Unveiling the structural features of CysE: a novel target for therapeutic interventions against persistent mycobacteria

World Health Organization (WHO) reports that one-third of the world’s population is infected with a persistent form of Mycobacterium tuberculosis (M.tb), the causative bacterium responsible for causing the dreaded tuberculosis disease. Targeting mycobacterial persisters is important for achieving WHO’s End TB target. The de-novo cysteine biosynthetic pathway is a novel target for addressing M.tb persistence. The two-step pathway comprises of serine acetyltransferase/CysE and O-acetyl-serine-sulfhydrylase/OASS/CysK. The present study is an attempt to understand the structural features of mycobacterial CysE by investigating the divergence amongst orthologous through phylogenetic analysis. Mapping of mycobacterial CysE sequences on the whole orthologous (COG1045) tree segregated the species into four clusters and several isoforms leading to their descendants identification. Interestingly the analysis revealed that the extended C-terminal α-helix believed unique to M.tb is also present in other organisms such as: Campylobacter ureolyticus, Bacillus cereus, Geminocystis herdmanii and Paenibacillus borealis. Further, the Hidden Markov model search against the whole Uniprot database suggests a plausible role of C-terminal α-helix of CysE in strengthening the substrate and/or co-factor binding. In addition, phylogenetic analysis of CysE sequences from the Mycobacteriaceae family facilitates grouping them under ten well-formed and six monophyletic clades, each based on characteristic features with respect to domain architecture, oligomeric assembly, C-terminal tetra-peptide tail, regulatory and feedback mechanism etc. Employing molecular phylogeny in conjunction with structural analysis has provided detailed insights for mycobacterial CysEs as drug target