Cell factories for insulin production

The rapid increase in the number of diabetic patients globally and exploration of alternate insulin delivery methods such as inhalation or oral route that rely on higher doses, is bound to escalate the demand for recombinant insulin in near future. Current manufacturing technologies would be unable to meet the growing demand of affordable insulin due to limitation in production capacity and high production cost. Manufacturing of therapeutic recombinant proteins require an appropriate host organism with efficient machinery for posttranslational modifications and protein refolding. Recombinant human insulin has been produced predominantly using E. coli and Saccharomyces cerevisiae for therapeutic use in human. We would focus in this review, on various approaches that can be exploited to increase the production of a biologically active insulin and its analogues in E. coli and yeast. Transgenic plants are also very attractive expression system, which can be exploited to produce insulin in large quantities for therapeutic use in human. Plant-based expression system hold tremendous potential for high-capacity production of insulin in very cost-effective manner. Very high level of expression of biologically active proinsulin in seeds or leaves with long-term stability, offers a low-cost technology for both injectable as well as oral delivery of proinsulin.

[1]  L. Thim,et al.  BIOSYNTHESIS OF HUMAN INSULIN IN YEAST VIA SINGLE-CHAIN PRECURSORS , 1987 .

[2]  M. Aebi,et al.  Engineering N-linked protein glycosylation with diverse O antigen lipopolysaccharide structures in Escherichia coli. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. A. Carroll,et al.  High-yield production of a human therapeutic protein in tobacco chloroplasts , 2000, Nature Biotechnology.

[4]  M. Romanos Advances in the use of Pichia pastoris for high-level gene expression , 1995 .

[5]  B. Ahmad Review: Pharmacology of insulin: , 2004 .

[6]  Pichia Pastoris,et al.  Pichia pastoris , 2014 .

[7]  R. Chance,et al.  Research, Development, Production, and Safety of Biosynthetic Human Insulin , 1993, Diabetes Care.

[8]  C. Shin,et al.  Enhanced Production of Human Mini‐Proinsulin in Fed‐Batch Cultures at High Cell Density of Escherichia coli BL21(DE3) [pET‐3aT2M2] , 1997, Biotechnology progress.

[9]  A. Baum,et al.  Chapter 24. The Case for Recombinant Production of Pharmaceutical Proteins in Plants , 1999 .

[10]  H. Daniell,et al.  Low-cost production of proinsulin in tobacco and lettuce chloroplasts for injectable or oral delivery of functional insulin and C-peptide. , 2011, Plant biotechnology journal.

[11]  T. Takeuchi,et al.  Processing of mutated proinsulin with tetrabasic cleavage sites to bioactive insulin in the non‐endocrine cell line, COS‐7 , 1992, FEBS letters.

[12]  Sudhir Sahdev,et al.  Production of active eukaryotic proteins through bacterial expression systems: a review of the existing biotechnology strategies , 2007, Molecular and Cellular Biochemistry.

[13]  L. Thim,et al.  Secretion and processing of insulin precursors in yeast. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Sergio Tisminetzky,et al.  Application of simple fed-batch technique to high-level secretory production of insulin precursor using Pichia pastoris with subsequent purification and conversion to human insulin , 2010, Microbial cell factories.

[15]  Brendan Murphy,et al.  Biopharmaceuticals: An Industrial Perspective , 2009 .

[16]  S. Wild,et al.  Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. , 2004, Diabetes care.

[17]  Gary Walsh,et al.  Therapeutic insulins and their large-scale manufacture , 2005, Applied Microbiology and Biotechnology.

[18]  V. Celer,et al.  Expression of porcine circovirus 2 ORF2 gene requires codon optimized E. coli cells , 2007, Virus Genes.

[19]  G. Walsh Biopharmaceuticals : Approvals and addroval trends in 2004 , 2005 .

[20]  J. Cabral,et al.  Evaluation of bottlenecks in proinsulin secretion by Escherichia coli. , 2004, Journal of biotechnology.

[21]  Saurabh Aggarwal,et al.  What's fueling the biotech engine--2010 to 2011. , 2011, Nature biotechnology.

[22]  T. Gingeras,et al.  Isolation of alcohol oxidase and two other methanol regulatable genes from the yeast Pichia pastoris , 1985, Molecular and cellular biology.

