory effect. Notably, C18-alkyl chain conjugated epolactaene (compound 5) was the strongest inhibitor of DNA polymerase alpha, beta, lambda (pol alpha, beta, lambda) and topo II, with IC50 values of 13, 135, 4.4 and 5 microM, respectively, and 500 microg of compound 5 caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 65.0%). Compound 5 did not influence the activities of plant or prokaryotic DNA polymerases, or of other DNA metabolic enzymes such as telomerase, RNA polymerase and deoxyribonuclease I. Based on these results, the relationship among the three-dimensional structure of epolactaene derivatives and the inhibition of polymerases and topo II, and anti-inflammation is discussed.
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PMID:Structural analysis of epolactaene derivatives as DNA polymerase inhibitors and anti-inflammatory compounds. 1580 99

Studies of mammalian terminal deoxyribonucleotidyltransferase (TdT) are facilitated by use of inhibitors that selectively knock down the activity of the enzyme. We have screened for selective inhibitors of TdT and identified a natural compound with this property in the Japanese vegetable, Arctium lappa. The compound has little effect on the activities of mammalian DNA polymerases, such as alpha, beta, delta or lambda polymerase, and prokaryotic DNA polymerases, such as Taq DNA polymerase, T4 DNA polymerase and Klenow fragment. H1- and C13-NMR spectroscopic analyses showed the compound to be baicalin, a compound previously reported as an anti-inflammatory or antipyretic agent. The IC50 value of baicalin to TdT was 18.6 microM. We also found that genistin, a baicalin derivative known to be antimutagenic, more selectively inhibited TdT activity than baicalin, although its IC50 value was weaker (28.7 microM). Genistin and baicalin also inhibited the activity of truncated TdT (the so-called pol beta core domain) in which the BRCT motif was deleted in its N-terminal region. In kinetic analyses, inhibition by either genistin or baicalin was competitive with the primer and non-competitive with the dNTP substrate. The compounds may, therefore, bind directly to the primer-binding site of TdT and simultaneously disturb dNTP substrate incorporation into the primer. Genistin and baicalin should prove to be useful agents for studying TdT.
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PMID:Selective inhibitors of terminal deoxyribonucleotidyltransferase (TdT): baicalin and genistin. 1609 7

Mispyric acid is a novel natural triterpene dicarboxylic acid which has inhibitory activity against DNA polymerase beta (pol beta) isolated from the plant, Mischocarpus pyriformis. In this report, we examine the selectivity of the inhibitory activity against mammalian pols and the mode of inhibition in vitro. Natural mispyric acid (compound 1) inhibited the activities of all the mammalian pols tested (pol alpha, beta, gamma, delta and epsilon) with an IC50 value in the range of 3.6-44.5 microM. The inhibition was strongest for pol gamma among these five pols. The enantiomer of mispyric acid (compound 2, ent-mispyric acid) had similar effects to those of the natural compound. However, derivatives of compounds 1 and 2 with hydroxyl groups instead of carboxyl groups (i.e., compounds 3 and 4, respectively) exhibited no inhibitory effect on mammalian pols. The moiety of two carboxylic acids in mispyric acid was important for the inhibition of pols, and the stereoisomers of mispyric acid had no inhibitory effect.
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PMID:Inhibitory effect of mispyric acid on mammalian DNA polymerases. 1611 82

Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-alpha, beta-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-alpha, beta-unsaturated aldehyde ends, and can act with DNA polymerase beta and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.
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PMID:Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3'-phosphate and 3'-phosphoglycolate ends. 1751 53


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