用于抑制尿嘧啶DNA糖基化酶的双分型过渡态模拟物的优点。

The merits of bipartite transition-state mimics for inhibition of uracil DNA glycosylase.

作者信息

Jiang Yu Lin, Cao Chunyang, Stivers James T, Song Fenhong, Ichikawa Yoshi

机构信息

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-2185, USA.

出版信息

Bioorg Chem. 2004 Aug;32(4):244-62. doi: 10.1016/j.bioorg.2004.03.001.

DOI:10.1016/j.bioorg.2004.03.001

PMID:15210339

Abstract

The glycosidic bond hydrolysis reaction of the enzyme uracil DNA glycosylase (UDG) occurs by a two-step mechanism involving complete bond breakage to the uracil anion leaving group in the first step, formation of a discrete glycosyl cation-uracil anion intermediate, followed by water attack in a second transition-state leading to the enzyme-bound products of uracil and abasic DNA. We have synthesized and determined the binding affinities of unimolecular mimics of the substrate and first transition-state (TS1) in which the uracil base is covalently attached to the sugar, and in addition, bimolecular mimics of the second addition transition state (TS2) in which the base and sugar are detached. We find that the bipartite mimics of TS2 are superior to the TS1 mimics. These results indicate that bipartite TS2 inhibitors could be useful for inhibition of glycosylases that proceed by stepwise reaction mechanisms.

摘要

尿嘧啶DNA糖基化酶（UDG）的糖苷键水解反应通过两步机制进行，第一步涉及与尿嘧啶阴离子离去基团的完全键断裂，形成离散的糖基阳离子 - 尿嘧啶阴离子中间体，随后在第二个过渡态中发生水攻击，导致形成与酶结合的尿嘧啶和无碱基DNA产物。我们合成并测定了底物和第一个过渡态（TS1）的单分子模拟物的结合亲和力，其中尿嘧啶碱基共价连接到糖上，此外，还合成并测定了第二个加成过渡态（TS2）的双分子模拟物的结合亲和力，其中碱基和糖是分离的。我们发现TS2的二分模拟物优于TS1模拟物。这些结果表明，二分TS2抑制剂可能有助于抑制通过逐步反应机制进行的糖基化酶。