Abstract
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, and Leishmania mexicana G6PDHs have been characterized. The parasites' G6PDHs contain a unique 37 amino acid long N-terminal extension that in T. cruzi seems to regulate the enzyme activity in a redox-state-dependent manner. T. brucei and T. cruzi G6PDHs, but not their Leishmania spp. counterpart, are inhibited, in an uncompetitive way, by steroids such as dehydroepiandrosterone and derivatives. The Trypanosoma enzymes are more susceptible to inhibition by these compounds than the human G6PDH. The steroids also effectively kill cultured trypanosomes but not Leishmania and are presently considered as promising leads for the development of new parasite-selective chemotherapeutic agents.
Highlights
The family Trypanosomatidae, belonging to the order Kinetoplastida, contains a large number of species, distributed over several genera
WT (−Tet) WT (+Tet) RNAiG6PDH A (−Tet) RNAiG6PDH A (+Tet) RNAiG6PDH B (−Tet) RNAiG6PDH B (+Tet). These RNA interference (RNAi) experiments genetically validated glucose-6-phosphate dehydrogenase (G6PDH) as a drug target in bloodstream forms of T. brucei and suggested that the NADPH produced by other enzymes than G6PDH is not sufficient to deal with oxidative stress experienced during normal or stress conditions (Figure 4)
The mechanism by which DHEA and EA kill T. brucei bloodstream forms has been evaluated, by exploiting the fact that these compounds showed no inhibitory effect on the recombinant L. mexicana G6PDH
Summary
The family Trypanosomatidae, belonging to the order Kinetoplastida, contains a large number of species, distributed over several genera. The humaninfective trypanosomatids are grouped in species of two genera, Trypanosoma and Leishmania They are responsible for a wide spectrum of diseases in tropical and subtropical countries. Different species of Leishmania cause a variety of clinical symptoms, collectively called Leishmaniases Leishmania transmission occurs via the byte of sandflies which inject metacyclic promastigote parasites into the skin These forms enter macrophages where they reside as multiplying amastigotes within the phagolysosomes [7]. Several enzymes involved in various metabolic processes have been characterized and established as promising drug targets [14, 15] Among these validated targets is glucose6-phosphate dehydrogenase (G6PDH; EC 1.1.1.49), a key enzyme of the pentosephosphate pathway. G6PDH deficiency is the most common human enzyme defect, occurring in more than 400 million people worldwide [21]
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