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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

DOI: 10.1107/S2059798323003613 DOI Help

Authors: Kate Sowerby (Durham University) , Stefanie Freitag-Pohl (Durham University) , Ana Milena Murillo (University of Sao Paulo) , Ariel Mariano Silber (University of Sao Paulo) , Ehmke Pohl (University of Durham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section D Structural Biology , VOL 79

State: Published (Approved)
Published: June 2023
Diamond Proposal Number(s): 24948

Open Access Open Access

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 Keywords: amino-acid metabolism; cysteine synthase; PLP-dependent enzymes; X-ray crystallography; Chagas disease; leishmaniasis; Trypanosoma theileri; Trypanosoma cruzi; Leishmania infantum

Diamond Keywords: Chagas Disease; Leishmaniasis; Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 21/05/2023 16:32

Acta Crystallographica Section D - 2023 - Sowerby - Cysteine synthase multiple structures of a key enzyme in cysteine.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)