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A Markov chain model for N-linked protein glycosylation – towards a low-parameter tool for model-driven glycoengineering

Paper ID Volume ID Publish Year Pages File Format Full-Text
31476 44800 2016 15 PDF Available
Title
A Markov chain model for N-linked protein glycosylation – towards a low-parameter tool for model-driven glycoengineering
Abstract

•A non-kinetic low-parameter Markov model for N-glycosylation is presented.•The model is fit to experimental glycoprofiles.•The model can be used to predict the effect of glycosyltransferase knock-downs.•We show validation data on IgG, EPO and the secretome.

Glycosylation is a critical quality attribute of most recombinant biotherapeutics. Consequently, drug development requires careful control of glycoforms to meet bioactivity and biosafety requirements. However, glycoengineering can be extraordinarily difficult given the complex reaction networks underlying glycosylation and the vast number of different glycans that can be synthesized in a host cell. Computational modeling offers an intriguing option to rationally guide glycoengineering, but the high parametric demands of current modeling approaches pose challenges to their application. Here we present a novel low-parameter approach to describe glycosylation using flux-balance and Markov chain modeling. The model recapitulates the biological complexity of glycosylation, but does not require user-provided kinetic information. We use this method to predict and experimentally validate glycoprofiles on EPO, IgG as well as the endogenous secretome following glycosyltransferase knock-out in different Chinese hamster ovary (CHO) cell lines. Our approach offers a flexible and user-friendly platform that can serve as a basis for powerful computational engineering efforts in mammalian cell factories for biopharmaceutical production.

Keywords
GlcNAc, N-acetylglucosamine; GalT, β-1-4-galactosyltransferase; Fut8, α-1-6-fucosyltransferase 8; GnTIV, N-acetylglucosamine-transferase IV; CHO, Chinese hamster ovary; EPO, erythropoietin; mAb, monoclonal antibody; IgG, immunoglobulinGlycosylation; Glyco
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A Markov chain model for N-linked protein glycosylation – towards a low-parameter tool for model-driven glycoengineering
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Publisher
Database: Elsevier - ScienceDirect
Journal: Metabolic Engineering - Volume 33, January 2016, Pages 52–66
Authors
, , , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us