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Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation

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Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation. / Fyfe, Paul K.; Westrop, Gareth D.; Silva, Ana Marta; Coombs, Graham H.; Hunter, William N. (Lead / Corresponding author).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 29, 2012, p. 11693-11698.

Research output: Contribution to journalArticle

Harvard

Fyfe, PK, Westrop, GD, Silva, AM, Coombs, GH & Hunter, WN 2012, 'Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation' Proceedings of the National Academy of Sciences of the United States of America, vol 109, no. 29, pp. 11693-11698.

APA

Fyfe, P. K., Westrop, G. D., Silva, A. M., Coombs, G. H., & Hunter, W. N. (2012). Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation. Proceedings of the National Academy of Sciences of the United States of America, 109(29), 11693-11698doi: 10.1073/pnas.1202593109

Vancouver

Fyfe PK, Westrop GD, Silva AM, Coombs GH, Hunter WN. Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(29):11693-11698.

Author

Fyfe, Paul K.; Westrop, Gareth D.; Silva, Ana Marta; Coombs, Graham H.; Hunter, William N. (Lead / Corresponding author) / Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 29, 2012, p. 11693-11698.

Research output: Contribution to journalArticle

Bibtex - Download

@article{cbc1ae96599741ffb383993d532a59ac,
title = "Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation",
author = "Fyfe, {Paul K.} and Westrop, {Gareth D.} and Silva, {Ana Marta} and Coombs, {Graham H.} and Hunter, {William N.}",
year = "2012",
volume = "109",
number = "29",
pages = "11693--11698",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Leishmania TDR1 structure, a unique trimeric glutathione transferase capable of deglutathionylation and antimonial prodrug activation

A1 - Fyfe,Paul K.

A1 - Westrop,Gareth D.

A1 - Silva,Ana Marta

A1 - Coombs,Graham H.

A1 - Hunter,William N.

AU - Fyfe,Paul K.

AU - Westrop,Gareth D.

AU - Silva,Ana Marta

AU - Coombs,Graham H.

AU - Hunter,William N.

PY - 2012

Y1 - 2012

N2 - Thiol-dependent reductase I (TDR1), an enzyme found in parasitic Leishmania species and Trypanosoma cruzi, is implicated in deglutathionylation and activation of antimonial prodrugs used to treat leishmaniasis. The 2.3 Å resolution structure of TDR1 reveals a unique trimer of subunits each containing two glutathione-S-transferase (GST) domains. The similarities of individual domains and comparisons with GST classes suggest that TDR1 evolved by gene duplication, diversification, and gene fusion; a combination of events previously unknown in the GST protein superfamily and potentially explaining the distinctive enzyme properties of TDR1. The deglutathionylation activity of TDR1 implies that glutathione itself has regulatory intracellular roles in addition to being a precursor for trypanothione, the major low mass thiol present in trypanosomatids. We propose that activation of antiparasite Sb (V)-drugs is a legacy of the deglutathionylation activity of TDR1 and involves processing glutathione adducts with concomitant reduction of the metalloid to active Sb(III) species.

AB - Thiol-dependent reductase I (TDR1), an enzyme found in parasitic Leishmania species and Trypanosoma cruzi, is implicated in deglutathionylation and activation of antimonial prodrugs used to treat leishmaniasis. The 2.3 Å resolution structure of TDR1 reveals a unique trimer of subunits each containing two glutathione-S-transferase (GST) domains. The similarities of individual domains and comparisons with GST classes suggest that TDR1 evolved by gene duplication, diversification, and gene fusion; a combination of events previously unknown in the GST protein superfamily and potentially explaining the distinctive enzyme properties of TDR1. The deglutathionylation activity of TDR1 implies that glutathione itself has regulatory intracellular roles in addition to being a precursor for trypanothione, the major low mass thiol present in trypanosomatids. We propose that activation of antiparasite Sb (V)-drugs is a legacy of the deglutathionylation activity of TDR1 and involves processing glutathione adducts with concomitant reduction of the metalloid to active Sb(III) species.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84863884120&md5=074171ecffa956c10bd4a57eb7403c2c

U2 - 10.1073/pnas.1202593109

DO - 10.1073/pnas.1202593109

M1 - Article

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 29

VL - 109

SP - 11693

EP - 11698

ER -

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