ACYCLIC GUANOSINE ANALOGS INHIBIT DNA POLYMERASE-ALPHA, POLYMERASE-DELTA, POLYMERASE-EPSILON WITH VERY DIFFERENT POTENCIES AND HAVE UNIQUE MECHANISMS OF ACTION

被引:103
作者
ILSLEY, DD
LEE, SH
MILLER, WH
KUCHTA, RD
机构
[1] UNIV COLORADO, DEPT CHEM & BIOCHEM, BOULDER, CO 80309 USA
[2] ST JUDE CHILDRENS RES HOSP, DEPT VIROL & MOLEC BIOL, MEMPHIS, TN 38101 USA
[3] WELLCOME RES LABS, DIV EXPTL THERAPY, RES TRIANGLE PK, NC 27709 USA
关键词
D O I
10.1021/bi00008a014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 K-i for inhibition of pol delta was 2 mu M (competitive with dGTP), while the K(i)s for inhibition of pol alpha and epsilon were 80 and 140 mu M, 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.
引用
收藏
页码:2504 / 2510
页数:7
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