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Yeast Expression Systems: Overview and Recent Advances

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Abstract

Yeasts are outstanding hosts for the production of functional recombinant proteins with industrial or medical applications. Great attention has been emerged on yeast due to the inherent advantages and new developments in this host cell. For the production of each specific product, the most appropriate expression system should be identified and optimized both on the genetic and fermentation levels, considering the features of the host, vector and expression strategies. Currently, several new systems are commercially available; some of them are private and need licensing. The potential for secretory expression of heterologous proteins in yeast proposed this system as a candidate for the production of complex eukaryotic proteins. The common yeast expression hosts used for recombinant proteins’ expression include Saccharomyces cerevisiae, Pichia pastoris, Hansenula polymorpha, Yarrowia lipolytica, Arxula adeninivorans, Kluyveromyces lactis, and Schizosaccharomyces pombe. This review is dedicated to discuss on significant characteristics of the most common methylotrophic and non-methylotrophic yeast expression systems with an emphasis on their advantages and new developments.

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References

  1. Kim, H. J., & Kim, H. J. (2016). Yeast as an expression system for producing virus-like particles: What factors do we need to consider? Letters in Applied Microbiology, 64, 111–123.

    Article  CAS  PubMed  Google Scholar 

  2. Han, M., & Yu, X. (2015). Enhanced expression of heterologous proteins in yeast cells via the modification of N-glycosylation sites. Bioengineered, 6, 115–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nielsen, J. (2013). Production of biopharmaceutical proteins by yeast: Advances through metabolic engineering. Bioengineered, 4, 207–211.

    Article  PubMed  Google Scholar 

  4. Baghban, R., Farajnia, S., Ghasemi, Y., Mortazavi, M., Zarghami, N., & Samadi, N. (2018). New developments in Pichia pastoris expression system, review and update. Current Pharmaceutical Biotechnology, 19, 451–467.

    Article  CAS  PubMed  Google Scholar 

  5. Llopis, S., Hernandez-Haro, C., Monteoliva, L., Querol, A., Molina, M., & Fernández-Espinar, M. T. (2014). Pathogenic potential of Saccharomyces strains isolated from dietary supplements. PLoS ONE, 9, 1–21.

    Article  CAS  Google Scholar 

  6. Çelik, E., & Çalık, P. (2012). Production of recombinant proteins by yeast cells. Biotechnology Advances, 30, 1108–1118.

    Article  CAS  PubMed  Google Scholar 

  7. Matheson, K., Parsons, L., & Gammie, A. (2017). Whole-genome sequence and variant analysis of W303, a widely-used strain of Saccharomyces cerevisiae. G3 Genes Genomes Genetics, 7, 2219–2226.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Duina, A. A., Miller, M. E., & Keeney, J. B. (2014). Budding yeast for budding geneticists: A primer on the Saccharomyces cerevisiae model system. Genetics, 197, 33–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tesfaw, A., & Assefa, F. (2014) Current trends in bioethanol production by Saccharomyces cerevisiae: Substrate, inhibitor reduction, growth variables, coculture, and immobilization. International Scholarly Research Notices. https://doi.org/10.1155/2014/532852.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Liu, Z., Tyo, K. E., Martínez, J. L., Petranovic, D., & Nielsen, J. (2012). Different expression systems for production of recombinant proteins in Saccharomyces cerevisiae. Biotechnology and Bioengineering, 109, 1259–1268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hahn-Hägerdal, B., Karhumaa, K., Fonseca, C., Spencer-Martins, I., & Gorwa-Grauslund, M. F. (2007). Towards industrial pentose-fermenting yeast strains. Applied Microbiology and Biotechnology, 74, 937–953.

    Article  CAS  PubMed  Google Scholar 

  12. Biddick, R., & Young, E. T. (2009). The disorderly study of ordered recruitment. Yeast, 26, 205–220.

    Article  CAS  PubMed  Google Scholar 

  13. Hohmann, S., Krantz, M., & Nordlander, B. (2007) Yeast osmoregulation. Methods in Enzymology, 428, 29–45.

    Article  CAS  PubMed  Google Scholar 

  14. Murakami, C., & Kaeberlein, M. (2009). Quantifying yeast chronological life span by outgrowth of aged cells. Journal of Visualized Experiments, 27, 1–4.

    Google Scholar 

  15. Owsianowski, E., Walter, D., & Fahrenkrog, B. (2008). Negative regulation of apoptosis in yeast. Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, 1783, 1303–1310.

    Article  CAS  Google Scholar 

  16. Brocard-Masson, C., & Dumas, B. (2006). The fascinating world of steroids: S. cerevisiae as a model organism for the study of hydrocortisone biosynthesis. Biotechnology and Genetic Engineering Reviews, 22, 213–252.

    Article  CAS  PubMed  Google Scholar 

  17. López-Mirabal, H. R., & Winther, J. R. (2008). Redox characteristics of the eukaryotic cytosol. Biochimica et Biophysica Acta Molecular Cell Research, 1783, 629–640.

    Article  CAS  Google Scholar 

  18. Nasheuer, H.-P., Smith, R., Bauerschmidt, C., Grosse, F., & Weisshart, K. (2002). Initiation of eukaryotic DNA replication: Regulation and mechanisms. Progress in Nucleic Acid Research and Molecular Biology, 72, 41–94.

    Article  CAS  PubMed  Google Scholar 

  19. Munoz, A. J., Wanichthanarak, K., Meza, E., & Petranovic, D. (2012). Systems biology of yeast cell death. FEMS Yeast Research, 12, 249–265.

    Article  CAS  PubMed  Google Scholar 

  20. Miller-Fleming, L., Giorgini, F., & Outeiro, T. F. (2008). Yeast as a model for studying human neurodegenerative disorders. Biotechnology Journal, 3, 325–338.

    Article  CAS  PubMed  Google Scholar 

  21. Reggiori, F., & Klionsky, D. J. (2013). Autophagic processes in yeast: Mechanism, machinery and regulation. Genetics, 194, 341–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Karathia, H., Vilaprinyo, E., Sorribas, A., & Alves, R. (2011). Saccharomyces cerevisiae as a model organism: A comparative study. PLoS ONE, 6, 1–10.

    Article  CAS  Google Scholar 

  23. Tang, H., Wang, S., Wang, J., Song, M., Xu, M., Zhang, M., Shen, Y., Hou, J., & Bao, X. (2016). N-hypermannose glycosylation disruption enhances recombinant protein production by regulating secretory pathway and cell wall integrity in Saccharomyces cerevisiae. Scientific Reports 6, 1–13.

    Article  CAS  Google Scholar 

  24. Ahmad, M., Hirz, M., Pichler, H., & Schwab, H. (2014). Protein expression in Pichia pastoris: Recent achievements and perspectives for heterologous protein production. Applied Microbiology and Biotechnology, 98, 5301–5317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Demain, A. L., & Vaishnav, P. (2009). Production of recombinant proteins by microbes and higher organisms. Biotechnology Advances, 27, 297–306.

    Article  CAS  PubMed  Google Scholar 

  26. Xie,Y.,Han,X.andMiao,Y.(2018)An effective recombinant protein expression and purification system in Saccharomyces cerevisiae. Current Protocols in Molecular Biology, 123, 1–16.

    Article  CAS  Google Scholar 

  27. Muñoz, P., Bouza, E., Cuenca-Estrella, M., Eiros, J. M., Pérez, M. J., Sánchez-Somolinos, M., Rincón, C., Hortal, J., & Peláez, T. (2005). Saccharomyces cerevisiae fungemia: An emerging infectious disease. Clinical Infectious Diseases, 40, 1625–1634.

    Article  PubMed  Google Scholar 

  28. Bekatorou, A., Psarianos, C., & Koutinas, A. A. (2006). Production of food grade yeasts. Food Technology and Biotechnology, 44, 407–415.

    Google Scholar 

  29. Mortimer, R. K., & Johnston, J. R. (1986). Genealogy of principal strains of the yeast genetic stock center. Genetics, 113, 35–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Schacherer, J., Ruderfer, D. M., Gresham, D., Dolinski, K., Botstein, D., & Kruglyak, L. (2007). Genome-wide analysis of nucleotide-level variation in commonly used Saccharomyces cerevisiae strains. PLoS ONE, 2, 1–7.

    Article  CAS  Google Scholar 

  31. Charron, M. J., Dubin, R. A., & Michels, C. A. (1986). Structural and functional analysis of the MAL1 locus of Saccharomyces cerevisiae. Molecular and Cellular Biology, 6, 3891–3899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gagiano, M., Bauer, F. F., & Pretorius, I. S. (2002). The sensing of nutritional status and the relationship to filamentous growth in Saccharomyces cerevisiae. FEMS Yeast Research, 2, 433–470.

    CAS  PubMed  Google Scholar 

  33. Hanscho, M., Ruckerbauer, E., Chauhan, D., Hofbauer, N. F., Krahulec, H., Nidetzky, S., Kohlwein, B. D., Zanghellini, S., Natter, J., K (2012). Nutritional requirements of the BY series of Saccharomyces cerevisiae strains for optimum growth. FEMS Yeast Research, 12, 796–808.

    Article  CAS  PubMed  Google Scholar 

  34. Van Dijken, J., Bauer, J., Brambilla, L., Duboc, P., Francois, J., Gancedo, C., Giuseppin, M., Heijnen, J., Hoare, M., & Lange, H. (2000). An interlaboratory comparison of physiological and genetic properties of four Saccharomyces cerevisiae strains. Enzyme and Microbial Technology, 26, 706–714.

    Article  PubMed  Google Scholar 

  35. Nomura, M., Nakamori, S., & Takagi, H. (2003). Characterization of novel acetyltransferases found in budding and fission yeasts that detoxify a proline analogue, azetidine-2-carboxylic acid. Journal of Biochemistry, 133, 67–74.

    Article  CAS  PubMed  Google Scholar 

  36. Williams, R. M., Primig, M., Washburn, B. K., Winzeler, E. A., Bellis, M., de Menthiere, C. S., Davis, R. W., & Esposito, R. E. (2002). The Ume6 regulon coordinates metabolic and meiotic gene expression in yeast. Proceedings of the National Academy of Sciences of the United States of America, 99, 13431–13436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Young, C. L., Raden, D. L., & Robinson, A. S. (2013). Analysis of ER resident proteins in Saccharomyces cerevisiae: Implementation of H/KDEL retrieval sequences. Traffic, 14, 365–381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Madzak, C., & Beckerich, J.-M. (2013) Heterologous protein expression and secretion. In G. Barth (Eds.), Yarrowia lipolytica. Microbiology monographs (Vol. 25, pp. 1–76). Berlin: Springer.

    Chapter  Google Scholar 

  39. Santos, E. O., Michelon, M., Gallas, J. A., Kalil, S. J., & Burkert, C. A. V. (2013). Raw glycerol as substrate for the production of yeast biomass. International Journal of Food Engineering, 9, 413–420.

    CAS  Google Scholar 

  40. Bonnet, C., Rigaud, C., Chanteclaire, E., Blandais, C., Tassy-Freches, E., Arico, C., & Javaud, C. (2013). PCR on yeast colonies: An improved method for glyco-engineered Saccharomyces cerevisiae. BMC Research Notes, 6, 1–9.

    Article  CAS  Google Scholar 

  41. Piirainen, M. A., Boer, H., de Ruijter, J. C., & Frey, A. D. (2016). A dual approach for improving homogeneity of a human-type N-glycan structure in Saccharomyces cerevisiae. Glycoconjugate Journal, 33, 189–199.

    Article  CAS  PubMed  Google Scholar 

  42. DiCarlo, J. E., Norville, J. E., Mali, P., Rios, X., Aach, J., & Church, G. M. (2013). Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acids Research, 41, 4336–4343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Madzak, C., Gaillardin, C., & Beckerich, J.-M. (2004). Heterologous protein expression and secretion in the non-conventional yeast Yarrowia lipolytica: A review. Journal of Biotechnology, 109, 63–81.

    Article  CAS  PubMed  Google Scholar 

  44. Groenewald, M., Boekhout, T., Neuvéglise, C., Gaillardin, C., Van Dijck, P. W., & Wyss, M. (2014). Yarrowia lipolytica: Safety assessment of an oleaginous yeast with a great industrial potential. Critical Reviews in Microbiology, 40, 187–206.

    Article  CAS  PubMed  Google Scholar 

  45. Trassaert, M., Vandermies, M., Carly, F., Denies, O., Thomas, S., Fickers, P., & Nicaud, J.-M. (2017). New inducible promoter for gene expression and synthetic biology in Yarrowia lipolytica. Microbial Cell Factories, 16, 1–17.

    Article  CAS  Google Scholar 

  46. Madzak, C. (2015). Yarrowia lipolytica: Recent achievements in heterologous protein expression and pathway engineering. Applied Microbiology and Biotechnology, 99, 4559–4577.

    Article  CAS  PubMed  Google Scholar 

  47. Ryu, S., Hipp, J., & Trinh, C. T. (2016). Activating and elucidating metabolism of complex sugars in Yarrowia lipolytica. Applied and Environmental Microbiology, 82, 1334–1345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zimmermann, R., Eyrisch, S., Ahmad, M., & Helms, V. (2011). Protein translocation across the ER membrane. Biochimica et Biophysica Acta, 1808, 912–924.

    Article  CAS  PubMed  Google Scholar 

  49. Cui, W., Wang, Q., Zhang, F., Zhang, S. C., Chi, Z. M., & Madzak, C. (2011). Direct conversion of inulin into single cell protein by the engineered Yarrowia lipolytica carrying inulinase gene. Process Biochemistry, 46, 1442–1448.

    Article  CAS  Google Scholar 

  50. Liu, X. Y., Chi, Z., Liu, G. L., Wang, F., Madzak, C., & Chi, Z. M. (2010). Inulin hydrolysis and citric acid production from inulin using the surfaceengineered Yarrowia lipolytica displaying inulinase. Metabolic Engineering, 12, 469–476.

    Article  CAS  PubMed  Google Scholar 

  51. Looser, V., Bruhlmann, B., Bumbak, F., Stenger, C., Costa, M., Camattari, A., Fotiadis, D., & Kovar, K. (2015). Cultivation strategies to enhance the productivity of Pichia pastoris: A review. Biotechnology Advances, 33, 1177–1193.

    Article  CAS  PubMed  Google Scholar 

  52. Irani, Z. A., Kerkhoven, E. J., Shojaosadati, S. A., & Nielsen, J. (2016). Genome-scale metabolic model of Pichia pastoris with native and humanized glycosylation of recombinant proteins. Biotechnology and Bioengineering, 113, 961–969.

    Article  CAS  PubMed  Google Scholar 

  53. Schmidt, F. (2004). Recombinant expression systems in the pharmaceutical industry. Applied Microbiology and Biotechnology, 65, 363–372.

    Article  CAS  PubMed  Google Scholar 

  54. Vieira, S. M., da Rocha, S. L. G., da Neves-Ferreira, A. G., Almeida, R. V., & Perales, J. (2017). Heterologous expression of the antimyotoxic protein DM64 in Pichia pastoris. PLoS Neglected Tropical Diseases, 11, 1–20.

    Article  CAS  Google Scholar 

  55. Potvin, G., Ahmad, A., & Zhang, Z. (2012). Bioprocess engineering aspects of heterologous protein production in Pichia pastoris: A review. Biochemical Engineering Journal, 64, 91–105.