[23]  H. P. Sørensen,et al.  Production of recombinant thermostable proteins expressed in Escherichia coli: completion of protein synthesis is the bottleneck. , 2003, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[24]  W. Duckworth,et al.  Recombinant DNA technology in the treatment of diabetes: insulin analogs. , 2001, Endocrine reviews.

[25]  Gary Walsh,et al.  Biopharmaceutical benchmarks 2010 , 2010, Nature Biotechnology.

[26]  M. Aebi,et al.  Substrate specificity of bacterial oligosaccharyltransferase suggests a common transfer mechanism for the bacterial and eukaryotic systems. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Hollenberg,et al.  Production of recombinant proteins by methylotrophic yeasts. , 1997, Current opinion in biotechnology.

[28]  B. Zinman,et al.  Insulins today and beyond , 2001, The Lancet.

[29]  Michael Goodman Market watch: Sales of biologics to show robust growth through to 2013 , 2009, Nature Reviews Drug Discovery.

[30]  D. Yansura,et al.  Production of Monoclonal Antibodies in E. coli , 2010 .

[31]  Christopher G. Tate,et al.  Overcoming barriers to membrane protein structure determination , 2011, Nature Biotechnology.

[32]  Adam C. Fisher,et al.  Production of Secretory and Extracellular N-Linked Glycoproteins in Escherichia coli , 2010, Applied and Environmental Microbiology.

[33]  N. Ferrer-Miralles,et al.  Bacterial cell factories for recombinant protein production; expanding the catalogue , 2013, Microbial Cell Factories.

[34]  T. Kjeldsen,et al.  Secretory expression and characterization of insulin in Pichia pastoris , 1999, Biotechnology and applied biochemistry.

[35]  M. Uhlén,et al.  Integrated production of human insulin and its C-peptide. , 1996, Journal of biotechnology.

[36]  Simon J North,et al.  N-linked glycosylation in Campylobacter jejuni and its functional transfer into E. coli. , 2002, Science.

[37]  L. Thöny-Meyer,et al.  Production of glycoprotein vaccines in Escherichia coli , 2010, Microbial cell factories.

[38]  C. Nykiforuk,et al.  Transgenic expression and recovery of biologically active recombinant human insulin from Arabidopsis thaliana seeds. , 2006, Plant biotechnology journal.

[39]  M. Morange,et al.  Microbial Cell Factories , 2006 .

[40]  Tom L. Blundell,et al.  Insulin: The Structure in the Crystal and its Reflection in Chemistry and Biology by , 1972 .

[41]  A. Burden The pharmacology of insulin , 1988 .

[42]  Saurabh Aggarwal,et al.  What's fueling the biotech engine? , 2007, Nature Biotechnology.

[43]  U. Ribel,et al.  The Mechanism of Protraction of Insulin Detemir, a Long-Acting, Acylated Analog of Human Insulin , 2004, Pharmaceutical Research.

[44]  Ronald E. Chance,et al.  Insulin Lispro (Humalog) , 1999 .

[45]  J. Kane,et al.  Effects of rare codon clusters on high-level expression of heterologous proteins in Escherichia coli. , 1995, Current opinion in biotechnology.

[46]  J. Tschopp,et al.  High-Level Secretion of Glycosylated Invertase in the Methylotrophic Yeast, Pichia Pastoris , 1987, Bio/Technology.

[47]  Jie Yu,et al.  A plant-based cholera toxin B subunit–insulin fusion protein protects against the development of autoimmune diabetes , 1998, Nature Biotechnology.

[48]  A. C. Chang,et al.  Construction of biologically functional bacterial plasmids in vitro. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[49]  P. Wright,et al.  Improving N‐glycosylation efficiency in Escherichia coli using shotgun proteomics, metabolic network analysis, and selective reaction monitoring , 2011, Biotechnology and bioengineering.

[50]  D. Owens,et al.  Comparison of Subcutaneous Soluble Human Insulin and Insulin Analogues (AspB9, GluB27; AspB10; AspB28) on Meal-Related Plasma Glucose Excursions in Type I Diabetic Subjects , 1991, Diabetes Care.

[51]  Gary Walsh Biopharmaceuticals : Approval Trends in 2007 , 2006 .

[52]  M. Aebi,et al.  N-Linked glycosylation of antibody fragments in Escherichia coli. , 2011, Bioconjugate chemistry.

