Valine feeding reduces ammonia production through rearrangement of metabolic fluxes in central carbon metabolism of CHO cells.

Szczegóły
Abstrakt

Tytuł:: Valine feeding reduces ammonia production through rearrangement of metabolic fluxes in central carbon metabolism of CHO cells.
Autorzy:: Savizi ISP; Biotechnology Department, Faculty of Chemical Engineering, Tarbiat Modares University, P.O. Box 14155-4838, Tehran, Iran.
Maghsoudi N; Neuroscience Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran.
Motamedian E; Biotechnology Department, Faculty of Chemical Engineering, Tarbiat Modares University, P.O. Box 14155-4838, Tehran, Iran.
Lewis NE; Department of Bioengineering, University of California, La Jolla, San Diego, CA, USA.; School of Medicine, Novo Nordisk Foundation Center for Biosustainability at the University of California, La Jolla, San Diego, CA, USA.; Department of Pediatrics, School of Medicine, University of California, La Jolla, San Diego, CA, USA.
Shojaosadati SA; Biotechnology Department, Faculty of Chemical Engineering, Tarbiat Modares University, P.O. Box 14155-4838, Tehran, Iran. Shoja_.
Źródło:: Applied microbiology and biotechnology [Appl Microbiol Biotechnol] 2022 Feb; Vol. 106 (3), pp. 1113-1126. Date of Electronic Publication: 2022 Jan 19.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Berlin ; New York : Springer International, c1984-
MeSH Terms:: Ammonia*
Carbon*
Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Lactic Acid ; Valine
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Contributed Indexing:: Keywords: Amino acids; Ammonium; CHO cell; Sialylation; Systems biology
Substance Nomenclature:: 33X04XA5AT (Lactic Acid)
7440-44-0 (Carbon)
7664-41-7 (Ammonia)
HG18B9YRS7 (Valine)
Entry Date(s):: Date Created: 20220119 Date Completed: 20220208 Latest Revision: 20220208
Update Code:: 20240105
DOI:: 10.1007/s00253-021-11755-4
PMID:: 35044498
: Czasopismo naukowe

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Ammonia is a toxic byproduct of CHO cell metabolism, which inhibits cell growth, reduces cell viability, alters glycosylation, and decreases recombinant protein productivity. In an attempt to minimize the ammonium accumulation in cell culture media, different amino acids were added individually to the culture medium before the production phase to alleviate the negative effects of ammonium on cell culture performance. Among all the amino acids examined in this study, valine showed the most positive impact on CHO cell culture performance. When the cultured CHO cells were fed with 5 mM valine, EPO titer was increased by 25% compared to the control medium, and ammonium and lactate production were decreased by 23 and 26%, respectively, relative to the control culture. Moreover, the sialic acid content of the EPO protein in valine-fed culture was higher than in the control culture, most likely because of the lower ammonium concentration. Flux balance analysis (FBA) results demonstrated that the citric acid cycle was enriched by valine feeding. The measurement of TCA cycle activity supported this finding. The analysis revealed that there might be a link between promoting tricarboxylic acid (TCA) cycle metabolism in valine-fed culture and reduction in lactate and ammonia accumulation. Furthermore, in valine-fed culture, FBA outcomes showed that alanine was excreted into the medium as the primary mechanism for reducing ammonium concentration. It was predicted that the elevated TCA cycle metabolism was concurrent with an increment in recombinant protein production. Taken together, our data demonstrate that valine addition could be an effective strategy for mitigating the negative impacts of ammonium and enhancing glycoprotein production in both quality and quantity. KEY POINTS: • Valine feeding can mitigate the negative impacts of ammonia on CHO cell growth. • Valine addition assists the ammonia removal mechanism by enriching the TCA cycle. • Ammonia is removed from the media through alanine excretion in valine-fed culture.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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