    Article  CAS  Google Scholar 

  56. Baghban, R., Gargari, S. L. M., Rajabibazl, M., Nazarian, S., & Bakherad, H. (2016). Camelid-derived heavy-chain nanobody against Clostridium botulinum neurotoxin E in Pichia pastoris. Applied Biochemistry and Biotechnology, 63, 200–205.

    Article  CAS  Google Scholar 

  57. Xia, W.-R., Fu, W.-L., Cai, L., Cai, X., Wang, Y.-Y., Zou, M.-J., & Xu, D.-G. (2012). Expression, purification and characterization of recombinant human angiogenin in Pichia pastoris. Bioscience, Biotechnology, and Biochemistry, 76, 1384–1388.

    Article  CAS  PubMed  Google Scholar 

  58. Rothan, H. A., Teh, S. H., Haron, K., & Mohamed, Z. (2012). A comparative study on the expression, purification and functional characterization of human adiponectin in Pichia pastoris and Escherichia coli. International Journal of Molecular Sciences, 13, 3549–3562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fan, G., Katrolia, P., Jia, H., Yang, S., Yan, Q., & Jiang, Z. (2012). High-level expression of a xylanase gene from the thermophilic fungus Paecilomyces thermophila in Pichia pastoris. Biotechnology Letters, 34, 2043–2048.

    Article  CAS  PubMed  Google Scholar 

  60. Gach, J. S., Maurer, M., Hahn, R., Gasser, B., Mattanovich, D., Katinger, H., & Kunert, R. (2007). High level expression of a promising anti-idiotypic antibody fragment vaccine against HIV-1 in Pichia pastoris. Journal of Biotechnology, 128, 735–746.

    Article  CAS  PubMed  Google Scholar 

  61. Cregg, J. M., Cereghino, J. L., Shi, J., & Higgins, D. R. (2000). Recombinant protein expression in Pichia pastoris. Molecular Biotechnology, 16, 23–52.

    Article  CAS  PubMed  Google Scholar 

  62. Fickers, P. (2014). Pichia pastoris: A workhorse for recombinant protein production. Current Research in Microbiology and Biotechnology, 2, 354–363.

    Google Scholar 

  63. Cos, O., Serrano, A., Montesinos, J. L., Ferrer, P., Cregg, J. M., & Valero, F. (2005). Combined effect of the methanol utilization (Mut) phenotype and gene dosage on recombinant protein production in Pichia pastoris fed-batch cultures. Journal of Biotechnology, 116, 321–335.

    Article  CAS  PubMed  Google Scholar 

  64. Daly, R., & Hearn, M. T. (2005). Expression of heterologous proteins in Pichia pastoris: A useful experimental tool in protein engineering and production. Journal of Molecular Recognition: An Interdisciplinary Journal, 18, 119–138.

    Article  CAS  Google Scholar 

  65. Yin, J., Li, G., Ren, X., & Herrler, G. (2007). Select what you need: A comparative evaluation of the advantages and limitations of frequently used expression systems for foreign genes. Journal of Biotechnology, 127, 335–347.

    Article  CAS  PubMed  Google Scholar 

  66. Vanz, A., Lünsdorf, H., Adnan, A., Nimtz, M., Gurramkonda, C., Khanna, N., & Rinas, U. (2012). Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: Catabolic adaptation, stress responses, and autophagic processes. Microbial Cell Factories, 11, 1–11.

    Article  CAS  Google Scholar 

  67. Charoenrat, T., Khumruaengsri, N., Promdonkoy, P., Rattanaphan, N., Eurwilaichitr, L., Tanapongpipat, S., & Roongsawang, N. (2013). Improvement of recombinant endoglucanase produced in Pichia pastoris KM71 through the use of synthetic medium for inoculum and pH control of proteolysis. Journal of Bioscience and Bioengineering, 116, 193–198.

    Article  CAS  PubMed  Google Scholar 

  68. Stöckmann, C., Scheidle, M., Dittrich, B., Merckelbach, A., Hehmann, G., Melmer, G., Klee, D., Büchs, J., Kang, H. A., & Gellissen, G. (2009). Process development in Hansenula polymorpha and Arxula adeninivorans, a re-assessment. Microbial Cell Factories, 8, 1–10.

    Article  CAS  Google Scholar 

  69. Weninger, A., Hatzl, A.-M., Schmid, C., Vogl, T., & Glieder, A. (2016). Combinatorial optimization of CRISPR/Cas9 expression enables precision genome engineering in the methylotrophic yeast Pichia pastoris. Journal of Biotechnology, 235, 139–149.

    Article  CAS  PubMed  Google Scholar 

  70. Zahrl, R. J., Peña, D. A., Mattanovich, D., & Gasser, B. (2017). Systems biotechnology for protein production in Pichia pastoris. FEMS Yeast Research, 17, 1–31.

    Article  CAS  Google Scholar 

  71. Vogl, T., Ahmad, M., Krainer, F. W., Schwab, H., & Glieder, A. (2015). Restriction site free cloning (RSFC) plasmid family for seamless, sequence independent cloning in Pichia pastoris. Microbial Cell Factories, 14, 1–15.

    Article  CAS  Google Scholar 

  72. Prielhofer, R., Barrero, J. J., Steuer, S., Gassler, T., Zahrl, R., Baumann, K., Sauer, M., Mattanovich, D., Gasser, B., & Marx, H. (2017). Golden Pi CS: A Golden Gate-derived modular cloning system for applied synthetic biology in the yeast Pichia pastoris. BMC Systems Biology, 11, 1–14.

    Article  CAS  Google Scholar 

  73. Suwannarangsee, S., Kim, S., Kim, O.-C., Oh, D.-B., Seo, J.-W., Kim, C. H., Rhee, S. K., Kang, H. A., Chulalaksananukul, W., & Kwon, O. (2012). Characterization of alcohol dehydrogenase 3 of the thermotolerant methylotrophic yeast Hansenula polymorpha. Applied Microbiology and Biotechnology, 96, 697–709.

    Article  CAS  PubMed  Google Scholar 

  74. Ishchuk, O. P., Voronovsky, A. Y., Stasyk, O. V., Gayda, G. Z., Gonchar, M. V., Abbas, C. A., & Sibirny, A. A. (2008). Overexpression of pyruvate decarboxylase in the yeast Hansenula polymorpha results in increased ethanol yield in high-temperature fermentation of xylose. FEMS Yeast Research, 8, 1164–1174.

    Article  CAS  PubMed  Google Scholar 

  75. Sohn, M. J., Oh, D. B., Kim, E. J., Cheon, S. A., Kwon, O., Kim, J. Y., Lee, S. Y., & Kang, H. A. (2012). HpYPS1 and HpYPS7 encode functional aspartyl proteases localized at the cell surface in the thermotolerant methylotrophic yeast Hansenula polymorpha. Yeas., 29, 1–16.

    Article  CAS  Google Scholar 

  76. Park, J.-N., Sohn, M. J., Oh, D.-B., Kwon, O., Rhee, S. K., Hur, C.-G., Lee, S. Y., Gellissen, G., & Kang, H. A. (2007). Identification of the cadmium-inducible Hansenula polymorpha SEO1 gene promoter by transcriptome analysis and its application to whole-cell heavy-metal detection systems. Applied and Environmental Microbiology, 73, 5990–6000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kim, M. W., Kim, E. J., Kim, J.-Y., Park, J.-S., Oh, D.-B., Shimma, Y., Chiba, Y., Jigami, Y., Rhee, S. K., & Kang, H. A. (2006). Functional characterization of the Hansenula polymorpha HOC1, OCH1, and OCR1 genes as members of the yeast OCH1 mannosyltransferase family involved in protein glycosylation. Journal of Biological Chemistry, 281, 6261–6272.

    Article  CAS  PubMed  Google Scholar 

  78. Oh, D. B., Park, J. S., Kim, M. W., Cheon, S. A., Kim, E. J., Moon, H. Y., Kwon, O., Rhee, S. K., & Kang, H. A. (2008). Glycoengineering of the methylotrophic yeast Hansenula polymorpha for the production of glycoproteins with trimannosyl core N-glycan by blocking core oligosaccharide assembly. Biotechnology Journal: Healthcare Nutrition Technology., 3, 659–668.

    Article  CAS  Google Scholar 

  79. Gellissen, G., Kunze, G., Gaillardin, C., Cregg, J. M., Berardi, E., Veenhuis, M., & van der Klei, I. (2005). New yeast expression platforms based on methylotrophic Hansenula polymorpha and Pichia pastoris and on dimorphic Arxula adeninivorans and Yarrowia lipolytica–a comparison. FEMS Yeast Research, 5, 1079–1096.

    Article  CAS  PubMed  Google Scholar 

  80. Mayer, A., Hellmuth, K., Schlieker, H., Lopez-Ulibarri, R., Oertel, S., Dahlems, U., Strasser, A., & Van Loon, A. (1999). An expression system matures: A highly efficient and cost-effective process for phytase production by recombinant strains of Hansenula polymorpha. Biotechnology and Bioengineering, 63, 373–381.

    Article  CAS  PubMed  Google Scholar 

  81. Stoyanov, A., Petrova, P., Lyutskanova, D., & Lahtchev, K. (2014). Structural and functional analysis of PUR2, 5 gene encoding bifunctional enzyme of de novo purine biosynthesis in Ogataea (Hansenula) polymorpha CBS 4732 T. Microbiological Research, 169, 378–387.

    Article  CAS  PubMed  Google Scholar 

  82. Ravin, N. V., Eldarov, M. A., Kadnikov, V. V., Beletsky, A. V., Schneider, J., Mardanova, E. S., Smekalova, E. M., Zvereva, M. I., Dontsova, O. A., & Mardanov, A. V. (2013). Genome sequence and analysis of methylotrophic yeast Hansenula polymorpha DL1. BMC Genomics, 14, 1–20.

    Article  CAS  Google Scholar 

  83. Ishchuk, O. P., Voronovsky, A. Y., Abbas, C. A., & Sibirny, A. A. (2009). Construction of Hansenula polymorpha strains with improved thermotolerance. Biotechnology and Bioengineering, 104, 911–919.

    Article  CAS  PubMed  Google Scholar 

  84. Péter, G., Tornai-Lehoczki, J., Shin, K. S., & Dlauchy, D. (2007). Ogataea thermophila sp. nov., the teleomorph of Candida thermophila. FEMS Yeast Research, 7, 494–496.

    Article  CAS  PubMed  Google Scholar 

  85. Kata, I., Semkiv, M. V., Ruchala, J., Dmytruk, K. V., & Sibirny, A. A. (2016). Overexpression of the genes PDC1 and ADH1 activates glycerol conversion to ethanol in the thermotolerant yeast Ogataea (Hansenula) polymorpha. Yeast, 33, 471–478.

    Article  CAS  PubMed  Google Scholar 

  86. Ryabova, O. B., Chmil, O. M., & Sibirny, A. A. (2003). Xylose and cellobiose fermentation to ethanol by the thermotolerant methylotrophic yeast Hansenula polymorpha. FEMS Yeast Research, 4, 157–164.

    Article  CAS  PubMed  Google Scholar 

  87. Voronovsky, A. Y., Ryabova, O. B., Verba, O. V., Ishchuk, O. P., Dmytruk, K. V., & Sibirny, A. A. (2005). Expression of xylA genes encoding xylose isomerases from Escherichia coli and Streptomyces coelicolor in the methylotrophic yeast Hansenula polymorpha. FEMS Yeast Research, 5, 1055–1062.

    Article  CAS  PubMed  Google Scholar 

  88. Ruchala, J., Kurylenko, O. O., Soontorngun, N., Dmytruk, K. V., & Sibirny, A. A. (2017). Transcriptional activator Cat8 is involved in regulation of xylose alcoholic fermentation in the thermotolerant yeast Ogataea (Hansenula) polymorpha. Microbial Cell Factories, 16, 1–13.

    Article  CAS  Google Scholar 

  89. Steinborn, G., Böer, E., Scholz, A., Tag, K., Kunze, G., & Gellissen, G. (2006). Application of a wide-range yeast vector (CoMed™) system to recombinant protein production in dimorphic Arxula adeninivorans, methylotrophic Hansenula polymorpha and other yeasts. Microbial Cell Factories, 5, 1–13.

    Article  CAS  Google Scholar 

  90. Gnügge, R., & Rudolf, F. (2017). Saccharomyces cerevisiae Shuttle vectors. Yeast, 34, 205–221.

    Article  CAS  PubMed  Google Scholar 

  91. Chou, C.-C., Patel, M. T., & Gartenberg, M. R. (2015). A series of conditional shuttle vectors for targeted genomic integration in budding yeast. FEMS Yeast Research, 15, 1–9.

    Article  CAS  Google Scholar 

  92. Hinnen, A., Buxton, F., Chaudhuri, B., Heim, J., Hottiger, T., Meyhack, B., & Pohlig, G. (1994). Gene expression in recombinant yeast. In A. Smith (Ed.), Gene expression in recombinant microorganisms (pp. 121–193). New York: Marcel Dekker.

    Google Scholar 

  93. Kojo, H., Greenberg, B. D., & Sugino, A. (1981). Yeast 2-micrometer plasmid DNA replication in vitro: Origin and direction. Proceedings of the National Academy of Sciences of the United States of America, 78, 7261–7265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gellissen, G., & Hollenberg, C. P. (1997). Application of yeasts in gene expression studies: A comparison of Saccharomyces cerevisiae, Hansenula polymorpha and Kluyveromyces lactis-a review. Gene, 190, 87–97.

    Article  CAS  PubMed  Google Scholar 

  95. Klabunde, J., Kunze, G., Gellissen, G., & Hollenberg, C. P. (2003). Integration of heterologous genes in several yeast species using vectors containing a Hansenula polymorpha-derived rDNA-targeting element. FEMS Yeast Research, 4, 185–193.

    Article  CAS  PubMed  Google Scholar 

  96. Cregg, J. M., Barringer, K., Hessler, A., & Madden, K. (1985). Pichia pastoris as a host system for transformations. Molecular and Cellular Biology, 5, 3376–3385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Degelmann, A., Müller, F., Sieber, H., Jenzelewski, V., Suckow, M., Strasser, A. W., & Gellissen, G. (2002). Strain and process development for the production of human cytokines in Hansenula polymorpha. FEMS Yeast Research, 2, 349–361.

    CAS  PubMed  Google Scholar 

  98. Liu, Y., Li, Y., Liu, L., Hu, X., & Qiu, B. (2005). Design of vectors for efficient integration and transformation in Hansenula polymorpha. Biotechnology Letters, 27, 1529–1534.

    Article  CAS  PubMed  Google Scholar 

  99. Shen, M. W., Fang, F., Sandmeyer, S., & Da Silva, N. A. (2012). Development and characterization of a vector set with regulated promoters for systematic metabolic engineering in Saccharomyces cerevisiae. Yeast, 29, 495–503.

    Article  CAS  PubMed  Google Scholar 

  100. Machens, F., Balazadeh, S., Mueller-Roeber, B., & Messerschmidt, K. (2017). synthetic promoters and transcription factors for heterologous protein expression in Saccharomyces cerevisiae. Frontiers in Bioengineering and Biotechnology, 5, 1–11.

    Article  Google Scholar 

  101. Vickers, C. E., Bydder, S. F., Zhou, Y., & Nielsen, L. K. (2013). Dual gene expression cassette vectors with antibiotic selection markers for engineering in Saccharomyces cerevisiae. Microbial Cell Factories, 12, 1–11.

    Article  CAS  Google Scholar 

  102. Meurer, M., Chevyreva, V., Cerulus, B., & Knop, M. (2016). The regulatable MAL32 promoter in S. cerevisiae: Characteristics and tools. bioRxiv, 28, 1–18.

    Google Scholar 

  103. Nicaud, J.-M., Madzak, C., van den Broek, P., Gysler, C., Duboc, P., Niederberger, P., & Gaillardin, C. (2002). Protein expression and secretion in the yeast Yarrowia lipolytica. FEMS Yeast Research, 2, 371–379.

    CAS  PubMed  Google Scholar 

  104. Juretzek, T., Dall, L., Mauersberger, M. T., Gaillardin, S., Barth, C., G. and Nicaud, J. M. (2001). Vectors for gene expression and amplification in the yeast Yarrowia lipolytica. Yeast, 18, 97–113.

    Article  CAS  PubMed  Google Scholar 

  105. Madzak, C., Tréton, B., & Blanchin-Roland, S. (2000). Strong hybrid promoters and integrative expression/secretion vectors for quasi-constitutive expression of heterologous proteins in the yeast Yarrowia lipolytica. Journal of Molecular Microbiology and Biotechnology, 2, 207–216.

    CAS  PubMed  Google Scholar 

  106. Verbeke, J., Beopoulos, A., & Nicaud, J.-M. (2013). Efficient homologous recombination with short length flanking fragments in Ku70 deficient Yarrowia lipolytica strains. Biotechnology Letters, 35, 571–576.

    Article  CAS  PubMed  Google Scholar 

  107. Liu, L., Otoupal, P., Pan, A., & Alper, H. S. (2014). Increasing expression level and copy number of a Yarrowia lipolytica plasmid through regulated centromere function. FEMS Yeast Research, 14, 1124–1127.

    CAS  PubMed  Google Scholar 

  108. Higgins, D. R., Busser, K., Comiskey, J., Whittier, P. S., Purcell, T. J., & Hoeffler, J. P. (1998) Small vectors for expression based on dominant drug resistance with direct multicopy selection. In D. R. Higgins & J. M. Cregg (Eds.), Pichia protocols, (pp. 41–53). New York: Springer.

    Chapter  Google Scholar 

  109. Li, P., Anumanthan, A., Gao, X.-G., Ilangovan, K., Suzara, V. V., Düzgüneş, N., & Renugopalakrishnan, V. (2007). Expression of recombinant proteins in Pichia pastoris. Applied Biochemistry and Biotechnology, 142, 105–124.

    Article  CAS  PubMed  Google Scholar 

  110. Li, D., Zhang, B., Li, S., Zhou, J., Cao, H., Huang, Y., & Cui, Z. (2017). A novel vector for construction of markerless multicopy overexpression transformants in Pichia pastoris. Frontiers in Microbiology, 8, 1–12.

    Google Scholar 

  111. Kang, H. A., Sohn, J. H., Agaphonov, M. O., Choi, E. S., Ter-Avanesyan, M. D., & Rhee, S. K. (2002) Development of expression systems for the production of recombinant proteins in Hansenula polymorpha DL-1. In G. Gellissen (Ed.), Hansenula polymorpha: Biology and applications, (pp. 124–146). Hpboken: Wiley.

    Google Scholar 

  112. Agaphonov, M. O., Trushkina, P. M., Sohn, J., Choi, E., Rhee, S., & Ter-Avanesyan, M. D. (1999). Vectors for rapid selection of integrants with different plasmid copy numbers in the yeast Hansenula polymorpha DL1. Yeast, 15, 541–551.

    Article  CAS  PubMed  Google Scholar 

  113. Saraya, R., Krikken, A. M., Kiel, J. A., Baerends, R. J., Veenhuis, M., & van der Klei, I. J. (2012). Novel genetic tools for Hansenula polymorpha. FEMS Yeast Research, 12, 271–278.

    Article  CAS  PubMed  Google Scholar 

  114. Partow, S., Siewers, V., Bjørn, S., Nielsen, J., & Maury, J. (2010). Characterization of different promoters for designing a new expression vector in Saccharomyces cerevisiae. Yeast, 27, 955–964.

    Article  CAS  PubMed  Google Scholar 

  115. Blount, B. A., Weenink, T., Vasylechko, S., & Ellis, T. (2012). Rational diversification of a promoter providing fine-tuned expression and orthogonal regulation for synthetic biology. PLoS ONE, 7, 1–11.

    Google Scholar 

  116. Rantasalo, A., Czeizler, E., Virtanen, R., Rousu, J., Lähdesmäki, H., Penttilä, M., Jäntti, J., & Mojzita, D. (2016). Synthetic transcription amplifier system for orthogonal control of gene expression in Saccharomyces cerevisiae. PLoS ONE, 11, 1–19.

    Article  CAS  Google Scholar 

  117. Öztürk, S., Ergün, B. G., & Çalık, P. (2017). Double promoter expression systems for recombinant protein production by industrial microorganisms. Applied Microbiology and Biotechnology, 101, 7459–7475.

    Article  CAS  PubMed  Google Scholar 

  118. Park, Y.-K., Korpys, P., Kubiak, M., Celińska, E., Soudier, P., Trébulle, P., Larroude, M., Rossignol, T., & Nicaud, J.-M. (2018). Engineering the architecture of erythritol-inducible promoters for regulated and enhanced gene expression in Yarrowia lipolytica. FEMS Yeast Research, 19, 1–32.

    Google Scholar 

  119. Larroude, M., Rossignol, T., Nicaud, J.-M., & Ledesma-Amaro, R. (2018). Synthetic biology tools for engineering Yarrowia lipolytica. Biotechnology Advances, 36, 2150–2164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Çelik, E., Çalık, P., & Oliver, S. G. (2010). Metabolic flux analysis for recombinant protein production by Pichia pastoris using dual carbon sources: Effects of methanol feeding rate. Biotechnology and Bioengineering, 105, 317–329.

    Article  CAS  PubMed  Google Scholar 

  121. Arruda, A., Reis, V. C. B., Batista, V. D. F., Daher, B. S., Piva, L. C., De Marco, J. L., de Moraes, L. M. P., & Torres, F. A. G. (2016). A constitutive expression system for Pichia pastoris based on the PGK1 promoter. Biotechnology Letters, 38, 509–517.

    Article  CAS  PubMed  Google Scholar 

  122. Tschopp, J. F., Brust, P. F., Cregg, J. M., Stillman, C. A., & Gingeras, T. R. (1987). Expression of the lacZ gene from two methanol-regulated promoters in Pichia pastoris. Nucleic Acids Research, 15, 3859–3876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dusny, C., & Schmid, A. (2016). The MOX promoter in Hansenula polymorpha is ultrasensitive to glucose-mediated carbon catabolite repression. FEMS Yeast Research, 16, 1–15.

    Article  CAS  Google Scholar 

  124. Suppi, S., Michelson, T., Viigand, K., & Alamäe, T. (2013). Repression vs. activation of MOX. FMD, MPP1 and MAL1 promoters by sugars in Hansenula polymorpha: The outcome depends on cell’s ability to phosphorylate sugar. FEMS Yeast Research, 13, 219–232.

    Article  CAS  PubMed  Google Scholar 

  125. Bae, J. H., Sohn, J. H., Rhee, S. K., & Choi, E. S. (2005). Cloning and characterization of the Hansenula polymorpha PEP4 gene encoding proteinase A. Yeast, 22, 13–19.

    Article  CAS  PubMed  Google Scholar 

  126. Heo, J.-H., Hong, W. K., Cho, E. Y., Kim, M. W., Kim, J.-Y., Kim, C. H., Rhee, S. K., & Kang, H. A. (2003). Properties of the Hansenula polymorpha-derived constitutive GAP promoter, assessed using an HSA reporter gene. FEMS Yeast Research, 4, 175–184.

