Plasmodium falciparum is the parasite responsible for more than 90% of deaths caused by the global epidemic of malaria.The enzyme thymidylate synthase-dihydrofolate reductase (TS-DHFR) is a major antimalarial drug target, and mutations in this enzyme have caused widespread resistance.Our work comprises the first systematic, mechanistic characterization of TS-DHFR and its non-active site regions.Our kinetic data show this bifunctional enzyme is regulated by elegant interdomain communication, as well as catalytic contributions from distant structural regions, far from the active sites. Understanding the role of these unique regions may lead to more specific, less toxic therapies.Also, molecular docking and virtual screening of this enzyme identified a lead compound which inhibits both wildtype and drug-resistant parasites.Co-crystal structures of enzyme with compound suggest a molecular basis for overcoming drug resistance.This work demonstrates how in-depth kinetic analyses can be used to identify novel intramolecular targets for rational drug design, and should be useful specially to students of enzymology, protein biochemistry and pharmacology.
Plasmodium falciparum is the parasite responsible for more than 90% of deaths caused by the global epidemic of malaria.The enzyme thymidylate synthase-dihydrofolate reductase (TS-DHFR) is a major antimalarial drug target, and mutations in this enzyme have caused widespread resistance.Our work comprises the first systematic, mechanistic characterization of TS-DHFR and its non-active site regions.Our kinetic data show this bifunctional enzyme is regulated by elegant interdomain communication, as well as catalytic contributions from distant structural regions, far from the active sites. Understanding the role of these unique regions may lead to more specific, less toxic therapies.Also, molecular docking and virtual screening of this enzyme identified a lead compound which inhibits both wildtype and drug-resistant parasites.Co-crystal structures of enzyme with compound suggest a molecular basis for overcoming drug resistance.This work demonstrates how in-depth kinetic analyses can be used to identify novel intramolecular targets for rational drug design, and should be useful specially to students of enzymology, protein biochemistry and pharmacology.
This work has been selected by scholars as being culturally important, and is part of the knowledge base of civilization as we know it. This work was reproduced from the original artifact, and...
Introduction to the Study of Malarial Diseases is a comprehensive book on the study of malaria, written by Reinhold Friedrich Ruge and first published in 1903. The book covers a wide range of topics...
This work has been selected by scholars as being culturally important, and is part of the knowledge base of civilization as we know it.This work is in the "public domain in the United States of...
Advances in understanding the molecular mechanisms of disease together with the advent of recombinant DNA and other technologies have opened opportunities for a vast array of novel therapeutic...
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