Ilsley D D, Lee S H, Miller W H, Kuchta R D
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309.
Biochemistry. 1995 Feb 28;34(8):2504-10. doi: 10.1021/bi00008a014.
Acyclovir triphosphate, ganciclovir triphosphate and penciclovir triphosphate inhibited DNA polymerases alpha, delta, and epsilon. Each triphosphate preferentially inhibited pol delta, although ganciclovir triphosphate was the most impressive of the three; the Ki for inhibition of pol delta was 2 microM (competitive with dGTP), while the Kis for inhibition of pol alpha and epsilon were 80 and 140 microM, respectively. Each of the compounds was polymerized by pol alpha, delta, and epsilon. Incorporation of acyclovir triphosphate resulted in immediate chain termination, whereas incorporation of ganciclovir triphosphate often allowed polymerization of additional dNTPs. Interestingly, chain termination most often occurred after polymerization of just one additional dNTP onto the ganciclovir monophosphate. All three compounds were very weak inhibitors of DNA primase. Acyclovir triphosphate, however, was a unique inhibitor of the pol alpha-catalyzed elongation of primase-synthesized primers. Immediately after DNA primase synthesized a primer, pol alpha frequently incorporated acyclovir triphosphate with consequent chain termination. If, however, pol alpha did not immediately polymerize acyclovir triphosphate onto the primase-synthesized primer, further dNTPs were readily added and acyclovir triphosphate was incorporated much less frequently.
阿昔洛韦三磷酸、更昔洛韦三磷酸和喷昔洛韦三磷酸可抑制DNA聚合酶α、δ和ε。每种三磷酸酯均优先抑制聚合酶δ，不过更昔洛韦三磷酸是三者中作用最显著的；抑制聚合酶δ的Ki为2微摩尔（与dGTP竞争），而抑制聚合酶α和ε的Ki分别为80和140微摩尔。每种化合物均可被聚合酶α、δ和ε聚合。阿昔洛韦三磷酸的掺入导致立即链终止，而更昔洛韦三磷酸的掺入通常允许额外的脱氧核苷三磷酸聚合。有趣的是，链终止最常发生在仅一个额外的脱氧核苷三磷酸聚合到更昔洛韦单磷酸上之后。所有三种化合物都是非常弱的DNA引发酶抑制剂。然而，阿昔洛韦三磷酸是聚合酶α催化的引发酶合成引物延伸的独特抑制剂。DNA引发酶合成引物后，聚合酶α经常掺入阿昔洛韦三磷酸并随之发生链终止。然而，如果聚合酶α没有立即将阿昔洛韦三磷酸聚合到引发酶合成的引物上，则很容易添加更多的脱氧核苷三磷酸，且阿昔洛韦三磷酸的掺入频率会低得多。
