Transition-state analogs as inhibitors of human and malarial hypoxanthine-guanine phosphoribosyltransferases

被引：104

作者：

Li C.M. ^{[1
]}

Tyler P.C. ^{[2
]}

Furneaux R.H. ^{[2
]}

Kicska G. ^{[1
]}

Xu Y. ^{[3
]}

Grubmeyer C. ^{[3
]}

Girvin M.E. ^{[1
]}

Schramm V.L. ^{[1
]}

机构：

[1] Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461

[2] Carbohydrate Chemistry Team, Industrial Research Ltd., Lower Hutt

[3] Department of Biochemistry, Fels Research Institute, Temple University School of Medicine, Philadelphia

来源：

Nature Structural Biology | 1999年 / 6卷 / 6期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

D O I：

10.1038/9367

中图分类号：

学科分类号：

摘要：

The proposed transition state for hypoxanthine-guanine phosphoribosyltransferases (HGPRTs) has been used to design and synthesize powerful inhibitors that contain features of the transition state. The iminoribitols (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D- ribitol 5-phosphate (immucillinHP) and (1S)-1-(9-deazaguanin-9-yl)-1,4- dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinGP) are the most powerful inhibitors yet reported for both human and malarial HGPRTs. Equilibrium binding constants are >1,000-fold tighter than the binding of the nucleotide substrate. The NMR spectrum of malaria HGXPRT in the Michaelis complex reveals downfield hydrogen-bonded protons. The chemical shifts move farther downfield with bound inhibitor. The inhibitors are lead compounds for species-specific antibiotics against parasitic protozoa. The high-resolution crystal structure of human HGPRT with immucillinGP is reported in the companion paper.

引用

页码：582 / 587

页数：5

共 34 条

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