Divergent regulation of dihydrofolate reductase between malaria parasite and human host.
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.
Zhang
Kai
K
Department of Biology, The Catholic University of America, Washington, DC 20064, USA.
Rathod
Pradipsinh K
PK
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006790:Host-Parasite Interactions; D006801:Humans; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016053:RNA, Protozoan / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology
D000962:Antimalarials; D005493:Folic Acid Antagonists; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D016053:RNA, Protozoan; D011994:Recombinant Proteins; D014227:Triazines; C056930:thymidylate synthase-dihydrofolate reductase; C006201:BRL 6231; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase