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Glycobiology Advance Access originally published online on August 12, 2009
Glycobiology 2009 19(12):1382-1401; doi:10.1093/glycob/cwp115
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

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Metabolic glycoengineering: Sialic acid and beyond

Jian Du, M Adam Meledeo, Zhiyun Wang, Hargun S Khanna, Venkata D P Paruchuri and Kevin J Yarema1

Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA

1 To whom correspondence should be addressed: Tel: +1-410-516-4914; Fax: +1-410-516-8152; e-mail: kyarema1{at}jhu.edu

Received on June 12, 2009; revised on July 28, 2009; accepted on July 28, 2009

This report provides a perspective on metabolic glycoengineering methodology developed over the past two decades that allows natural sialic acids to be replaced with chemical variants in living cells and animals. Examples are given demonstrating how this technology provides the glycoscientist with chemical tools that are beginning to reproduce Mother Nature's control over complex biological systems – such as the human brain – through subtle modifications in sialic acid chemistry. Several metabolic substrates (e.g., ManNAc, Neu5Ac, and CMP-Neu5Ac analogs) can be used to feed flux into the sialic acid biosynthetic pathway resulting in numerous – and sometime quite unexpected – biological repercussions upon nonnatural sialoside display in cellular glycans. Once on the cell surface, ketone-, azide-, thiol-, or alkyne-modified glycans can be transformed with numerous ligands via bioorthogonal chemoselective ligation reactions, greatly increasing the versatility and potential application of this technology. Recently, sialic acid glycoengineering methodology has been extended to other pathways with analog incorporation now possible in surface-displayed GalNAc and fucose residues as well as nucleocytoplasmic O-GlcNAc-modified proteins. Finally, recent efforts to increase the "druggability" of sugar analogs used in metabolic glycoengineering, which have resulted in unanticipated "scaffold-dependent" activities, are summarized.

Key words: carbohydrate-based drugs / glycosylation / metabolic glycoengineering / sialic acid


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