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

Author(s)

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

• Document type: Journal article
• Source: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY; v. 79, p. 13-pg., 2023-06-01.

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 angstrom for TcCS, 1.75 angstrom for LiCS and 2.75 angstrom 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. (AU)

• FAPESP's process: 21/12938-0 - Amino acid metabolism in Trypanosoma cruzi: a toolbox to survive in hostile environments
• Grantee: Ariel Mariano Silber
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/16553-0 - The role of the mitochondrial and glycosomal isoforms of fumarate reductase of Trypanosoma Cruzi
• Grantee: Ariel Mariano Silber
• Support Opportunities: Research Grants - Visiting Researcher Grant - International