Glucose-6-Phosphate Dehydrogenase of Trypanosomatids: Characterization, Target Validation, and Drug Discovery

摘要

In trypanosomatids, glucose-6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentosephosphate pathway, is essential for the defense of the parasite against oxidative stress.Trypanosoma brucei, Trypanosoma cruzi, andLeishmania mexicanaG6PDHs have been characterized. The parasites' G6PDHs contain a unique 37 amino acid long N-terminal extension that inT. cruziseems to regulate the enzyme activity in a redox-state-dependent manner.T. bruceiandT. cruziG6PDHs, but not theirLeishmaniaspp. counterpart, are inhibited, in an uncompetitive way, by steroids such as dehydroepiandrosterone and derivatives. TheTrypanosomaenzymes are more susceptible to inhibition by these compounds than the human G6PDH. The steroids also effectively kill cultured trypanosomes but notLeishmaniaand are presently considered as promising leads for the development of new parasite-selective chemotherapeutic agents.