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

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 str...
Source: Acta Crystallographica Section D - Category: Biochemistry Authors: Tags: amino-acid metabolism cysteine synthase PLP-dependent enzymes X-ray crystallography Chagas disease leishmaniasis Trypanosoma theileri Trypanosoma cruzi Leishmania infantum research papers Source Type: research