EXPLORING THE MOLECULAR MECHANISM OF DIHYDROFOLATE-REDUCTASE

被引:44
作者
BROWN, KA
KRAUT, J
机构
来源
FARADAY DISCUSSIONS | 1992年 / 93卷
关键词
D O I
10.1039/fd9929300217
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
A description of the transition-state complex of the enzyme dihydrofolate reductase is presented based upon extensive crystallographic studies of substrate/cofactor complexes from various sources. Structural elements of DHFR have been identified which contribute in different ways to effect the chemical step involving protonation and hydride transfer. Emphasis is placed upon residues, structures and solvent which create the appropriate environment for stabilization of the positively charged carbenium ions which are thought to be developed in the transition state of the enzyme-catalysed reaction. Changes in the positions of the substrate and cofactor in the active site which must occur to achieve the correct geometry for hydride transfer are also described. Finally, the structures of several site-directed mutants of DHFR are presented and the results are discussed in the context of the proposed structure for the transition state.
引用
收藏
页码:217 / 224
页数:8
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