Engineering of protein folding and secretion-strategies to overcome bottlenecks for efficient production of recombinant proteins.
CONCLUSIONS
Recombinant protein production has developed into a huge market with enormous positive implications for human health and for the future direction of a biobased economy. Limitations in the economic and technical feasibility of production processes are often related to bottlenecks of in vivo protein folding.


BACKGROUND
Based on cell biological knowledge, some major bottlenecks have been overcome by the overexpression of molecular chaperones and other folding related proteins, or by the deletion of deleterious pathways that may lead to misfolding, mistargeting, or degradation.


RESULTS
While important success could be achieved by this strategy, the list of reported unsuccessful cases is disappointingly long and obviously dependent on the recombinant protein to be produced. Singular engineering of protein folding steps may not lead to desired results if the pathway suffers from several limitations. In particular, the connection between folding quality control and proteolytic degradation needs further attention.


CONCLUSIONS
Based on recent understanding that multiple steps in the folding and secretion pathways limit productivity, synergistic combinations of the cell engineering approaches mentioned earlier need to be explored. In addition, systems biology-based whole cell analysis that also takes energy and redox metabolism into consideration will broaden the knowledge base for future rational engineering strategies.
1 Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU) , Vienna, Austria .
Marizela
M
Delic
Rebecca
R
Göngrich
Diethard
D
Mattanovich
Brigitte
B
Gasser
D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005057:Eukaryotic Cells / Q000378:metabolism; D006801:Humans; D015202:Protein Engineering; D017510:Protein Folding; D059748:Proteolysis; D011994:Recombinant Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D011994:Recombinant Proteins