Abstract:
Pantetheinylation is a form of post-translational modification that is essential across all three domains of life and is responsible for activating a wide range of primary and secondary metabolic pathways. Such pathways include the biogenesis of essential fatty acids, polyketides and non-ribosomal peptides that serve as virulence factors in pathogenic bacteria. Phosphopantetheinyl transferases (PPTases) covalently attach the pantetheine (4'-PP) cofactor group to their recipient carrier proteins (CPs). CPs then carry the metabolic intermediates, covalently tethered to the long and flexible 4'-PP arm, from one reaction centre to the next. Pantetheine attachment by PPTases is thus essential for the activity of key biosynthetic pathways and ultimately for the viability of the organisms. This research focused on PPTases from two pathogenic bacteria, AcpS and PptT from Mycobacterium tuberculosis (Mtb) and PcpS from Pseudomonas aeruginosa (Pa), and on selected CPs (MbtL, PpsC and AcpM) from Mtb. Structural and functional studies have been carried out to aid in developing selective inhibitors of these bacterial PPTases.
