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A Review on the Use of the Signal Peptide in Recombinant Interferon beta Secretion in Escherichia coli

Year 2019, Volume: 45 Issue: 1, 10 - 21, 30.04.2019

Mehmet Öztürk Yakup Ermurat

Abstract

Eukaryotic and prokaryotic expression systems are used with similar
processes for the production of rIFN-β1a and rIFN-β1b which are from the
recombinant interferon beta (rIFN-β) protein varieties. The difficulties in
purification of the produced rIFN-β1a by eukaryotic expression systems and the
influence of its biological activity make recombinant protein production
difficult with these processes. In the production of rIFN-β1b, where
prokaryotic expression systems were used, purification and activity problems
were found to be less frequent. Better use of product secretion capability in Escherichia coli from prokaryotic
bacteria indicates that this system will be preferred in the production of
rIfN-β1b. If the construct is designed to secrete recombinant proteins out of
the host cell from which the recombinant proteins are produced, it is envisaged
that the host cells will not fragment during purification, thereby facilitating
product purification processes. The use of E.
coli with type I and type II secretion in the production of rIFN-β1b
proteins will reduce the purification and activity problems in the secretion of
rIFN-β1b produced in this host, as well as the toxic effect of rIFN-β1b to the
host cell is expected to diminish. To this end, various approaches are
contemplated to overcome the disadvantages of the E. coli production system, such as transferring the DmsA signal
peptide, the Tat-type signal peptide, to the expression vector pET22b, in
addition to the PelB signal peptide, the Sec signal peptide. In this review,
information about the properties of IFNs, the clinical applications of rIFN-β
and the researches based on the investigations of rIFN-β1b production  methods, and information about the use of
signal peptides in the process of producing rIFN-β1b in E. coli host cells were highlighted.

Keywords

Recombinant interferon beta secretion signal peptides periplasmic protein

References

  • Allen J, Feng P, Patkar A, Haney KL, Chew L Sengchanthalangsy LLP (2015). Method for producing soluble recombinant interferon protein without denaturing. US20160032345A1.
  • Beladiya C, Tripathy RK, Bajaj P, Aggarwal G, Pande AH (2015). Expression, purification and immobilization of recombinant AiiA enzyme onto magnetic nanoparticles. Protein Expression and Purification 113: 56-62. DOI: 10.1016/j.pep.2015.04.014
  • Binet R, Létoffé S, Ghigo JM, Delepelaire P, Wandersman C (1997). Protein secretion by gram-negative bacterial ABC exporters–a review. Gene 192: 7-11. PMID: 9224868
  • Chelbi-Alix, M.K., Wietzerbin, J. (2007). “IFN, a growing cytokine family: 50 years of IFN research”, Biochimie, 89, 713-718. DOI: 10.1016/j.biochi.2007.05.001
  • Chevaliez S, Pawlotsky JM (2009). Interferons and Their Use in Persistent Viral Infections. In: Kräusslich HG, Bartenschlager R. (eds) Antiviral strategies. Handbook of Experimental Pharmacol 189 Springer Berlin Heidelberg. e-ISBN 978-3-540-79086-0
  • Choi JH, Lee SY (2004). Secretory and extracellular production of recombinant proteins using Escherichia coli. Appl Microbiol and Biotech 64: 625-635. DOI: 10.1007/s00253-004-1559-9
  • Cianciotto NP (2005). Type II secretion: a protein secretion system for all seasons. Trends in Microbiol 13(12): 581-588. DOI: 10.1016/j.tim.2005.09.005
  • Conradt HS, Egge H, Peter-Katalinic J, Reiser W, Siklosi T, Schaper K (1987). Structure of the carbohydrate moiety of human IFN-ß secreted by a recombinant Chinese hamster ovary cell line. J of Biological Chem 262: 14600-14605.
  • Dissing-Olesen L, Thaysen-Andersen M, Meldgaard M, Højrup P, Finsen B (2008). The function of the human IFN-ß 1a glycan determined in vivo. J of Pharmacol and Experimental Therapeutics 326: 338-347. DOI: 10.1124/jpet.108.138263
  • Feizi A, Österlund T, Petranovic D, Bordel S, Nielsen J (2013). Genome-scale modeling of the protein secretory machinery in yeast. PLoS One 8: 1-13. DOI: 10.1371/journal.pone.0063284
  • Goodbourn S, Didcock L, Randall RE (2000). Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J of General Virol 81: 2341–2364. DOI: 10.1099/0022-1317-81-10-2341
  • Hermant P, Michaels T (2014). Interferon-λ in the context of viral infections: production, response and therapeutic implications. J of Innate Immunity 6: 563-574. DOI: 10.1159/000360084
  • Kamionka, M (2011). Engineering of therapeutic proteins production in Escherichia coli. Current Pharmaceut Biotech 12: 268-274. DOI : 0.2174/138920111794295693
  • Kagawa Y, Takasaki S, Utsumi J, Hosoi K, Shimizu H, Kochibe N, Kobata A (1988). Comparative study of the asparagine-linked sugar chains of natural human IFN-β 1 and recombinant human IFN-β 1 produced by three different mammalian cells. J of Biological Chem 263: 17508-17515.
  • Kieseier BC, Arnold DL, Balcer LJ, Boyko AA, Pelletier J, Liu S, Zhu Y, Seddighzadeh A, Hung S, Deykin A, Sheikh SI, Calabresi PA (2015). Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE. Multiple Sclerosis J 21: 1025-1035. DOI: 10.1177/1352458514557986
  • Mark DF, Lu SD, Creasey AA, Yamamoto R, Lin LS (1984). Site-specific mutagenesis of the human fibroblast IFN gene. Proc Nat Acad Sci USA. 81: 5662-5666. DOI: 10.1073/pnas.81.18.5662
  • Mattanovich D, Gasser B, Hohenblum H, Sauer M (2004). Stress in recombinant protein producing yeasts. J of Biotech 113: 112-135. DOI: 10.1016/j.jbiotec.2004.04.035
  • Mergulhao FJ, Summers DK, Monteiro GA (2005). Recombinant protein secretion in Escherichia coli. Biotech Adv 23: 177-202. DOI: 10.1016/j.biotechadv.2004.11.003
  • Moradian C, Fazeli MR, Abedi D (2013). Over expression of the Interferon ß-1b by optimizing induction conditions using response surface methodology. J of Biology and Today's World 2: 217-226. DOI: 10.15412/J.JBTW.01020401
  • Morowvat MH, Babaeipour V, Rajabi-Memari H, Vahidi H, Maghsoudi N (2014). Overexpression of recombinant human beta interferon (rhINF-ß) in periplasmic space of Escherichia coli. Iranian J of Pharmaceut Res 13: 151-60.
  • Morowvat, M.H., Babaeipour, V., Memari, H.R., Vahidi, H. (2015). “Optimization of fermentation conditions for recombinant human interferon beta production by Escherichia coli using the response surface methodology”, Jundishapur J of Microbiol 8: 1-9 101. DOI: 10.5812/jjm.8(4)2015.16236
  • Parker BS, Rautela J, Hertzog PJ (2016). Antitumour actions of interferons: implications for cancer therapy. Nature Rev Cancer 16: 131-144. DOI: 10.1038/nrc.2016.14
  • Pestka S, Langer JA, Zoon KC, Samuel CE (1987). Interferons and their actions. Ann Rev of Biochem 56(1): 727-777. DOI: 10.1146/annurev.bi.56.070187.003455 Pestka S, Krause CD, Walter MR (2004). Interferons, interferon-like cytokines, and their receptors. Immunol Rev 202: 8-32. DOI: 10.1111/j.0105-2896.2004.00204.x
  • Rao DVK, Ramu CT, Rao JV, Narasu ML, Rao AKSB (2009). Cloning, High Expression and Purification of Recombinant Human Interferon-ß-1b in Escherichia coli. Appl Biochem Biotech 158: 140–154. DOI: 10.1007/s12010-008-8318-9
  • Randall RE, Goodbourn S (2008). Interferons and viruses: An interplay between induction, signalling, antiviral responses and virus countermeasures. J General Virology 89: 1–47. DOI: 10.1099/vir.0.83391-0
  • Rodriguez J, Spearman M, Tharmalingam T, Sunley K, Lodewyks C, Huzel N, Butler M (2010). High productivity of human recombinant beta-interferon from a low-temperature perfusion culture. J. Biotech 150: 509-518. DOI: 10.1016/j.jbiotec.2010.09.959
  • Sambrook J, Russel DW (2001). Molecular Cloning: A Laboratory Manual 3rd ed Cold Spring Harbor Laboratory Press, New York, USA.
  • Sasaki R, Kanda T, Nakamoto S, Haga Y, Nakamura M, Yasui S, Jiang X, Wu S, Arai M, Yokosuka O (2015). Natural interferon-beta treatment for patients with chronic hepatitis C in Japan. World J. Hepatol 7: 1125-1132. DOI: 10.4254/wjh.v7.i8.1125
  • Schmidt FR (2004). Recombinant expression systems in the pharmaceutical industry. Appl Microbiol Biotech 65: 363-372. DOI: 10.1007/s00253-004-1656-9
  • Sivashanmugam A, Murray V, Cui C, Zhang Y, Wang J, Li Q (2009). Practical protocols for production of very high yields of recombinant proteins using Escherichia coli. Protein Sci 18: 936-948. DOI: 10.1002/pro.102
  • Smeekens SP, Ng A, Kumar V, Johnson MD, Plantinga TS, van Diemen C, Arts P, Verwiel ET, Gresnigt MS, Fransen K, van Sommeren S, Oosting M, Cheng SC, Joosten LA, Hoischen A, Kullberg BJ, Scott WK, Perfect JR, van der Meer JW, Wijmenga C, Netea MG, Xavier RJ (2013). Functional genomics identifies type I IFN pathway as central for host defense against Candida albicans. Nature Commun 4: 1342. DOI: 10.1038/ncomms2343
  • Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnborg M, Stenager E, Koch-Henriksen N (2003). Danish Multiple Sclerosis Study Group. Clinical importance of neutralising antibodies against IFN β in patients with relapsing-remitting multiple sclerosis. Lancet 362: 1184-91. DOI: 10.1016/S0140-6736(03)14541-2
  • Stefan A, Alfarano P, Merulla D, Mattana P, Rolli E, Mangino P, Masotti L, Hochkoeppler A (2009). The regulatory elements of araBAD operon, contrary to lac-based expression systems, afford hypersynthesis of murine and human IFNs in Escherichia coli. Biotech Prog 25: 1612-1619. DOI: 10.1002/btpr.270
  • Stifter SA, Gould JA, Mangan NE, Reid HH, Rossjohn J, Hertzog PJ, de Weerd NA (2014). Purification and biological characterization of soluble, recombinant mouse IFN-ß expressed in insect cells. Protein Exp Purif 94: 7–14. DOI: 10.1016/j.pep.2013.10.019
  • Tayal V, Kalra BS (2008). Cytokines and anti-cytokines as therapeutics-an update. Eur J Pharmacol 579: 1-12. DOI: 10.1016/j.ejphar.2007.10.049
  • vanBeers MMC, Sauerborn M, Gilli F, Brinks V, Schellekens H, Jiskoot W (2011). Oxidized and aggregated recombinant human interferon beta is immunogenic in human interferon beta transgenic mice. Pharmaceut Res 28: 2393–2402. DOI: 10.1007/s11095-011-0451-4.
  • Villela AD, Renard G, Palma MS, Chies JM, Dalmora SL, Basso LA, Santos, DS (2010). Human IFN β1ser17: coding DNA synthesis, expression, purification and characterization of bioactive recombinant protein. J of Microbial & Biochemical Tech 2: 111-117.
  • Walsh G (2014). Biopharmaceut Benchmarks. Nature Biotech 32: 992–1000.

Escherichia coli’de Yenibileşenli İnterferon beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine bir Derleme

Year 2019, Volume: 45 Issue: 1, 10 - 21, 30.04.2019

Mehmet Öztürk Yakup Ermurat

Abstract

: Rekombinant
interferon beta (rİFN-β) proteini çeşitlerinden rİFN-β1a ve rİFN-β1b üretimi
için benzer süreçler ile ökaryotik ve prokaryotik ekspresyon sistemleri
kullanılmaktadır. Ökaryotik ekspresyon sistemleri ile üretilen rİFN-β1a’nın
saflaştırılmasında zorlukların yaşanması ve biyolojik aktivitesinin etkilenmesi
bu süreçler ile rekombinant protein üretimini güçleştirmektedir. Prokaryotik
ekspresyon sistemlerinin kullanıldığı rİFN-β1b üretiminde ise saflaştırma ve
aktivite sorunlarının daha az gerçekleştiği belirlenmiştir. Prokaryotik
bakterilerden Escherichia coli’de
bulunan ürün salgılama özelliğinin daha iyi kullanılması, bu sistemin rİFN-β1b
üretiminde daha fazla tercih edileceğini göstermektedir. Rekombinant
proteinlerin üretildikleri konakçı hücreden dışarı salgılatılacak şekilde yapı
tasarlanması durumunda, saflaştırma sırasında E. coli konakçı hücreler parçalanmayacağından ürün saflaştırma
işlemlerini kolaylaştıracağı öngörülmektedir. Tip I ve tip II salgılama
sistemine sahip olan E. coli’nin
rİFN-β1b proteinlerinin üretiminde kullanımı, bu konakçıda üretilen rİFN-β1b’nin
hücre dışına salgılatılmasında saflaştırma ve aktivite sorunlarını azaltacağı,
ayrıca rİFN-β1b’nin konakçı hücreye yapacağı toksik etkininde ortadan kalkacağı
tahmin edilmektedir. Bu amaçla E. coli
üretim sistemindeki dezavantajları gidermek için Sec sinyal peptidi olan PelB
sinyal peptidine ilave olarak Tat tipi sinyal peptidi olan DmsA sinyal
peptidi’nin pET22b ifade vektörüne aktarılmasıyla rİFN-β1b proteinlerinin hücre
dışına salgılatılması işlemi gibi çeşitli yaklaşımlar tasarlanmaktadır. Bu
derlemede, İFN’ların özelliklerine, rİFN-β’nın klinik uygulamalarına ve
rİFN-β1b üretim yöntemleri ile ilgili yapılmış araştırmalara dayalı bilgi ve ve
rİFN-β1b’nin E. coli konakçı
hücrelerinde üretilmesi sürecinde sinyal peptidlerinin kullanımı ile ilgili
bilgilere dikkat çekilmiştir.

Keywords

Rekombinant interferon beta salgılanması sinyal peptidler periplazmik protein

References

  • Allen J, Feng P, Patkar A, Haney KL, Chew L Sengchanthalangsy LLP (2015). Method for producing soluble recombinant interferon protein without denaturing. US20160032345A1.
  • Beladiya C, Tripathy RK, Bajaj P, Aggarwal G, Pande AH (2015). Expression, purification and immobilization of recombinant AiiA enzyme onto magnetic nanoparticles. Protein Expression and Purification 113: 56-62. DOI: 10.1016/j.pep.2015.04.014
  • Binet R, Létoffé S, Ghigo JM, Delepelaire P, Wandersman C (1997). Protein secretion by gram-negative bacterial ABC exporters–a review. Gene 192: 7-11. PMID: 9224868
  • Chelbi-Alix, M.K., Wietzerbin, J. (2007). “IFN, a growing cytokine family: 50 years of IFN research”, Biochimie, 89, 713-718. DOI: 10.1016/j.biochi.2007.05.001
  • Chevaliez S, Pawlotsky JM (2009). Interferons and Their Use in Persistent Viral Infections. In: Kräusslich HG, Bartenschlager R. (eds) Antiviral strategies. Handbook of Experimental Pharmacol 189 Springer Berlin Heidelberg. e-ISBN 978-3-540-79086-0
  • Choi JH, Lee SY (2004). Secretory and extracellular production of recombinant proteins using Escherichia coli. Appl Microbiol and Biotech 64: 625-635. DOI: 10.1007/s00253-004-1559-9
  • Cianciotto NP (2005). Type II secretion: a protein secretion system for all seasons. Trends in Microbiol 13(12): 581-588. DOI: 10.1016/j.tim.2005.09.005
  • Conradt HS, Egge H, Peter-Katalinic J, Reiser W, Siklosi T, Schaper K (1987). Structure of the carbohydrate moiety of human IFN-ß secreted by a recombinant Chinese hamster ovary cell line. J of Biological Chem 262: 14600-14605.
  • Dissing-Olesen L, Thaysen-Andersen M, Meldgaard M, Højrup P, Finsen B (2008). The function of the human IFN-ß 1a glycan determined in vivo. J of Pharmacol and Experimental Therapeutics 326: 338-347. DOI: 10.1124/jpet.108.138263
  • Feizi A, Österlund T, Petranovic D, Bordel S, Nielsen J (2013). Genome-scale modeling of the protein secretory machinery in yeast. PLoS One 8: 1-13. DOI: 10.1371/journal.pone.0063284
  • Goodbourn S, Didcock L, Randall RE (2000). Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J of General Virol 81: 2341–2364. DOI: 10.1099/0022-1317-81-10-2341
  • Hermant P, Michaels T (2014). Interferon-λ in the context of viral infections: production, response and therapeutic implications. J of Innate Immunity 6: 563-574. DOI: 10.1159/000360084
  • Kamionka, M (2011). Engineering of therapeutic proteins production in Escherichia coli. Current Pharmaceut Biotech 12: 268-274. DOI : 0.2174/138920111794295693
  • Kagawa Y, Takasaki S, Utsumi J, Hosoi K, Shimizu H, Kochibe N, Kobata A (1988). Comparative study of the asparagine-linked sugar chains of natural human IFN-β 1 and recombinant human IFN-β 1 produced by three different mammalian cells. J of Biological Chem 263: 17508-17515.
  • Kieseier BC, Arnold DL, Balcer LJ, Boyko AA, Pelletier J, Liu S, Zhu Y, Seddighzadeh A, Hung S, Deykin A, Sheikh SI, Calabresi PA (2015). Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE. Multiple Sclerosis J 21: 1025-1035. DOI: 10.1177/1352458514557986
  • Mark DF, Lu SD, Creasey AA, Yamamoto R, Lin LS (1984). Site-specific mutagenesis of the human fibroblast IFN gene. Proc Nat Acad Sci USA. 81: 5662-5666. DOI: 10.1073/pnas.81.18.5662
  • Mattanovich D, Gasser B, Hohenblum H, Sauer M (2004). Stress in recombinant protein producing yeasts. J of Biotech 113: 112-135. DOI: 10.1016/j.jbiotec.2004.04.035
  • Mergulhao FJ, Summers DK, Monteiro GA (2005). Recombinant protein secretion in Escherichia coli. Biotech Adv 23: 177-202. DOI: 10.1016/j.biotechadv.2004.11.003
  • Moradian C, Fazeli MR, Abedi D (2013). Over expression of the Interferon ß-1b by optimizing induction conditions using response surface methodology. J of Biology and Today's World 2: 217-226. DOI: 10.15412/J.JBTW.01020401
  • Morowvat MH, Babaeipour V, Rajabi-Memari H, Vahidi H, Maghsoudi N (2014). Overexpression of recombinant human beta interferon (rhINF-ß) in periplasmic space of Escherichia coli. Iranian J of Pharmaceut Res 13: 151-60.
  • Morowvat, M.H., Babaeipour, V., Memari, H.R., Vahidi, H. (2015). “Optimization of fermentation conditions for recombinant human interferon beta production by Escherichia coli using the response surface methodology”, Jundishapur J of Microbiol 8: 1-9 101. DOI: 10.5812/jjm.8(4)2015.16236
  • Parker BS, Rautela J, Hertzog PJ (2016). Antitumour actions of interferons: implications for cancer therapy. Nature Rev Cancer 16: 131-144. DOI: 10.1038/nrc.2016.14
  • Pestka S, Langer JA, Zoon KC, Samuel CE (1987). Interferons and their actions. Ann Rev of Biochem 56(1): 727-777. DOI: 10.1146/annurev.bi.56.070187.003455 Pestka S, Krause CD, Walter MR (2004). Interferons, interferon-like cytokines, and their receptors. Immunol Rev 202: 8-32. DOI: 10.1111/j.0105-2896.2004.00204.x
  • Rao DVK, Ramu CT, Rao JV, Narasu ML, Rao AKSB (2009). Cloning, High Expression and Purification of Recombinant Human Interferon-ß-1b in Escherichia coli. Appl Biochem Biotech 158: 140–154. DOI: 10.1007/s12010-008-8318-9
  • Randall RE, Goodbourn S (2008). Interferons and viruses: An interplay between induction, signalling, antiviral responses and virus countermeasures. J General Virology 89: 1–47. DOI: 10.1099/vir.0.83391-0
  • Rodriguez J, Spearman M, Tharmalingam T, Sunley K, Lodewyks C, Huzel N, Butler M (2010). High productivity of human recombinant beta-interferon from a low-temperature perfusion culture. J. Biotech 150: 509-518. DOI: 10.1016/j.jbiotec.2010.09.959
  • Sambrook J, Russel DW (2001). Molecular Cloning: A Laboratory Manual 3rd ed Cold Spring Harbor Laboratory Press, New York, USA.
  • Sasaki R, Kanda T, Nakamoto S, Haga Y, Nakamura M, Yasui S, Jiang X, Wu S, Arai M, Yokosuka O (2015). Natural interferon-beta treatment for patients with chronic hepatitis C in Japan. World J. Hepatol 7: 1125-1132. DOI: 10.4254/wjh.v7.i8.1125
  • Schmidt FR (2004). Recombinant expression systems in the pharmaceutical industry. Appl Microbiol Biotech 65: 363-372. DOI: 10.1007/s00253-004-1656-9
  • Sivashanmugam A, Murray V, Cui C, Zhang Y, Wang J, Li Q (2009). Practical protocols for production of very high yields of recombinant proteins using Escherichia coli. Protein Sci 18: 936-948. DOI: 10.1002/pro.102
  • Smeekens SP, Ng A, Kumar V, Johnson MD, Plantinga TS, van Diemen C, Arts P, Verwiel ET, Gresnigt MS, Fransen K, van Sommeren S, Oosting M, Cheng SC, Joosten LA, Hoischen A, Kullberg BJ, Scott WK, Perfect JR, van der Meer JW, Wijmenga C, Netea MG, Xavier RJ (2013). Functional genomics identifies type I IFN pathway as central for host defense against Candida albicans. Nature Commun 4: 1342. DOI: 10.1038/ncomms2343
  • Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnborg M, Stenager E, Koch-Henriksen N (2003). Danish Multiple Sclerosis Study Group. Clinical importance of neutralising antibodies against IFN β in patients with relapsing-remitting multiple sclerosis. Lancet 362: 1184-91. DOI: 10.1016/S0140-6736(03)14541-2
  • Stefan A, Alfarano P, Merulla D, Mattana P, Rolli E, Mangino P, Masotti L, Hochkoeppler A (2009). The regulatory elements of araBAD operon, contrary to lac-based expression systems, afford hypersynthesis of murine and human IFNs in Escherichia coli. Biotech Prog 25: 1612-1619. DOI: 10.1002/btpr.270
  • Stifter SA, Gould JA, Mangan NE, Reid HH, Rossjohn J, Hertzog PJ, de Weerd NA (2014). Purification and biological characterization of soluble, recombinant mouse IFN-ß expressed in insect cells. Protein Exp Purif 94: 7–14. DOI: 10.1016/j.pep.2013.10.019
  • Tayal V, Kalra BS (2008). Cytokines and anti-cytokines as therapeutics-an update. Eur J Pharmacol 579: 1-12. DOI: 10.1016/j.ejphar.2007.10.049
  • vanBeers MMC, Sauerborn M, Gilli F, Brinks V, Schellekens H, Jiskoot W (2011). Oxidized and aggregated recombinant human interferon beta is immunogenic in human interferon beta transgenic mice. Pharmaceut Res 28: 2393–2402. DOI: 10.1007/s11095-011-0451-4.
  • Villela AD, Renard G, Palma MS, Chies JM, Dalmora SL, Basso LA, Santos, DS (2010). Human IFN β1ser17: coding DNA synthesis, expression, purification and characterization of bioactive recombinant protein. J of Microbial & Biochemical Tech 2: 111-117.
  • Walsh G (2014). Biopharmaceut Benchmarks. Nature Biotech 32: 992–1000.
There are 38 citations in total.

