Neisseria meningitidis is one of the leading causes of bacterial meningitis worldwide. There are six-disease causing serogroups. Each serogroup is characterized by the capsular polysaccharides surrounding the pathogen. Our current focus, is the enzyme responsible for creating capsular polysaccharide in N. meningitidis serogroup W. The N. meningitidis serogroup W capsule polymerase enzyme, synthesizes a heteropolymer containing repeating units of α-1,4 linked galactose-sialic acid. While these sugars are important components of vaccines against meningococcal meningitis, there is relatively little mechanistic knowledge of the enzyme that synthesizes this polysaccharide. Increased mechanistic understanding will provide new avenues to optimize synthesis of well-defined carbohydrate structures for glycoconjugate vaccines. Our goal is to modulate activity of the capsule polymerase through (1) targeted site-directed mutagenesis and (2) competitive inhibition. In our work, we use chemoenzymatic synthesis to produce two modified CMP-Sialic Acid derivatives, CMP-SiaDAz and CMP-4-Ac-Sia. CMP-SiaDAz (diazirine-modified CMP-Sialic Acid) is a photo-crosslinking substrate that can aid in identification of catalytic amino acids. CMP-4-Ac-Sia (acetyl-modified CMP-Sialic Acid) is a chain terminating competitive inhibitor that can aid in controlling polysaccharide chain length. This presentation will describe our progress using these two tools and other interdisciplinary approaches to gain kinetic and mechanistic insight into the N. meningitidis capsule polymerase.

Chemoenzymatic strategies to investigate activity of a bifunctional Neisseria meningitidis capsule polymerase

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.