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Title: Structural studies of non-classical sialidases
Author: Owen, C. David
ISNI:       0000 0004 5992 0864
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2015
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Streptococcus pneumoniae is a common resident of the human nasorpharynx that can cause severe illness, including bacterial meningitis and pneumonia. Ruminococcus gnavus is a commensal resident of the human gastrointestinal tract, present in the vast majority and overrepresented in those with inflammatory bowel disease. Both bacteria exploit very different niches, however both make use of sialidases, a class of enzymes that releases terminal sialic acids from sialoglycoconjugates by hydrolysing the -glycosidic linkage. There are three pneumococcal sialidases: SpNanA, a hydrolytic sialdiase; SpNanB, an intra-molecular trans-sialidase; and SpNanC. The primary reaction product of SpNanC is Neu5Ac2en (2-deoxy-2,3-didehydro-N-acetylneuraminic acid, also known as DANA), a potent inhibitor of hydrolytic bacterial and viral sialidases. The crystal structure of SpNanC in complex with Neu5Ac2en has been solved and a reaction mechanism for its formation proposed. R. gnavus can grow on sialylated substrates however it does not grow on sialic acid. The crystal structure of RgNanH has also been solved, confirming that it is an intra-molecular trans-sialidase, like SpNanB, that produces 2,7-anhydro-Neu5Ac, a sialic acid derivative with an intra- molecular linkage. This suggests a method of partitioning an important carbon source in a competitive environment. These works highlight the importance of thorough structural characterisation of sialidases, because although they may appear superficially very similar, they have significant diversity in their reaction mechanisms and their responses to inhibitors.
Supervisor: Taylor, Garry L. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available