Mannosidase catches the boat

15-Apr-2009 - Canada

A boat conformation of the Michaelis complex of beta-mannosidase Man2A has been demonstrated by a collaboration of scientists in the UK and Canada.

Mannosidase catches the boat

Gideon Davies and Wendy Offen at the University of York and colleagues from Newcastle University, worked with scientists from Queen’s University, Ontario and University of British Columbia, Vancouver in a major collaborative, multi-disciplined effort. They have provided an intriguing snapshot of a boat shaped Michaelis complex, which provides a useful ‘missing-link’ in the conformational itinerary and also illustrates why sugar imidazoles are often such good glycosidase inhibitors.

The conformational itinerary of enzyme catalysed glycosyl transfer is a central topic in understanding conformational control of substitution. Mannosidases, biological catalysts that breakdown alpha- and beta-mannosides, have to overcome identical problems when directing displacement reactions at the anomeric centre. ‘Dissecting and understanding the reaction coordinate of enzymes is of great importance both fundamentally and to help aid the design of transition state mimicking inhibitors,’ Davies explains. ‘In this work we trap the Michaelis complex of an unhydrolysed substrate poised for catalysis in the active centre of beta-mannosidase, an enzyme that hydrolyses beta-mannosides.’

Mannose chemistry has always been a challenging area of research as synthesis of beta-mannosides are made difficult by unsympathetic anomeric and anchimeric effects, as well as steric hindrance.

The work presented here by the Davies group is valuable as it sheds new light on the related alpha-mannosidase transition states and will help aid inhibitor design, as alpha-mannosidases are particularly useful therapeutic targets. However future challenges facing the group include designing specific mannosidase inhibitors and their application in living cells.

Original article: Wendy A. Offen et al.; Chem. Commun. 2009

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