Evolutionary divergence and comparative homology modeling analysis of LpxC enzyme from human pathogenic bacteria

Multidrug defiant organisms result in severe mortality and stand as a big challenge worldwide. The gram negative bacilli (GNB) in particular is a massive cause of concern with high levels of resistance due to novel mechanisms. This study deals with thorough analysis of the phylogeny, evolutionary divergence and protein tertiary structure analysis of an important drug target, the bacterial metallo-amidase enzyme LpxC. The LpxC enzyme exists universally in all the gram-negative bacteria and catalyzes the first committed step of Lipid A biosynthesis. Evolutionary divergence study revealed the lpxC gene to be under strong degree of purifying selection in many highly pathogenic bacterial species. Homology modeling of the LpxC enzyme from different human pathogenic bacteria was carried out along with critical model evaluation and structural alignment analysis. Investigation of clefts on the LpxC protein surface demonstrated the presence of specific residues within the substrate-binding cleft. Preference for different secondary structural elements within the major cleft was also noticed in the LpxC enzyme from the sixteen selected pathogenic bacterial species.