Mutational 'hot-spots' in mammalian, bacterial and protozoal dihydrofolate reductases associated with antifolate resistance: Sequence and structural comparison

被引：28

作者：

Volpato, Jordan P. ^{[2
]}

Pelletier, Joelle N. ^{[1
,2
]}

机构：

[1] Univ Montreal, Dept Chim, Montreal, PQ H3C 3J7, Canada

[2] Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada

来源：

DRUG RESISTANCE UPDATES | 2009年 / 12卷 / 1-2期

基金：

加拿大健康研究院;

关键词：

Dihydrofolate reductase; Mutations; Antifolate; Drug resistance; Homology; THYMIDYLATE SYNTHASE GENE; HEMATOPOIETIC STEM-CELLS; IN-VITRO SELECTION; ADENINE-DINUCLEOTIDE PHOSPHATE; ACUTE LYMPHOBLASTIC-LEUKEMIA; PLASMODIUM-FALCIPARUM DHFR; AMINO-ACID SUBSTITUTION; CHINESE-HAMSTER OVARY; PYRIMETHAMINE RESISTANCE; PNEUMOCYSTIS-CARINII;

D O I：

10.1016/j.drup.2009.02.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Human dihydrofolate reductase (DHFR) is a primary target for antifolate drugs in cancer treatment, while DHFRs from Plasmodium falciparum, Plasmodium vivax and various bacterial species are primary targets in the treatment of malaria and bacterial infections. Mutations in each of these DHFRs can result in resistance towards clinically relevant antifolates. We review the structural and functional impact of active-site mutations with respect to enzyme activity and antifolate resistance of DHFRs from mammals, protozoa and bacteria. The high structural homology between DHFRs results in a number of cross-species, active-site 'hot-spots' for broad-based antifolate resistance. In addition, we identify mutations that confer species-specific resistance, or antifolate-specific resistance. This comparative review of antifolate binding in diverse species provides new insights into the relationship between antifolate design and the development of mutational resistance. It also presents avenues for designing antifolate-resistant mammalian DHFRs as chemoprotective agents. (c) 2009 Elsevier Ltd. All rights reserved.

引用

页码：28 / 41

页数：14

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