Glucose-6-phosphate dehydrogenase is the target for the trypanocidal action of human steroids

Shreedhara Gupta; Artur T Cordeiro; Paul A M Michels

doi:10.1016/j.molbiopara.2010.12.006

Glucose-6-phosphate dehydrogenase is the target for the trypanocidal action of human steroids

Mol Biochem Parasitol. 2011 Apr;176(2):112-5. doi: 10.1016/j.molbiopara.2010.12.006. Epub 2010 Dec 23.

Authors

Shreedhara Gupta¹, Artur T Cordeiro, Paul A M Michels

Affiliation

¹ Research Unit for Tropical Diseases, de Duve Institute, TROP 74.39, Avenue Hippocrate 74, B-1200 Brussels, Belgium. shree.chemistry@gmail.com

PMID: 21185333
DOI: 10.1016/j.molbiopara.2010.12.006

Abstract

Steroids such as dehydroepiandrosterone (DHEA) and epiandrosterone (EA) exert multiple effects in mammals including the inhibition of glucose-6-phosphate dehydrogenase (G6PDH). Initially, the inhibition was considered specific for the mammalian enzyme. The beneficial effect of these steroids on infections by protists and nematodes was attributed to stimulation of the immune system. However, we showed previously that DHEA and EA also inhibit Trypanosoma brucei and T. cruzi G6PDH, with low micromolar K(i)' values, but not the enzyme from Leishmania species, and kill in vitro cultured trypanosomes. We report here that, contrary to wild-type trypanosomes, mutant bloodstream-form T. brucei cells expressing L. mexicana G6PDH are not susceptible to the steroids, proving that G6PDH is the in situ target. Moreover, bromo-derivatives of the steroids show 50-100 fold lower K(i)' values for the enzyme and display an increased potency to kill the parasites. Therefore, the compounds offer promise for use in development of parasite-selective drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androsterone / pharmacology
Androsterone / therapeutic use
Cell Line
Chagas Disease / drug therapy
Chagas Disease / enzymology
Dehydroepiandrosterone / pharmacology
Dehydroepiandrosterone / therapeutic use
Dose-Response Relationship, Drug
Drug Design
Glucosephosphate Dehydrogenase / antagonists & inhibitors*
Glucosephosphate Dehydrogenase / genetics
Glucosephosphate Dehydrogenase / metabolism
Humans
Leishmania mexicana / enzymology*
Leishmaniasis / drug therapy
Leishmaniasis / enzymology
Leishmaniasis / parasitology
Organisms, Genetically Modified
Protozoan Proteins / genetics
Protozoan Proteins / metabolism*
Species Specificity
Trypanocidal Agents / pharmacology
Trypanocidal Agents / therapeutic use
Trypanosoma brucei brucei / cytology
Trypanosoma brucei brucei / enzymology
Trypanosoma cruzi / cytology
Trypanosoma cruzi / enzymology
Trypanosomiasis, African / drug therapy
Trypanosomiasis, African / enzymology

Substances

Protozoan Proteins
Trypanocidal Agents
Dehydroepiandrosterone
Androsterone
Glucosephosphate Dehydrogenase