Journal
SCIENCE
Volume 296, Issue 5567, Pages 545-547Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1068274
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Funding
- NIAID NIH HHS [AI40956, AI26912, R01 AI026912] Funding Source: Medline
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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.
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