Las bacterias como sistema de expresión de proteínas heterólogas terapéuticas: una revisión bibliográfica


  • Yurley Vanesa Álvarez G. Universidad de Antioquia
  • Alexander Arias N. Universidad de Antioquia

Palabras clave:

bacterias, expresión, proteínas heterólogas, proteínas terapéuticas


En la actualidad la producción de proteínas terapéuticas se ha convertido en uno de los campos de mayor impacto a nivel científico y biotecnológico. La expresión de proteínas recombinantes en sistemas procariontes, particularmente en E. coli han permitido el desarrollo de una gran variedad de proteínas terapéuticas. Sin embargo, para poder producir proteínas funcionales ha sido necesario buscar intensamente un equilibrio entre la calidad y la producción; por lo que es necesario innovar nuevas estrategias que permitan superar las dificultades inherentes a los sistemas de expresión procariote, por esto es esencial delimitar los alcances que pueden tener las bacterias más empleadas y aquellas que podrían representar alternativas prometedoras para la producción de proteínas de interés. La presente revisión bibliográfica está dirigida a realizar un estudio del estado del arte y de la técnica de los sistemas de expresión de proteínas heterólogas que existen en torno al empleo de bacterias, con impacto en la industria farmacéutica y biotecnológica.

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Biografía del autor/a

Yurley Vanesa Álvarez G., Universidad de Antioquia

Estudiante de Microbiología Industrial y Ambiental.

Alexander Arias N., Universidad de Antioquia

Asesor-Docente de la Facultad de Química Farmacéutica de la Universidad de Antioquia. Medellín, Colombia.


Graumann K, Premstaller A. Manufacturing of recombi-nant therapeutic proteins in microbial sys-tems. Biotechnol J. 2006; 1(2):164-86.

Pavlou AK, Reichert JM. Recombinant protein the-rapeutics success rates, market trends and values to 2010. NatBiotechnol 2004; 22:1513-9.

Datamonitor. Recombinant therapeutic proteins: 2010; Delive-ring a $200 billion mature market by 2020.

Smales CM. Therapeutic proteins: methods and pro-tocols. Humana Press. 2008.

Palomares LA, Estrada-Mondaca S, Ramírez OT. Production of recombinant proteins: challenges and solutions. Methods Mol Biol. 2004; 267:15-52.

Sahdev S, Khattar SK, Saini KS. Production of ac-tive eukaryotic proteins through bacterial expres-sion systems: a review of the existing biotechnolo-gy strategies. Molecular and Cellular Biochemistry. 2008; 307:249-64.

Terpe K. Overview of bacterial expression systems for heterologous protein production: from molecu-lar and biochemical fundamentals to commercial systems. Applied Microbiology and Biotechnology. 2006; 72:211-22.

Georgiou G, Segatori L. Preparative expression of secreted proteins in bacteria: status report and future prospects. Curr Opin Biotechnol. 2005; 16:538-45.

Sorensen HP, Mortensen KK. Advanced genetic strategies for recombinant protein expression in Escherichia coli. Journal of Biotechnology. 2005; 115: 113-28.

Demain AL, Vaishnav P. Production of recombinant proteins by microbes and higher organisms. Biotech-nology Advances. 2009; 27:297-306.

Chen R. Bacterial expression systems for recombi-nant protein production: E. coli and beyond. Biotech-nology Advances. 2012; 30:1102-7.

Ni Y, Chen R. Extracellular recombinant protein pro-duction from Escherichia coli. Biotechnol Lett. 2009; 31:1661-70.

Petsch D, Anspach FB. Endotoxin removal from pro-tein solutions. J. Biotechnol. 2000; 76:97-119.

Bakke I, Berg L, Aune TE, Brautaset T, Sletta H, Tondervik A, et al. Random mutagenesis of the PM promoter as a powerful strategy for improvement of recombinant-gene expression. Appl Environ Micro-biol. 2009; Apr; 75(7):2002-11.

Pacheco B, Crombet L, Loppnau P, Cossar D. A screening strategy for heterologous protein expres-sion in Escherichia coli with the highest return of in-vestment. Protein Expression and Purification, 2012; Vol. 81, p.33-41.

Denoncin K, Collet JF. Disulfide bond formation in the bacterial periplasm: major achievements and challenges ahead. Antioxid Redox Signal. 2013 Jul 1;19(1):63-71. doi: 10.1089/ars.2012.4864. Epub 2012; Oct 2. Review.

de Marco A. Recent contributions in the field of the recombinant expression of disulfide bonded prote-ins in bacteria. Microbial Cell Fact. 2012; 11:129.

du Plessis DJ, Nouwen N, Driessen AJ. The Sec translocase. Biochim Biophys Acta. 2011; 1808(3): 851-65.

Schlegel S, Rujas E, Ytterberg AJ, Zubarev RA, Lui-rink J, de Gier JW. Optimizing heterologous protein production in the periplasm of E. coli by regulating gene expression levels. Microbial Cell Factories. 2013; 12:24.

