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Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors

Published online by Cambridge University Press:  01 November 2004

Y. YUTHAVONG ,
J. YUVANIYAMA ,
P. CHITNUMSUB ,
J. VANICHTANANKUL ,
S. CHUSACULTANACHAI ,
B. TARNCHOMPOO ,
T. VILAIVAN  and
S. KAMCHONWONGPAISAN
Y. YUTHAVONG
Affiliation:
National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Science Park, 113 Phaholyothin Road, Pathumthani 12120, Thailand
J. YUVANIYAMA
Affiliation:
Center for Protein Structure and Function and Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
P. CHITNUMSUB
Affiliation:
National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Science Park, 113 Phaholyothin Road, Pathumthani 12120, Thailand
J. VANICHTANANKUL
Affiliation:
National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Science Park, 113 Phaholyothin Road, Pathumthani 12120, Thailand
S. CHUSACULTANACHAI
Affiliation:
National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Science Park, 113 Phaholyothin Road, Pathumthani 12120, Thailand
B. TARNCHOMPOO
Affiliation:
National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Science Park, 113 Phaholyothin Road, Pathumthani 12120, Thailand
T. VILAIVAN
Affiliation:
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
S. KAMCHONWONGPAISAN
Affiliation:
National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Science Park, 113 Phaholyothin Road, Pathumthani 12120, Thailand
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Abstract

Dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Plasmodium falciparum, a validated target for antifolate antimalarials, is a dimeric enzyme with interdomain interactions significantly mediated by the junction region as well as the Plasmodium-specific additional sequences (inserts) in the DHFR domain. The X-ray structures of both the wild-type and mutant enzymes associated with drug resistance, in complex with either a drug which lost, or which still retains, effectiveness for the mutants, reveal features which explain the basis of drug resistance resulting from mutations around the active site. Binding of rigid inhibitors like pyrimethamine and cycloguanil to the enzyme active site is affected by steric conflict with the side-chains of mutated residues 108 and 16, as well as by changes in the main chain configuration. The role of important residues on binding of inhibitors and substrates was further elucidated by site-directed and random mutagenesis studies. Guided by the active site structure and modes of inhibitor binding, new inhibitors with high affinity against both wild-type and mutant enzymes have been designed and synthesized, some of which have very potent antimalarial activities against drug-resistant P. falciparum bearing the mutant enzymes.

Keywords

Plasmodium falciparummalariadihydrofolate reductasethymidylate synthaseantifolateresistancemutationsdrug targetdrug design
Type
Review Article
Information
Parasitology , Volume 130 , Issue 3 , March 2005 , pp. 249 - 259
Copyright
2005 Cambridge University Press

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