Abstract
Leishmaniasis is a neglected disease caused by Leishmania, an intracellular protozoan parasite which possesses a unique thiol metabolism based on trypanothione. Trypanothione is used as a source of electrons by the tryparedoxin/tryparedoxin peroxidase system (TXN/TXNPx) to reduce the hydroperoxides produced by macrophages during infection. This detoxification pathway is not only unique to the parasite but is also essential for its survival; therefore, it constitutes a most attractive drug target. Several forms of TXNPx, with very high sequence identity to one another, have been found in Leishmania strains, one of which has been used as a component of a potential anti-leishmanial polyprotein vaccine. The structures of cytosolic TXN and TXNPx from L. major (LmTXN and LmTXNPx) offer a unique opportunity to study peroxide reduction in Leishmania parasites at a molecular level, and may provide new tools for multienzyme inhibition-based drug discovery. Structural analyses bring out key structural features to elucidate LmTXN and LmTXNPx function. LmTXN displays an unusual N-terminal α-helix which allows the formation of a stable domain-swapped dimer. In LmTXNPx, crystallized in reducing condition, both the locally unfolded (LU) and fully folded (FF) conformations, typical of the oxidized and reduced protein respectively, are populated. The structural analysis presented here points to a high flexibility of the loop that includes the peroxidatic cysteine which facilitates Cys52 to form an inter-chain disulfide bond with the resolving cysteine (Cys173), thereby preventing over-oxidation which would inactivate the enzyme. Analysis of the electrostatic surface potentials of both LmTXN and LmTXNPx unveils the structural elements at the basis of functionally relevant interaction between the two proteins. Finally, the structural analysis of TXNPx allows us to identify the position of the epitopes that make the protein antigenic and therefore potentially suitable to be used in an anti-leishmanial polyprotein vaccine.
Highlights
The term ‘‘Leishmaniasis’’ refers to a set of infectious diseases caused by protozoan parasites of the genus Leishmania, transmitted via the bite of phlebotomine sandflies
From the X-ray structure and from this model, we have identified the epitopes of tryparedoxin peroxidase, which is part of a potential threecomponent vaccine that is presently being studied in animal models and in human
The data on structural and solution properties reported in the present work reveal key structural features of LmTXN and LmTXNPx proteins that are relevant to their functional behavior
Summary
The term ‘‘Leishmaniasis’’ refers to a set of infectious diseases caused by protozoan parasites of the genus Leishmania, transmitted via the bite of phlebotomine sandflies. The trypanothione-dependent hydroperoxide metabolism, characteristic of Leishmania and Trypanosoma species, has been recognised as a promising potential target for antileishmanial drugs since it is both absent in the host and most of its components are essential to parasite survival [3,4,5,6,7,8]. These parasites lack catalase, selenium-dependent peroxidases, glutathione reductase and thioredoxin reductase, and their antioxidant defence is based on a system of enzymes that depends on the unique dithiol trypanothione (N1,N8-bis(glutathionyl)spermidine, T(SH)2)
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