CHOmpact: A reduced metabolic model of Chinese hamster ovary cells with enhanced interpretability

Author:

Jiménez del Val Ioscani1ORCID,Kyriakopoulos Sarantos2,Albrecht Simone3,Stockmann Henning3,Rudd Pauline M.3,Polizzi Karen M.4ORCID,Kontoravdi Cleo4

Affiliation:

1. School of Chemical & Bioprocess Engineering University College Dublin Dublin Ireland

2. Manufacturing Science and Technology BioMarin Pharmaceutical Cork Ireland Ireland

3. GlycoScience Group National Institute for Bioprocessing Research and Training Dublin Ireland

4. Department of Chemical Engineering Imperial College London London UK

Abstract

AbstractMetabolic modeling has emerged as a key tool for the characterization of biopharmaceutical cell culture processes. Metabolic models have also been instrumental in identifying genetic engineering targets and developing feeding strategies that optimize the growth and productivity of Chinese hamster ovary (CHO) cells. Despite their success, metabolic models of CHO cells still present considerable challenges. Genome‐scale metabolic models (GeMs) of CHO cells are very large (>6000 reactions) and are difficult to constrain to yield physiologically consistent flux distributions. The large scale of GeMs also makes the interpretation of their outputs difficult. To address these challenges, we have developed CHOmpact, a reduced metabolic network that encompasses 101 metabolites linked through 144 reactions. Our compact reaction network allows us to deploy robust, nonlinear optimization and ensure that the computed flux distributions are physiologically consistent. Furthermore, our CHOmpact model delivers enhanced interpretability of simulation results and has allowed us to identify the mechanisms governing shifts in the anaplerotic consumption of asparagine and glutamate as well as an important mechanism of ammonia detoxification within mitochondria. CHOmpact, thus, addresses key challenges of large‐scale metabolic models and will serve as a platform to develop dynamic metabolic models for the control and optimization of biopharmaceutical cell culture processes.

Funder

Science Foundation Ireland

Biotechnology and Biological Sciences Research Council

Engineering and Physical Sciences Research Council

Publisher

Wiley

Subject

Applied Microbiology and Biotechnology,Bioengineering,Biotechnology

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