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Bioinformatics Advance Access originally published online on October 7, 2008
Bioinformatics 2008 24(23):2740-2747; doi:10.1093/bioinformatics/btn515
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Systems-level modeling of cellular glycosylation reaction networks: O-linked glycan formation on natural selectin ligands

Gang Liu 1{dagger}, Dhananjay D. Marathe 1{dagger}, Khushi L. Matta 2 and Sriram Neelamegham 1,3,*

1Chemical and Biological Engineering, State University of New York, Buffalo, NY 14260, 2Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263 and 3NY State Center for Excellence in Bioinformatics and Life Sciences, State University of New York, Buffalo, NY 14260, USA

*To whom correspondence should be addressed.


  Abstract

Motivation: The emerging field of Glycomics requires the development of systems-based modeling strategies to relate glycosyltransferase gene expression and enzyme activity with carbohydrate structure and function.

Results: We describe the application of object oriented programming concepts to define glycans, enzymes, reactions, pathways and compartments for modeling cellular glycosylation reaction networks. These class definitions are combined with current biochemical knowledge to define potential reaction networks that participate in the formation of the sialyl Lewis-X (sLeX) epitope on O-glycans linked to a leukocyte cell-surface glycoprotein, P-selectin Glycoprotein Ligand-1 (PSGL-1). Subset modeling, hierarchical clustering, principal component analysis and adjoint sensitivity analysis are applied to refine the reaction network and to quantify individual glycosyltransferase rate constants. Wet-lab experiments validate estimates from computer modeling. Such analysis predicts that sLeX expression varies directly with sialyltransferase {alpha}2,3ST3Gal-IV expression and inversely with {alpha}2,3ST3Gal-I/II.

Availability: SBML files for all converged models are available at http://www.eng.buffalo.edu/~neel/bio_reaction_network.html

Contact: neel{at}eng.buffalo.edu

Supplementary information: Supplementary data are available at Bioinformatics online.

Associate Editor: Martin Bishop

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

Received on July 11, 2008; revised on September 3, 2008; accepted on October 2, 2008

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