Quinone antibiotics, alpha- and beta-rubromycin, were originally found as inhibitors of retroviral reverse transcriptase. We investigated the effects of these agents on DNA metabolic enzymes including DNA and RNA polymerases as retroviral reverse transcriptase is a kind of the polymerase. As expected, we found that alpha- and beta-rubromycin strongly inhibited not only the retroviral reverse transcriptase activity, but the activities of the mammalian DNA polymerases, telomerase and terminal deoxynucleotidyl transferase in vitro. These agents should therefore be classified as DNA polymerase inhibitors. The Ki values of alpha-rubromycin against nucleotide substrate were 0.66 and 0.17 microM for DNA polymerase alpha and beta (pol. alpha and beta), respectively, and those of beta-rubromycin was 2.40 and 10.5 microM, respectively. Alpha-rubromycin strongly inhibited the pol. beta activity, and showed the strongest pol. beta inhibitory effect reported to date. At least on pol. beta, alpha-rubromycin was suggested to bind to the active region competing with the nucleotide substrate, and subsequently inhibit the catalytic activity. alpha-Rubromycin directly competed with the nucleotide substrate, and indirectly but simultaneously and non-competitively disturbed the template-DNA interaction with pol. beta.

译文

醌类抗生素,α-和 β-红霉素,最初被发现作为逆转录病毒逆转录酶的抑制剂。我们研究了这些药物对包括DNA和RNA聚合酶在内的DNA代谢酶的影响,因为逆转录病毒逆转录酶是一种聚合酶。正如预期的那样,我们发现 α-和 β-红霉素不仅在体外强烈抑制逆转录病毒逆转录酶活性,而且在体外抑制哺乳动物DNA聚合酶,端粒酶和末端脱氧核苷酸转移酶的活性。因此,这些药物应归类为DNA聚合酶抑制剂。对于DNA聚合酶 α 和 β (pol α 和 β),α-红霉素对核苷酸底物的Ki值分别为0.66和0.17微米,β-红霉素的Ki值分别为2.40和10.5微米。Α-红霉素强烈抑制pol。Β 活性,并显示出最强的pol。迄今报告的 β 抑制作用。至少在pol上。建议将 β,α-红霉素与与核苷酸底物竞争的活性区域结合,并随后抑制催化活性。Α-红霉素直接与核苷酸底物竞争,并间接但同时和非竞争性地干扰了模板-DNA与pol的相互作用。β。

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