Details

Primary Language Turkish
Subjects Structural Biology
Journal Section Research Articles
Authors

Mehmet Öztürk

Yakup Ermurat

Publication Date April 30, 2019
Submission Date August 18, 2018
Published in Issue Year 2019 Volume: 45 Issue: 1

Cite

APA Öztürk, M., & Ermurat, Y. (2019). Escherichia coli’de Yenibileşenli İnterferon beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine bir Derleme. Selçuk Üniversitesi Fen Fakültesi Fen Dergisi, 45(1), 10-21.
AMA Öztürk M, Ermurat Y. Escherichia coli’de Yenibileşenli İnterferon beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine bir Derleme. sufefd. April 2019;45(1):10-21.
Chicago Öztürk, Mehmet, and Yakup Ermurat. “Escherichia coli’de Yenibileşenli İnterferon Beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine Bir Derleme”. Selçuk Üniversitesi Fen Fakültesi Fen Dergisi 45, no. 1 (April 2019): 10-21.
EndNote Öztürk M, Ermurat Y (April 1, 2019) Escherichia coli’de Yenibileşenli İnterferon beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine bir Derleme. Selçuk Üniversitesi Fen Fakültesi Fen Dergisi 45 1 10–21.
IEEE M. Öztürk and Y. Ermurat, “Escherichia coli’de Yenibileşenli İnterferon beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine bir Derleme”, sufefd, vol. 45, no. 1, pp. 10–21, 2019.
ISNAD Öztürk, Mehmet - Ermurat, Yakup. “Escherichia coli’de Yenibileşenli İnterferon Beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine Bir Derleme”. Selçuk Üniversitesi Fen Fakültesi Fen Dergisi 45/1 (April 2019), 10-21.
JAMA Öztürk M, Ermurat Y. Escherichia coli’de Yenibileşenli İnterferon beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine bir Derleme. sufefd. 2019;45:10–21.
MLA Öztürk, Mehmet and Yakup Ermurat. “Escherichia coli’de Yenibileşenli İnterferon Beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine Bir Derleme”. Selçuk Üniversitesi Fen Fakültesi Fen Dergisi, vol. 45, no. 1, 2019, pp. 10-21.
Vancouver Öztürk M, Ermurat Y. Escherichia coli’de Yenibileşenli İnterferon beta Salgılanmasında Sinyal Peptidi Kullanımı Üzerine bir Derleme. sufefd. 2019;45(1):10-21.
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It has been scanned in DergiPark since 2016.

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Selcuk University Journal of Science Faculty is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) License.