Active Site Heterogeneity Drives Differential Sialic Acid Metabolism in Enterobacteriaceae Pathogens

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Abstract
Enterobacteriaceae pathogens like E. coli, Shigella and Salmonella are mainly associated with the food poisoning and various mucosa associated infections. These pathogens invade the host and rely on the host derived nutrients for their survival. One such nutrient is sialic acid (N-acetylneuraminic acid is the common one) which is present in the mucosal linings throughout the body. Ability of these pathogens to breakdown and utilize sialic acid for their growth is a crucial factor for their survival and pathogenesis. However, the heterogeneity among these enteric pathogens remains unstudied. In this study, we explored the difference in the sialic acid utilization pattern among these pathogens and found that the interactions between the N-acetylneuraminic acid (Neu-5-Ac) and the NanA, an enzyme that catalyze the breakdown of sialic acid play a key role for this heterogeneity. Additionally, we found that the Neu-5-Ac interacted differently with the NanA from each strain because of the variations in the active sites/contact sites which made the strains to utilize sialic acid different. Finally, our results provide an insight into the current understanding of sialiobiology research by highlighting the active site/contact sites differences drived the pathogens’ ability to adapt to diverse host environments, potentially altering their pathogenicity and resistance to host immune responses. This study provides new insights into the evolution of Enterobacteriaceae and suggest potential targets for therapeutic intervention aimed at disrupting sialic acid utilization.

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