    Article  CAS  PubMed  Google Scholar 

  127. Peng, B., Wood, R. J., Nielsen, L. K., & Vickers, C. E. (2018). An expanded heterologous GAL promoter collection for diauxie-inducible expression in Saccharomyces cerevisiae. ACS Synthetic Biology, 7, 748–751.

    Article  CAS  PubMed  Google Scholar 

  128. He, Y., Swaminathan, A., & Lopes, J. M. (2012). Transcription regulation of the Saccharomyces cerevisiae PHO5 gene by the Ino2p and Ino4p basic helix–loop–helix proteins. Molecular Microbiology, 83, 395–407.

    Article  CAS  PubMed  Google Scholar 

  129. Juretzek, T., Wang, H.-J., Nicaud, J.-M., Mauersberger, S., & Barth, G. (2000). Comparison of promoters suitable for regulated overexpression of β-galactosidase in the alkane-utilizing yeast Yarrowia lipolytica. Biotechnology and Bioprocess Engineering, 5, 320–326.

    Article  CAS  Google Scholar 

  130. Hong, S. P., Seip, J., Walters-Pollak, D., Rupert, R., Jackson, R., Xue, Z., & Zhu, Q. (2012). Engineering Yarrowia lipolytica to express secretory invertase with strong FBA1IN promoter. Yeast, 29, 59–72.

    Article  CAS  PubMed  Google Scholar 

  131. Zeng, S. Y., Liu, H. H., Shi, T. Q., Song, P., Ren, L. J., Huang, H., & Ji, X. J. (2018). Recent advances in metabolic engineering of Yarrowia lipolytica for lipid overproduction. European Journal of Lipid Science and Technology, 120, 1–48.

    Article  CAS  Google Scholar 

  132. Mellitzer, A., Ruth, C., Gustafsson, C., Welch, M., Birner-Grünberger, R., Weis, R., Purkarthofer, T., & Glieder, A. (2014). Synergistic modular promoter and gene optimization to push cellulase secretion by Pichia pastoris beyond existing benchmarks. Journal of Biotechnology, 191, 187–195.

    Article  CAS  PubMed  Google Scholar 

  133. Stadlmayr, G., Mecklenbräuker, A., Rothmüller, M., Maurer, M., Sauer, M., Mattanovich, D., & Gasser, B. (2010). Identification and characterisation of novel Pichia pastoris promoters for heterologous protein production. Journal of Biotechnology, 150, 519–529.

    Article  CAS  PubMed  Google Scholar 

  134. Liang, S., Zou, C., Lin, Y., Zhang, X., & Ye, Y. (2013). Identification and characterization of PGCW14: A novel, strong constitutive promoter of Pichia pastoris. Biotechnology Letters, 35, 1865–1871.

    Article  CAS  PubMed  Google Scholar 

  135. Capone, S., Horvat, J., Herwig, C., & Spadiut, O. (2015). Development of a mixed feed strategy for a recombinant Pichia pastoris strain producing with a de-repression promoter. Microbial Cell Factories, 14, 1–10.

    Article  CAS  Google Scholar 

  136. Ruth, C., Zuellig, T., Mellitzer, A., Weis, R., Looser, V., Kovar, K., & Glieder, A. (2010). Variable production windows for porcine trypsinogen employing synthetic inducible promoter variants in Pichia pastoris. Systems and Synthetic Biology, 4, 181–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wang, J., Wang, X., Shi, L., Qi, F., Zhang, P., Zhang, Y., Zhou, X., Song, Z., & Cai, M. (2017). Methanol-independent protein expression by AOX1 promoter with trans-acting elements engineering and glucose-glycerol-shift induction in Pichia pastoris. Scientific Reports, 7, 1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Yang, M., Zhang, W., Ji, S., Cao, P., Chen, Y., & Zhao, X. (2013). Generation of an artificial double promoter for protein expression in Bacillus subtilis through a promoter trap system. PLoS ONE, 8, 1–9.

    Article  Google Scholar 

  139. Nokelainen, M., Tu, H., Vuorela, A., Notbohm, H., Kivirikko, K. I., & Myllyharju, J. (2001). High-level production of human type I collagen in the yeast Pichia pastoris. Yeast, 18, 797–806.

    Article  CAS  PubMed  Google Scholar 

  140. Kamei, H., Ohira, T., Yoshiura, Y., Uchida, N., Nagasawa, H., & Aida, K. (2003). Expression of a biologically active recombinant follicle stimulating hormone of Japanese eel Anguilla japonica using methylotropic yeast, Pichia pastoris. General and Comparative Endocrinology, 134, 244–254.

    Article  CAS  PubMed  Google Scholar 

  141. Gasser, B., Saloheimo, M., Rinas, U., Dragosits, M., Rodríguez-Carmona, E., Baumann, K., Giuliani, M., Parrilli, E., Branduardi, P., & Lang, C. (2008). Protein folding and conformational stress in microbial cells producing recombinant proteins: A host comparative overview. Microbial Cell Factories, 7, 1–18.

    Article  CAS  Google Scholar 

  142. Ata, Ö, Prielhofer, R., Gasser, B., Mattanovich, D., & Çalık, P. (2017). Transcriptional engineering of the glyceraldehyde-3-phosphate dehydrogenase promoter for improved heterologous protein production in Pichia pastoris. Biotechnology and Bioengineering, 114, 2319–2327.

    Article  CAS  PubMed  Google Scholar 

  143. Wagner, J. M., & Alper, H. S. (2016). Synthetic biology and molecular genetics in non-conventional yeasts: Current tools and future advances. Fungal Genetics and Biology, 89, 126–136.

    Article  CAS  PubMed  Google Scholar 

  144. Silvestrini, L., Rossi, B., Gallmetzer, A., Mathieu, M., Scazzocchio, C., Berardi, E., & Strauss, J. (2015). Interaction of Yna1 and Yna2 is required for nuclear accumulation and transcriptional activation of the nitrate assimilation pathway in the yeast Hansenula polymorpha. PLoS ONE, 10, 1–25.

    Article  CAS  Google Scholar 

  145. Cox, H., Mead, D., Sudbery, P., Eland, R. M., Mannazzu, I., & Evans, L. (2000). Constitutive expression of recombinant proteins in the methylotrophic yeast Hansenula polymorpha using the PMA1 promoter. Yeast, 16, 1191–1203.

    Article  CAS  PubMed  Google Scholar 

  146. Stovicek, V., Holkenbrink, C., & Borodina, I. (2017). CRISPR/Cas system for yeast genome engineering: Advances and applications. FEMS Yeast Research, 17, 1–16.

    Article  CAS  Google Scholar 

  147. Giersch, R. M., & Finnigan, G. C. (2017). Method for multiplexing CRISPR/Cas9 in Saccharomyces cerevisiae using artificial target DNA sequences. Bio-protocol, 7, 1–10.

    Article  CAS  Google Scholar 

  148. Shi, T.-Q., Huang, H., Kerkhoven, E. J., & Ji, X.-J. (2018). Advancing metabolic engineering of Yarrowia lipolytica using the CRISPR/Cas system. Applied Microbiology and Biotechnology, 102, 9541–9548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Löbs, A. K., Schwartz, C., & Wheeldon, I. (2017). Genome and metabolic engineering in non-conventional yeasts: Current advances and applications. Synthetic and Systems Biotechnology, 2, 198–207.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Baxter, M., Toms, G., Gadsby, R., & Griffiths, U. (2006). Empowering primary care practitioners to meet the growing challenge of diabetes care in the community. British Journal of Diabetes and Vascular Disease, 6, 245–248.

    Article  Google Scholar 

  151. Bonander, N., & Bill, R. M. (2012) Optimising yeast as a host for recombinant protein production (review). In R. Bill (Ed.), Recombinant protein production in yeast (Vol. 866, pp. 1–9), New York: Springer.

