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Science 19 April 2002:
Vol. 296. no. 5567, pp. 545 - 547
DOI: 10.1126/science.1068274
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Reports

Divergent Regulation of Dihydrofolate Reductase Between Malaria Parasite and Human Host

Kai Zhang, Pradipsinh K. Rathod*

For half a century, successful antifolate therapy against Plasmodium falciparum malaria has been attributed to host-parasite differences in drug binding to dihydrofolate reductase-thymidylate synthase (DHFR-TS). Selectivity may also arise through previously unappreciated differences in regulation of this drug target. The DHFR-TS of Plasmodium binds its cognate messenger RNA (mRNA) and inhibits its own translation. However, unlike translational regulation of DHFR or TS in humans, DHFR-TS mRNA binding is not coupled to enzyme active sites. Thus, antifolate treatment does not relieve translational inhibition and parasites cannot replenish dead enzyme.

Department of Chemistry, University of Washington, Seattle, WA 98195, USA, and Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
*   To whom correspondence should be addressed. E-mail: rathod{at}chem.washington.edu

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