Burgess-Brown NA, Sharma S, Sobott F, Loenarz C, Oppermann U, Gileadi O. Codon optimization can improve expression of human genes in Escherichia coli: A multi-gene study. Protein Expr Purif. 2008; 59(1):94-102.

Pfleger BF, Pitera DJ, Smolke CD, Keasling JD. Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes. Nat Biotechnol. 2006; 24(8):1027-32.

Kudla G, Murray AW, Tollervey D, Plotkin J. Co-ding-sequence determinants of gene expression in Escherichia coli. Science. 2009; 324(5924):255-8.

de Marco A. Protocol for preparing proteins with improved solubility by co-expressing with molecu-lar chaperones in Escherichia coli. Nat Protoc. 2007; 2(10):2632-9.

Cho HJ, Lee Y, Chang RS, Hahm MS, Kim MK, Kim YB, et al. Maltose binding protein facilitates high-level expression and functional purification of the chemokines RANTES and SDF-1alpha from Escherichia coli. Protein Expr Purif. 2008; 60(1):37-45.

López PJ, Marchand I, Joyce SA, Dreyfus M. The C-terminal half of RNase E, which organizes the Escheri-chia coli degradosome, participates in mRNA degra-dation but not rRNA processing in vivo. Mol Microbiol. 2000; 33(1):188-99.

Kadokura H, Katzen F, Beckwith J. Protein disulfide bond formation in prokaryotes. Annu Rev Biochem. 2003; 72:111-35.

de Marco A. Strategies for successful recombinant expression of disulfide bond-dependent proteins in Escherichia coli. Microb Cell Fact. 2009; 8:26.

Wacker M, Linton D, Hitchen PG, Nita-Lazar M, Haslam SM, North SJ, et al. N-linked glycosylation in Campylobacter jejuni and its functional transfer into E. coli. Science. 2002; 298(5599):1790-3.

Gautschi M, Just S, Mun A, Ross S, Rucknagel P, Dubaquie Y, et al. The yeast N(alpha)-acetyltransfe-rase NatA is quantitatively anchored to the ribosome and interacts with nascent polypeptides. Mol Cell Biol. 2012; 23(20):7403-14.

Fang H, Zhang X, Shen L, Si X, Ren Y, Dai H, et al. Ri-mJis responsible for N(alpha)-acetylation of thymosin alpha1 in Escherichia coli. Appl Microbiol Biotechnol. 2009; 84(1):99-104.

Tomohiro M, Georgios S, George G. Strain engi-neering for improved expression of recombinant proteins in bacteria. Microbial Cell Factories. 2011; 10:32.

Klein-Marcuschamer D, Santos CN, Yu H, Stepha-nopoulos G. Mutagenesis of the bacterial RNA polymerase alpha subunit for improvement of com-plex phenotypes. Appl Environ Microbiol. 2009; 75(9):2705-11.

Park KS, Jang YS, Lee H, Kim JS. Phenotypic altera-tion and target gene identification using combinato-rial libraries of zinc finger proteins in prokaryotic cells. J Bacteriol. 2005; 187(15):5496-9.

Tegel H, Ottosson J, Hober S. Enhancing the pro-tein production levels in Escherichia coli with a strong promoter. FEBS Journal 2011; 278: 729-39.

Tegel H, Tourle S, Ottosson J, Persson A. Increased levels of recombinant human proteins with the Esche-richia coli strain Rosetta (DE3). Protein Expr Purif. 2010; 69,159-67.

Welch M, Govindarajan S, Ness JE, Villalobos A, Gurney A, Minshull J, et al. Design parameters to control synthetic gene expression in Escherichia coli. PLoS ONE 4, e7002. 2009.

Becker NA, Peters JP, Maher LJ 3rd, Lionberger TA. Mechanism of promoter repression by Lac re-pressor-DNA loops. Nucleic Acids Res. 2013; Jan 7; 41(1):156-66.

Yu H, Ma Q, Lin J, Sun YF, Zheng F. Expression and purification of GST-FHL2 fusion protein. Genet Mol Res. 2013; 12(4):6372-8.

Kimberly J, Durniak, Scott Bailey, Thomas A, Steitz. The Structure of a Transcribing T7 RNA Polymerase in Transition from Initiation to Elongation. Science. 2008; Vol. 322 no. 5901 pp. 553-7.

Equbal MJ, Srivastava P, Agarwal GP, Deb JK. No-vel expression system for Corynebacterium acetoaci-dophilum and Escherichia coli based on the T7 RNA polymerase-dependent promoter. Appl Microbiol Biotechnol. 2013; 97(17): 7755-66.

