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Streptococcus pneumoniae NanC. Structural insights into the specificity and mechanism of a sialidase that produces a sialidase inhibitor

Research output: Contribution to journalArticle

Author(s)

C. David Owen, Petra Lukacik, Jane A. Potter, Olivia Sleator, Garry L. Taylor, Martin A. Walsh

School/Research organisations

Abstract

Streptococcus pneumoniae is an important human pathogen that causes a range of disease states. Sialidases are important bacterial virulence factors. There are three pneumococcal sialidases: NanA, NanB, and NanC. NanC is an unusual sialidase in that its primary reaction product is 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en, also known as DANA), a nonspecific hydrolytic sialidase inhibitor. The production of Neu5Ac2en from α2-3-linked sialosides by the catalytic domain is confirmed within a crystal structure. A covalent complex with 3-fluoro-β-N-acetylneuraminic acid is also presented, suggesting a common mechanism with other sialidases up to the final step of product formation. A conformation change in an active site hydrophobic loop on ligand binding constricts the entrance to the active site. In addition, the distance between the catalytic acid/base (Asp-315) and the ligand anomeric carbon is unusually short. These features facilitate a novel sialidase reaction in which the final step of product formation is direct abstraction of the C3 proton by the active site aspartic acid, forming Neu5Ac2en. NanC also possesses a carbohydrate-binding module, which is shown to bind α2-3- and α2-6-linked sialosides, as well as N-acetylneuraminic acid, which is captured in the crystal structure following hydration of Neu5Ac2en by NanC. Overall, the pneumococcal sialidases show remarkable mechanistic diversity while maintaining a common structural scaffold.

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Details

Original languageEnglish
Pages (from-to)27736-27748
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number46
Early online date14 Sep 2015
DOIs
StatePublished - 13 Nov 2015

    Research areas

  • Glycoside hydrolase, Neuraminidase, Sialic acid, Sialidase, Streptococcus, NanC, Carbohydrate-binding module, neu5ac2en, Pneumococcus

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