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

共 129 条

[21] OVERPRODUCTION OF A BIFUNCTIONAL THYMIDYLATE SYNTHETASE-DIHYDROFOLATE REDUCTASE AND DNA AMPLIFICATION IN METHOTREXATE-RESISTANT LEISHMANIA-TROPICA [J].

CODERRE, JA ;

BEVERLEY, SM ;

SCHIMKE, RT ;

SANTI, DV .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1983, 80 (08) :2132-2136

[22] Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+ [J].

Cody, V ;

Galitsky, N ;

Rak, D ;

Luft, JR ;

Pangborn, W ;

Queener, SF .

BIOCHEMISTRY, 1999, 38 (14) :4303-4312

[23] Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH [J].

Cody, V ;

Luft, JR ;

Pangborn, W .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2005, 61 :147-155

[24] Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523 [J].

Cody, V ;

Galitsky, N ;

Luft, JR ;

Pangborn, W ;

Rosowsky, A ;

Blakley, RL .

BIOCHEMISTRY, 1997, 36 (45) :13897-13903

[25] AMINO-ACID CHANGES LINKED TO PYRIMETHAMINE RESISTANCE IN THE DIHYDROFOLATE-REDUCTASE THYMIDYLATE SYNTHASE GENE OF PLASMODIUM-FALCIPARUM [J].

COWMAN, AF ;

MORRY, MJ ;

BIGGS, BA ;

CROSS, GAM ;

FOOTE, SJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (23) :9109-9113

[26] A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance [J].

Dale, GE ;

Broger, C ;

DArcy, A ;

Hartman, PG ;

DeHoogt, R ;

Jolidon, S ;

Kompis, I ;

Labhardt, AM ;

Langen, H ;

Locher, H ;

Page, MGP ;

Stuber, D ;

Then, RL ;

Wipf, B ;

Oefner, C .

JOURNAL OF MOLECULAR BIOLOGY, 1997, 266 (01) :23-30

[27]

Das JR, 2006, ANTICANCER RES, V26, P1877

[28] CRYSTAL-STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE-REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZAFOLATE [J].

DAVIES, JF ;

DELCAMP, TJ ;

PRENDERGAST, NJ ;

ASHFORD, VA ;

FREISHEIM, JH ;

KRAUT, J .

BIOCHEMISTRY, 1990, 29 (40) :9467-9479

[29] Metastatic osteosarcoma - Results of two consecutive therapeutic trials at St. Jude Children's Research Hospital [J].

Daw, NC ;

Billups, CA ;

Rodriguez-Galindo, C ;

McCarville, MB ;

Rao, BN ;

Cain, AM ;

Jenkins, JJ ;

Neel, MD ;

Meyer, WH .

CANCER, 2006, 106 (02) :403-412

[30] Sequence variations in the Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene and their relationship with pyrimethamine resistance [J].

de Pécoulas, PE ;

Tahar, R ;

Ouatas, T ;

Mazabraud, A ;

Basco, LK .

MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 1998, 92 (02) :265-273

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