    Chapter  Google Scholar 

  152. Wang, T., Xu, Y., Liu, W., Sun, Y., & Jin, L. (2011). Expression of Apostichopus japonicus lysozyme in the methylotrophic yeast Pichia pastoris. Protein Expression and Purification, 77, 20–25.

    Article  CAS  PubMed  Google Scholar 

  153. Jahic, M., Gustavsson, M., Jansen, A.-K., Martinelle, M., & Enfors, S.-O. (2003). Analysis and control of proteolysis of a fusion protein in Pichia pastoris fed-batch processes. Journal of Biotechnology, 102, 45–53.

    Article  CAS  PubMed  Google Scholar 

  154. Mayson, B. E., Kilburn, D. G., Zamost, B. L., Raymond, C. K., & Lesnicki, G. J. (2003). Effects of methanol concentration on expression levels of recombinant protein in fed-batch cultures of Pichia methanolica. Biotechnology and Bioengineering, 81, 291–298.

    Article  CAS  PubMed  Google Scholar 

  155. Jungo, C., Marison, I., & von Stockar, U. (2007). Regulation of alcohol oxidase of a recombinant Pichia pastoris Mut+ strain in transient continuous cultures. Journal of Biotechnology, 130, 236–246.

    Article  CAS  PubMed  Google Scholar 

  156. Zhang, P., Zhang, W., Zhou, X., Bai, P., Cregg, J. M., & Zhang, Y. (2010). Catabolite repression of Aox in Pichia pastoris is dependent on hexose transporter PpHxt1 and pexophagy. Applied and Environmental Microbiology, 76, 6108–6118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Arias, C. A. D., Marques, D. d. A. V., Malpiedi, L. P., Maranhão, A. Q., Parra, D. A. S., Converti, A., & Junior, A. P. (2017). Cultivation of Pichia pastoris carrying the scFv anti LDL (–) antibody fragment. Effect of preculture carbon source. Brazilian Journal of Microbiology, 4, 419–426.

    Article  CAS  Google Scholar 

  158. Mahboubi, A., Mortazavi, S. A., Naghdi, N., & Azadi, S. (2017). Evaluation of sorbitol-methanol co-feeding strategy on production of recombinant human growth hormone in Pichia Pastoris. Iranian Journal of Pharmaceutical Research, 16, 1555–1564.

    PubMed  Google Scholar 

  159. Trentmann, O., Khatri, N. K., & Hoffmann, F. (2004). Reduced oxygen supply increases process stability and product yield with recombinant Pichia pastoris. Biotechnology Progress, 20, 1766–1775.

    Article  CAS  PubMed  Google Scholar 

  160. Hellwig, S., Emde, F., Raven, N. P., Henke, M., van der Logt, P., & Fischer, R. (2001). Analysis of single-chain antibody production in Pichia pastoris using on-line methanol control in fed-batch and mixed-feed fermentations. Biotechnology and Bioengineering, 74, 344–352.

    Article  CAS  PubMed  Google Scholar 

  161. Jazini, M., & Herwig, C. (2014). Two-compartment processing as a tool to boost recombinant protein production. Engineering in Life Sciences, 14, 118–128.

    Article  CAS  Google Scholar 

  162. Jazini, M., Cekici, G., & Herwig, C. (2013). Quantifying the effects of frequency and amplitude of periodic oxygen-related stress on recombinant protein production in Pichia pastoris. Bioengineering, 1, 47–61.

    Article  CAS  Google Scholar 

  163. Gasmi, N., Ayed, A., Ammar, B. B. H., Zrigui, R., Nicaud, J.-M., & Kallel, H. (2011). Development of a cultivation process for the enhancement of human interferon alpha 2b production in the oleaginous yeast, Yarrowia lipolytica. Microbial Cell Factories, 10, 90–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Ahmadzadeh, V., Farajnia, S., Feizi, M. A. H., & Nejad, R. A. K. (2014). Antibody humanization methods for development of therapeutic applications. Monoclonal Antibodies in Immunodiagnosis and Immunotherapy, 33, 67–73.

    Article  CAS  PubMed  Google Scholar 

  165. Safdari, Y., Farajnia, S., Asgharzadeh, M., & Khalili, M. (2013). Antibody humanization methods–a review and update. Biotechnology and Genetic Engineering Reviews, 29, 175–186.

    Article  CAS  PubMed  Google Scholar 

  166. Dicker, M., & Strasser, R. (2015). Using glyco-engineering to produce therapeutic proteins. Expert Opinion on Biological Therapy, 15, 1501–1516.

    Article  CAS  PubMed  Google Scholar 

  167. Fidan, O., & Zhan, J. (2015). Recent advances in engineering yeast for pharmaceutical protein production. RSC Advances, 5, 86665–86674.

    Article  CAS  Google Scholar 

  168. Jacobs, P. P., Geysens, S., Vervecken, W., Contreras, R., & Callewaert, N. (2008). Engineering complex-type N-glycosylation in Pichia pastoris using GlycoSwitch technology. Nature Protocols, 4, 58–70.

    Article  CAS  Google Scholar 

  169. He, T., Xu, S., Zhang, G., Nakanishi, H., & Gao, X. (2014). Reconstruction of N-glycosylation pathway for producing human glycoproteins in Saccharomyces cerevisiae. Wei sheng wu xue bao = Acta Microbiologica Sinica, 54, 509–516.

    CAS  PubMed  Google Scholar 

  170. Khan, A. H., Bayat, H., Rajabibazl, M., Sabri, S., & Rahimpour, A. (2017). Humanizing glycosylation pathways in eukaryotic expression systems. World Journal of Microbiology and Biotechnology, 33, 1–12.

    Article  CAS  Google Scholar 

  171. De Pourcq, K., Vervecken, W., Dewerte, I., Valevska, A., Van Hecke, A., & Callewaert, N. (2012). Engineering the yeast Yarrowia lipolytica for the production of therapeutic proteins homogeneously glycosylated with Man 8 GlcNAc 2 and Man 5 GlcNAc 2. Microbial Cell Factories, 11, 1–12.

    Article  CAS  Google Scholar 

  172. Park, J.-N., Song, Y., Cheon, S. A., Kwon, O., Oh, D.-B., Jigami, Y., Kim, J.-Y., & Kang, H. A. (2011). Essential role of YlMPO1, a novel Yarrowia lipolytica homologue of Saccharomyces cerevisiae MNN4, in mannosylphosphorylation of N-and O-linked glycans. Applied and Environmental Microbiology, 77, 1187–1195.

    Article  CAS  PubMed  Google Scholar 

  173. Krainer, F. W., Gmeiner, C., Neutsch, L., Windwarder, M., Pletzenauer, R., Herwig, C., Altmann, F., Glieder, A., & Spadiut, O. (2013). Knockout of an endogenous mannosyltransferase increases the homogeneity of glycoproteins produced in Pichia pastoris. Scientific Reports, 3, 1–13.

    Article  Google Scholar 

  174. Kunze, G., Kang, H. A., & Gellissen, G. (2009). Hansenula polymorpha (Pichia angusta): Biology and applications. In T. Satyanarayana & G. Kunze (Eds.), Yeast biotechnology: Diversity and applications (pp. 47–64). Dordrecht: Springer.

    Google Scholar 

  175. Huang, M., Bao, J., & Nielsen, J. (2014). Biopharmaceutical protein production by Saccharomyces cerevisiae: Current state and future prospects. Pharmaceutical Bioprocessing, 2, 167–182.

    Article  Google Scholar 

  176. Huang, C.-J., Lowe, A. J., & Batt, C. A. (2010). Recombinant immunotherapeutics: Current state and perspectives regarding the feasibility and market. Applied Microbiology and Biotechnology, 87, 401–410.

