TY - JOUR
T1 - A community reconstruction of Chinese hamster metabolism and structural systems biology elucidate metabolic rewiring in lactate-free CHO cells
AU - Di Giusto, Pablo
AU - Choi, Dong-Hyuk
AU - Antonakoudis, Athanasios
AU - Duraikannan, Vikash Gokul
AU - Craveur, Pierrick
AU - Cowie, Nicholas Luke
AU - Ganapathy, Tejaswini
AU - Ramesh, Kannan
AU - Benavidez-López, Santiago
AU - Orellana, Camila A.
AU - Jiménez, Natalia E.
AU - Dworkin, Leo Alexander
AU - Morrissey, James
AU - Marin de Mas, Igor
AU - Strain, Benjamin
AU - Valdez-Cruz, Norma A.
AU - Trujillo-Roldán, Mauricio A.
AU - Marzluf, Jannis
AU - Martínez, Verónica S.
AU - Zehetner, Leopold
AU - Altamirano, Claudia
AU - Vega-Letter, Ana Maria
AU - Priem, Bradley
AU - Cao, Haoyu Chris
AU - Hold, Martin
AU - Ma, Junyu
AU - Hong, Yi Fan
AU - Gopalakrishnan, Saratram
AU - Enuh, Blaise Manga
AU - Tarzi, Chaimaa
AU - Pang, Kuin Tian
AU - Angione, Claudio
AU - Zanghellini, Jürgen
AU - Kontoravdi, Cleo
AU - Hefzi, Hooman
AU - Betenbaugh, Michael J
AU - Nielsen, Lars K.
AU - Lakshmanan, Meiyappan
AU - Lee, Dong-Yup
AU - Richelle, Anne
AU - Lewis, Nathan E.
PY - 2026
Y1 - 2026
N2 - Genome-scale metabolic models (GEMs) are indispensable for studying cellular metabolism. We present iCHO3K, a community-consensus, manually curated reconstruction of the Chinese hamster metabolic network. Spanning 11,004 reactions linked to 3,597 genes, iCHO3K augments the network with 3,489 protein structures and physicochemical descriptors for >70% of 7,377 metabolites, enabling structure-aware analyses. We applied iCHO3K to contextualize transcriptomics and metabolomics from a fed-batch Chinese hamster ovary (CHO) cell line engineered to abolish lactate secretion. The model indicated reduced glycolytic flux with enhanced tricarboxylic acid (TCA) activity and elevated intracellular NADH and phosphoenolpyruvate (PEP), consistent with experimental measurements. Leveraging iCHO3K's structural annotations, we evaluated potential off-target binding of NADH and PEP across early glycolytic enzymes and identified a putative allosteric PEP interaction with phosphofructokinase, suggesting a structural mechanism underlying reduced glucose uptake and glycolytic flux. Overall, iCHO3K provides a framework for systematic multi-omics integration, improved flux prediction, and structure-guided mechanistic insight, advancing CHO cell engineering and biomanufacturing. A record of this paper's transparent peer review process is included in the supplemental information.
AB - Genome-scale metabolic models (GEMs) are indispensable for studying cellular metabolism. We present iCHO3K, a community-consensus, manually curated reconstruction of the Chinese hamster metabolic network. Spanning 11,004 reactions linked to 3,597 genes, iCHO3K augments the network with 3,489 protein structures and physicochemical descriptors for >70% of 7,377 metabolites, enabling structure-aware analyses. We applied iCHO3K to contextualize transcriptomics and metabolomics from a fed-batch Chinese hamster ovary (CHO) cell line engineered to abolish lactate secretion. The model indicated reduced glycolytic flux with enhanced tricarboxylic acid (TCA) activity and elevated intracellular NADH and phosphoenolpyruvate (PEP), consistent with experimental measurements. Leveraging iCHO3K's structural annotations, we evaluated potential off-target binding of NADH and PEP across early glycolytic enzymes and identified a putative allosteric PEP interaction with phosphofructokinase, suggesting a structural mechanism underlying reduced glucose uptake and glycolytic flux. Overall, iCHO3K provides a framework for systematic multi-omics integration, improved flux prediction, and structure-guided mechanistic insight, advancing CHO cell engineering and biomanufacturing. A record of this paper's transparent peer review process is included in the supplemental information.
U2 - 10.1016/j.cels.2026.101574
DO - 10.1016/j.cels.2026.101574
M3 - Journal article
C2 - 41990742
SN - 2405-4712
JO - Cell Systems
JF - Cell Systems
M1 - 101574
ER -