Reduction of anti-leishmanial pentavalent antimonial drugs by a parasite-specific thiol-dependent reductase, TDR1.
The reason why Leishmania parasites are susceptible to organic antimonial drugs, the standard chemotherapeutic agents for over 50 years, apparently lies in the fact that the mammalian stage of the parasite reduces the pentavalent form of the administered drug to a trivalent form that causes parasite death. We have identified and characterized a parasite-specific enzyme that can catalyse the reduction of pentavalent antimonials and may therefore be central to the anti-parasite activity of the drug. The unusual protein, a trimer of two-domain monomers in which each domain has some similarity to the Omega class glutathione S-transferases, is a thiol-dependent reductase (designated TDR1) that converts pentavalent antimonials into trivalent antimonials using glutathione as the reductant. The higher abundance of the enzyme in the mammalian stage of the parasite could explain why this parasite form is more susceptible to the drug.
Denton
Helen
H
Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Joseph Black Building, Glasgow G12 8QQ, UK.
McGregor
Joanne C
JC
Coombs
Graham H
GH
D000595:Amino Acid Sequence; D000818:Animals; D000965:Antimony / Q000378:metabolism; D000967:Antimony Sodium Gluconate / Q000378:metabolism; D000981:Antiprotozoal Agents / Q000378:metabolism*; D001151:Arsenic / Q000378:metabolism; D003001:Cloning, Molecular / Q000379:methods; D054477:Glutaredoxins; D005982:Glutathione Transferase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018320:Leishmania major / Q000201:enzymology / Q000254:growth & development; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011490:Protein Disulfide Reductase (Glutathione) / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry; D011994:Recombinant Proteins / Q000235:genetics; D016415:Sequence Alignment / Q000379:methods
C097550:52-kDa protein, Trypanosoma cruzi; D000981:Antiprotozoal Agents; D054477:Glutaredoxins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D000965:Antimony; D010088:Oxidoreductases; C494061:TDR1 protein, Leishmania major; D011490:Protein Disulfide Reductase (Glutathione); C020666:glutathione dehydrogenase (ascorbate); C490476:GSTO1 protein, human; D005982:Glutathione Transferase; D001151:Arsenic; D000967:Antimony Sodium Gluconate