    Article  CAS  PubMed  Google Scholar 

  177. Kannan, V., Narayanaswamy, P., Gadamsetty, D., Hazra, P., Khedkar, A., & Iyer, H. (2009). A tandem mass spectrometric approach to the identification of O-glycosylated glargine glycoforms in active pharmaceutical ingredient expressed in Pichia pastoris. European Journal of Lipid Science and Technology, 23, 1035–1042.

    CAS  Google Scholar 

  178. Shu, M., Shen, W., Wang, X., Wang, F., Ma, L., & Zhai, C. (2015). Expression, activation and characterization of porcine trypsin in Pichia pastoris GS115. Protein Expression and Purification, 114, 149–155.

    Article  CAS  PubMed  Google Scholar 

  179. Yang, H., Zhai, C., Yu, X., Li, Z., Tang, W., Liu, Y., Ma, X., Zhong, X., Li, G., & Wu, D. (2016). High-level expression of Proteinase K from Tritirachium album Limber in Pichia pastoris using multi-copy expression strains. Protein Expression and Purification, 122, 38–44.

    Article  CAS  PubMed  Google Scholar 

  180. Cicardi, M., Levy, R. J., McNeil, D. L., Li, H. H., Sheffer, A. L., Campion, M., Horn, P. T., & Pullman, W. E. (2010). Ecallantide for the treatment of acute attacks in hereditary angioedema. New England Journal of Medicine, 363, 523–531.

    Article  CAS  PubMed  Google Scholar 

  181. Tran, A.-M., Nguyen, T.-T., Nguyen, C.-T., Huynh-Thi, X.-M., Nguyen, C.-T., Trinh, M.-T., Tran, L.-T., Cartwright, S. P., Bill, R. M., & Tran-Van, H. (2017). Pichia pastoris versus Saccharomyces cerevisiae: A case study on the recombinant production of human granulocyte-macrophage colony-stimulating factor. BMC Research Notes, 10, 1–8.

    Article  CAS  Google Scholar 

  182. Müller, I. I., Tieke, F., Waschk, A., Mühle, D., Müller, C., Seigelchifer, F., Pesce, M., Jenzelewski, A., V. and Gellissen, G. (2002). Production of IFNα-2 in Hansenula polymorpha. Process Biochemistry, 38, 15–25.

    Article  Google Scholar 

  183. Matthäus, F., Ketelhot, M., Gatter, M., & Barth, G. (2014). Production of lycopene in the non-carotenoid-producing yeast Yarrowia lipolytica. Applied and Environmental Microbiology, 80, 1660–1669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Blazeck, J., Hill, A., Liu, L., Knight, R., Miller, J., Pan, A., Otoupal, P., & Alper, H. S. (2014). Harnessing Yarrowia lipolytica lipogenesis to create a platform for lipid and biofuel production. Nature Communications, 5, 1–10.

    Article  CAS  Google Scholar 

  185. Yovkova, V., Otto, C., Aurich, A., Mauersberger, S., & Barth, G. (2014). Engineering the α-ketoglutarate overproduction from raw glycerol by overexpression of the genes encoding NADP+-dependent isocitrate dehydrogenase and pyruvate carboxylase in Yarrowia lipolytica. Applied Microbiology and Biotechnology, 98, 2003–2013.

    Article  CAS  PubMed  Google Scholar 

  186. Mirończuk, A. M., Furgała, J., Rakicka, M., & Rymowicz, W. (2014). Enhanced production of erythritol by Yarrowia lipolytica on glycerol in repeated batch cultures. Journal of Industrial Microbiology & Biotechnology, 41, 57–64.

    Article  CAS  Google Scholar 

  187. Xue, Z., Sharpe, P. L., Hong, S.-P., Yadav, N. S., Xie, D., Short, D. R., Damude, H. G., Rupert, R. A., Seip, J. E., & Wang, J. (2013). Production of omega-3 eicosapentaenoic acid by metabolic engineering of Yarrowia lipolytica. Nature Biotechnology, 31, 734–740.

    Article  CAS  PubMed  Google Scholar 

  188. Harzevili, F. D. (2014) Yarrowia lipolytica in biotechnological applications. In D. Harzevili (Ed.), Biotechnological applications of the yeast Yarrowia lipolytica (pp. 17–74). Cham: Springer.

    Chapter  Google Scholar 

  189. Domínguez, Á, Fermiñán, E., Sánchez, M., González, F. M., Pérez-Campo, F. M., García, S., Herrero, A. B., Vicente, S. A., Cabello, J., & Prado, M. (2010). Non-conventional yeasts as hosts for heterologous protein production. International Microbiology, 1, 131–142.

    Google Scholar 

  190. Safder, I., Khan, S., Islam, I., & Kazim, M. (2018). Pichia pastoris expression system: A potential candidate to express protein in industrial and biopharmaceutical domains. Biomedical Letters, 4, 1–13.

    Google Scholar 

  191. Andes, D., Craig, W., Nielsen, L., & Kristensen, H. (2009). In vivo pharmacodynamic characterization of a novel plectasin antibiotic, NZ2114, in a murine infection model. Antimicrobial Agents and Chemotherapy, 53, 3003–3009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Mygind, P. H., Fischer, R. L., Schnorr, K. M., Hansen, M. T., Sönksen, C. P., Ludvigsen, S., Raventós, D., Buskov, S., Christensen, B., & De Maria, L. (2005). Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature., 437, 975–980.

    Article  CAS  PubMed  Google Scholar 

  193. Qian, W., Liu, Y., Zhang, C., Niu, Z., Song, H., & Qiu, B. (2009). Expression of bovine follicle-stimulating hormone subunits in a Hansenula polymorpha expression system increases the secretion and bioactivity in vivo. Protein Expression and Purification, 68, 183–189.

    Article  CAS  PubMed  Google Scholar 

  194. Ganeva, V., Galutzov, B., Angelova, B., & Suckow, M. (2018). Electroinduced extraction of human ferritin heavy chain expressed in Hansenula polymorpha. Applied Biochemistry and Biotechnology, 184, 1286–1307.

    Article  CAS  PubMed  Google Scholar 

  195. Wang, N., Wang, Y., Li, G., Sun, N., & Liu, D. (2011). Expression, characterization, and antimicrobial ability of t4 lysozyme from methylotrophic yeast hansenula polymorpha a16. Science China Life Sciences, 54, 520–526.

    Article  CAS  PubMed  Google Scholar 

  196. Cook, M., & Thygesen, H. (2003). Safety evaluation of a hexose oxidase expressed in Hansenula polymorpha. Food and Chemical Toxicology, 41, 523–529.

    Article  CAS  PubMed  Google Scholar 

  197. Gibson, D. G., Benders, G. A., Axelrod, K. C., Zaveri, J., Algire, M. A., Moodie, M., Montague, M. G., Venter, J. C., Smith, H. O., & Hutchison, C. A. (2008) One-step assembly in yeast of 25 overlapping DNA fragments to form a complete synthetic Mycoplasma genitalium genome. Proceedings of the National Academy of Sciences of the United States of America, 105, 20404–20409.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Lartigue, C., Vashee, S., Algire, M. A., Chuang, R.-Y., Benders, G. A., Ma, L., Noskov, V. N., Denisova, E. A., Gibson, D. G., & Assad-Garcia, N. (2009). Creating bacterial strains from genomes that have been cloned and engineered in yeast. Science, 325, 1693–1696.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by a Grant from the Biotechnology Research Center Tabriz University of Medical Science.

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Correspondence to Safar Farajnia or Masoumeh Rajabibazl.

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Baghban, R., Farajnia, S., Rajabibazl, M. et al. Yeast Expression Systems: Overview and Recent Advances. Mol Biotechnol 61, 365–384 (2019). https://doi.org/10.1007/s12033-019-00164-8

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