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Cysteine synthase: multiple structures of a key enzyme in cysteine synthesis and a potential drug target for Chagas disease and leishmaniasis

Sowerby, Kate; Freitag-Pohl, Stefanie; Murillo, Ana Milena; Silber, Ariel Mariano; Pohl, Ehmke

Cysteine synthase: multiple structures of a key enzyme in cysteine synthesis and a potential drug target for Chagas disease and leishmaniasis Thumbnail


Authors

Ana Milena Murillo

Ariel Mariano Silber



Abstract

Chagas disease is a neglected tropical disease (NTD) caused by Trypanosoma cruzi, whilst leishmaniasis, which is caused by over 20 species of Leishmania, represents a group of NTDs endemic to most countries in the tropical and subtropical belt of the planet. These diseases remain a significant health problem both in endemic countries and globally. These parasites and other trypano­somatids, including T. theileri, a bovine pathogen, rely on cysteine biosynthesis for the production of trypanothione, which is essential for parasite survival in hosts. The de novo pathway of cysteine biosynthesis requires the conversion of O-acetyl-L-serine into L-cysteine, which is catalysed by cysteine synthase (CS). These enzymes present potential for drug development against T. cruzi, Leishmania spp. and T. theileri. To enable these possibilities, biochemical and crystallographic studies of CS from T. cruzi (TcCS), L. infantum (LiCS) and T. theileri (TthCS) were conducted. Crystal structures of the three enzymes were determined at resolutions of 1.80 Å for TcCS, 1.75 Å for LiCS and 2.75 Å for TthCS. These three homodimeric structures show the same overall fold and demonstrate that the active-site geometry is conserved, supporting a common reaction mechanism. Detailed structural analysis revealed reaction intermediates of the de novo pathway ranging from an apo structure of LiCS and holo structures of both TcCS and TthCS to the substrate-bound structure of TcCS. These structures will allow exploration of the active site for the design of novel inhibitors. Additionally, unexpected binding sites discovered at the dimer interface represent new potential for the development of protein–protein inhibitors.

Journal Article Type Article
Acceptance Date Apr 20, 2023
Online Publication Date May 19, 2023
Publication Date 2023
Deposit Date Jun 14, 2023
Publicly Available Date Jun 14, 2023
Journal Acta Crystallographica Section D Structural Biology
Print ISSN 2059-7983
Publisher International Union of Crystallography
Peer Reviewed Peer Reviewed
Volume 79
Issue 6
Pages 518-530
DOI https://doi.org/10.1107/s2059798323003613
Public URL https://durham-repository.worktribe.com/output/1170142

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.






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