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 Ebdrup
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 Faustrup
AU - Voldborg, Bjørn Gunnar
AU - Gerdtzen, Ziomara P.
AU - Betenbaugh, Michael J.
AU - Palsson, Bernhard
AU - Andersen, Mikael Rørdam
AU - Nielsen, Lars K.
AU - Borth, Nicole
AU - Lee, Dong-Yup
AU - Lewis, Nathan E.
PY - 2016
Y1 - 2016
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.
KW - CHO
KW - Chinese hamster ovary
KW - Biotherapeutic protein production
KW - Genome-scale model
KW - Metabolic network
KW - Systems biology
U2 - 10.1016/j.cels.2016.10.020
DO - 10.1016/j.cels.2016.10.020
M3 - Journal article
C2 - 27883890
SN - 2405-4712
VL - 3
SP - 434
EP - 443
JO - Cell Systems
JF - Cell Systems
IS - 5
ER -