TY - JOUR
T1 - A Consensus Genome-scale Reconstruction of Chinese Hamster Ovary Cell Metabolism
AU - Hefzi, Hooman
AU - Ang, Kok Siong
AU - Hanscho, Michael
AU - Bordbar, Aarash
AU - Ruckerbauer, David
AU - Lakshmanan, Meiyappan
AU - Orellana, Camila A.
AU - Baycin-Hizal, Deniz
AU - Huang, Yingxiang
AU - Ley, Daniel
AU - Martinez, Veronica S.
AU - Kyriakopoulos, Sarantos
AU - Jiménez, Natalia E.
AU - Zielinski, Daniel C.
AU - Quek, Lake-Ee
AU - Wulff, Tune
AU - Arnsdorf, Johnny
AU - Li, Shangzhong
AU - Lee, Jae Seong
AU - Paglia, Giuseppe
AU - Loira, Nicolas
AU - Spahn, Philipp N.
AU - Pedersen, Lasse E.
AU - Gutierrez, Jahir M.
AU - King, Zachary A.
AU - Lund, Anne Mathilde
AU - Nagarajan, Harish
AU - Thomas, Alex
AU - Abdel-Haleem, Alyaa M.
AU - Zanghellini, Juergen
AU - Kildegaard, Helene F.
AU - Voldborg, Bjørn G.
AU - Gerdtzen, Ziomara P.
AU - Betenbaugh, Michael J.
AU - Palsson, Bernhard O.
AU - Andersen, Mikael R.
AU - Nielsen, Lars K.
AU - Borth, Nicole
AU - Lee, Dong-Yup
AU - Lewis, Nathan E.
N1 - KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: National Institutes of Health[R35 GM119850]
PY - 2016/11/23
Y1 - 2016/11/23
N2 - Chinese hamster ovary (CHO) cells dominate biotherapeutic protein production and are widely used in mammalian cell line engineering research. To elucidate metabolic bottlenecks in protein production and to guide cell engineering and bioprocess optimization, we reconstructed the metabolic pathways in CHO and associated them with >1,700 genes in the Cricetulus griseus genome. The genome-scale metabolic model based on this reconstruction, iCHO1766, and cell-line-specific models for CHO-K1, CHO-S, and CHO-DG44 cells provide the biochemical basis of growth and recombinant protein production. The models accurately predict growth phenotypes and known auxotrophies in CHO cells. With the models, we quantify the protein synthesis capacity of CHO cells and demonstrate that common bioprocess treatments, such as histone deacetylase inhibitors, inefficiently increase product yield. However, our simulations show that the metabolic resources in CHO are more than three times more efficiently utilized for growth or recombinant protein synthesis following targeted efforts to engineer the CHO secretory pathway. This model will further accelerate CHO cell engineering and help optimize bioprocesses.
AB - Chinese hamster ovary (CHO) cells dominate biotherapeutic protein production and are widely used in mammalian cell line engineering research. To elucidate metabolic bottlenecks in protein production and to guide cell engineering and bioprocess optimization, we reconstructed the metabolic pathways in CHO and associated them with >1,700 genes in the Cricetulus griseus genome. The genome-scale metabolic model based on this reconstruction, iCHO1766, and cell-line-specific models for CHO-K1, CHO-S, and CHO-DG44 cells provide the biochemical basis of growth and recombinant protein production. The models accurately predict growth phenotypes and known auxotrophies in CHO cells. With the models, we quantify the protein synthesis capacity of CHO cells and demonstrate that common bioprocess treatments, such as histone deacetylase inhibitors, inefficiently increase product yield. However, our simulations show that the metabolic resources in CHO are more than three times more efficiently utilized for growth or recombinant protein synthesis following targeted efforts to engineer the CHO secretory pathway. This model will further accelerate CHO cell engineering and help optimize bioprocesses.
UR - http://hdl.handle.net/10754/622161
UR - http://www.sciencedirect.com/science/article/pii/S2405471216303635
UR - http://www.scopus.com/inward/record.url?scp=84996956349&partnerID=8YFLogxK
U2 - 10.1016/j.cels.2016.10.020
DO - 10.1016/j.cels.2016.10.020
M3 - Article
C2 - 27883890
SN - 2405-4712
VL - 3
SP - 434-443.e8
JO - Cell Systems
JF - Cell Systems
IS - 5
ER -