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The impact of phosphate scarcity on pharmaceutical protein production in S. cerevisiae: linking transcriptomic insights to phenotypic responses

Kazemi Seresht, Ali, 1980 (author)
Chalmers tekniska högskola,Chalmers University of Technology
Palmqvist, E. A. (author)
Novo Nordisk A/S,Novo Nordisk
Olsson, Lisbeth, 1963 (author)
Chalmers tekniska högskola,Chalmers University of Technology
 (creator_code:org_t)
2011-12-07
2011
English.
In: Microbial Cell Factories. - : Springer Science and Business Media LLC. - 1475-2859. ; 10
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Background:The adaptation of unicellular organisms like Saccharomyces cerevisiae to alternating nutrient availability is of great fundamental and applied interest, as understanding how eukaryotic cells respond to variations in their nutrient supply has implications spanning from physiological insights to biotechnological applications.Results:The impact of a step-wise restricted supply of phosphate on the physiological state of S. cerevisiae cells producing human Insulin was studied. The focus was to determine the changes within the global gene expression of cells being cultured to an industrially relevant high cell density of 33 g/l cell dry weight and under six distinct phosphate concentrations, ranging from 33 mM (unlimited) to 2.6 mM (limited). An increased flux through the secretory pathway, being induced by the PHO circuit during low Pi supplementation, proved to enhance the secretory production of the heterologous protein. The re-distribution of the carbon flux from biomass formation towards increased glycerol production under low phosphate led to increased transcript levels of the insulin gene, which was under the regulation of the TPI1 promoter.Conclusions:Our study underlines the dynamic character of adaptive responses of cells towards a change in their nutrient access. The gradual decrease of the phosphate supply resulted in a step-wise modulated phenotypic response, thereby alternating the specific productivity and the secretory flux. Our work emphasizes the importance of reduced phosphate supply for improved secretory production of heterologous proteins.

Subject headings

TEKNIK OCH TEKNOLOGIER  -- Industriell bioteknik (hsv//swe)
ENGINEERING AND TECHNOLOGY  -- Industrial Biotechnology (hsv//eng)

Keyword

TPI1 promoter
Phosphate regulation
secretory flux
heterologous protein production
chemostat cultivations
human insulin

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art (subject category)
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