[53]  Antonio Villaverde,et al.  Role of molecular chaperones in inclusion body formation , 2003, FEBS letters.

[54]  M. Moloney,et al.  Plant seed oil-bodies as carriers for foreign proteins. , 1995, Bio/technology.

[55]  S. Havelund,et al.  Prepro-leaders lacking N-linked glycosylation for secretory expression in the yeast Saccharomyces cerevisiae. , 1998, Protein expression and purification.

[56]  Tim W. Overton,et al.  Recombinant protein production in bacterial hosts. , 2014, Drug discovery today.

[57]  C. Hollenberg,et al.  Application of yeasts in gene expression studies: a comparison of Saccharomyces cerevisiae, Hansenula polymorpha and Kluyveromyces lactis -- a review. , 1997, Gene.

[58]  Michael Sauer,et al.  Recombinant protein production in yeasts , 2005, Molecular biotechnology.

[59]  F. Wurm Production of recombinant protein therapeutics in cultivated mammalian cells , 2004, Nature Biotechnology.

[60]  V. Besada,et al.  Multiple gene copy number enhances insulin precursor secretion in the yeast Pichia pastoris , 2005, Biotechnology Letters.

[61]  A. Marco Protocol for preparing proteins with improved solubility by co-expressing with molecular chaperones in Escherichia coli , 2007, Nature Protocols.

[62]  J. Brange,et al.  Monomeric insulins obtained by protein engineering and their medical implications , 1988, Nature.

[63]  Nigel Jenkins,et al.  Modifications of therapeutic proteins: challenges and prospects , 2007, Cytotechnology.

[64]  J. Tschopp,et al.  Size distribution and general structural features of N‐linked oligosaccharides from the methylotrophic yeast, Pichia pastoris , 1989, Yeast.

[65]  Jin Hou,et al.  Metabolic engineering of recombinant protein secretion by Saccharomyces cerevisiae. , 2012, FEMS yeast research.

[66]  Saurabh Aggarwal,et al.  What's fueling the biotech engine—2012 to 2013 , 2014, Nature Biotechnology.

[67]  S. Havelund,et al.  Effect of fatty acids and selected drugs on the albumin binding of a long-acting, acylated insulin analogue. , 1997, Journal of pharmaceutical sciences.

[68]  Jens Nielsen,et al.  Production of biopharmaceutical proteins by yeast , 2012, Bioengineered.

[69]  S. Wildt,et al.  The humanization of N-glycosylation pathways in yeast , 2005, Nature Reviews Microbiology.

[70]  Gary Walsh,et al.  Post-translational modifications in the context of therapeutic proteins , 2006, Nature Biotechnology.

[71]  Chung-Jr Huang,et al.  Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements , 2012, Journal of Industrial Microbiology & Biotechnology.

[72]  T. Kjeldsen,et al.  Yeast secretory expression of insulin precursors , 2000, Applied Microbiology and Biotechnology.

[73]  J. Pickup Biotechnology of insulin therapy , 1991 .

[74]  M. Piontek,et al.  High-level secretion of hirudin by Hansenula polymorpha —authentic processing of three different preprohirudins , 1995, Applied Microbiology and Biotechnology.

[75]  Michael Sauer,et al.  Production of recombinant proteins and metabolites in yeasts , 2011, Applied Microbiology and Biotechnology.

[76]  T. Gerngross,et al.  Advances in the production of human therapeutic proteins in yeasts and filamentous fungi , 2004, Nature Biotechnology.

[77]  Rachel Chen Bacterial expression systems for recombinant protein production: E. coli and beyond. , 2012, Biotechnology advances.

[78]  T. Gingeras,et al.  Expression of the lacZ gene from two methanol-regulated promoters in Pichia pastoris. , 1987, Nucleic acids research.

[79]  D R Owens,et al.  Monomeric Insulins and Their Experimental and Clinical Implications , 1990, Diabetes Care.

[80]  A. Bhattacharya,et al.  Dictyostelium discoideum—a promising expression system for the production of eukaryotic proteins , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[81]  Esther Vázquez,et al.  Microbial factories for recombinant pharmaceuticals , 2009 .

[82]  Gary Walsh,et al.  Biopharmaceutical benchmarks , 2000, Nature Biotechnology.