Kogenaru M, Tans S. An improved Escherichia coli strain to host gene regulatory networks involving both the AraC and LacI inducible transcription factors. Journal of Biological Engineering. 2014; 8:2

Xin-tian Li, Lynn C, Thomason, James A. Sawitzke, Nina Costantino, and Donald L. Court (2013). Positive and negative selection using the tetA-sacB cassette: recombineering and P1 transduction in Escherichia coli. Nucleic Acids Research, 2013, Vol. 41, No. 22.

Wegerer A, Sun T, Altenbuchner J. Optimization of an E. coli L-rhamnose- inducible expression vector: test of various genetic module combinations. BMC Biotechnology. 2008; 8:2.

Ferrer-Miralles N, Villaverde A. Bacterial cell facto-ries for recombinant protein production; expanding the catalogue. Microbial Cell Factories. 2013; 12:113.

Arendt EK, Moroni A, Zannini E. Medical nutrition therapy: use of sourdough lactic acid bacteria as a cell factory for delivering functional biomolecules and food ingredients in gluten free bread. Microb Cell Fact. 2011; 10(1):S15.

Simon B, Nomellini J, Chiou P, Bingle W, Thornton J, Smit J, et al. Recombinant vaccines against infec-tious hematopoietic necrosis virus: production by the Caulobacter crescentus S-layer protein secretion system and evaluation in laboratory trials. Dis Aquat Organ. 2001; 44:17-27.

Duncan G, Tarling CA, Bingle WH, Nomellini JF, Yamage M, Dorocicz IR, et al. Evaluation of a new system for developing particulate enzymes based on the surface (S)-layer protein (RsaA) of Caulobacter crescentus: fusion with the beta-1,4-glycanase (Cex) from the cellulolytic bacterium Cellulomonas fimi yields a robust, catalytically active product. Appl Biochem Biotechnol. 2005; 127:95-110.

Laible PD, Scott HN, Henry L, Hanson DK. Towards higher-throughput membrane protein production for structural genomics initiatives. J Struct Funct Geno-mics. 2004; 5:167-72.

Giuliani M, Parrilli E, Ferrer P, Baumann K, Marino C, Tutino ML. Process optimization for recombinant protein production in the psychrophilic bacterium Pseudoalteromonas haloplanktis. Process Biochem. 2011; 46:953-9.

Vigentini I, Merico A, Tutino ML, Compagno C, Marino G. Optimization of recombinant human nerve growth factor production in the psychrophilic Pseudoalteromonas haloplanktis. J Biotechnol. 2006; 127:141-50.

Jin H, Cantin GT, Maki S, Chew LC, Resnick SM, Ngai J, et al. Soluble periplasmic production of hu-man granulocyte colony-stimulating factor (G-CSF) in Pseudomonas fluorescens. Protein Expr Purif. 2011; 78:69-77. 52.

Dammeyer T, Steinwand M, Kruger SC, Dubel S, Hust M, Timmis KN. Efficient production of soluble recombinant single chain Fv fragments by a Pseudo-monas putida strain KT2440 cell factory. Microb Cell Fact. 2011; 10:11.

Krzeslak J, Braun P, Voulhoux R, Cool RH, Quax WJ.Heterologous production of Escherichia coli pe-nicillin G acylase in Pseudomonas aeruginosa. J Biote-chnol. 2009; 142:250-8.

Ayala JC, Pimienta E, Rodríguez C, Anné J, Vallín C, Milanés MT, et al. Use of Strep-tag II for rapid detec-tion and purification of Mycobacterium tuberculosisrecombinant antigens secreted by Streptomyces livi-dans. J Microbiol Methods. 2013; 94:192-8.

Guo XQ, Wei YM, Yu B. Recombinant Mycobacterium smegmatis expressing Hsp65-hIL-2 fusion protein and its influence on lymphocyte function in mice. Asian Pac J Trop Med. 2012; 5:347-51.

Yang M, Zhang W, Ji S, Cao P, Chen Y, Zhao X. Ge-neration of an artificial double promoter for protein expression in Bacillus subtilis through a promoter trap system. PLoS One. 8:e56321. 2013.

Zhao LL, Liu M, Ge JW, Qiao XY, Li YJ, Liu DQ. Ex-pression of infectious pancreatic necrosis virus (IPNV) VP2-VP3 fusion protein in Lactobacillus casei and immunogenicity in rainbow trouts. Vaccine. 2012; 30:1823-9.

Eom JE, Moon SK, Moon GS. Heterologous produc-tion of pediocin PA-1 in Lactobacillus reuteri. J Micro-biol Biotechnol. 2010; 20:1215-8.

Damelin LH, Mavri-Damelin D, Klaenhammer TR, Tiemessen CT. Plasmid transduction using bacte-riophage Phi(adh) for expression of CC chemokines by Lactobacillus gasseri ADH. Appl Environ Microbiol. 2010; 76:3878-85.




Cómo citar

Álvarez G., Y. V. ., & Arias N., A. . (2014). Las bacterias como sistema de expresión de proteínas heterólogas terapéuticas: una revisión bibliográfica. Hechos Microbiológicos, 4(2), 106–116. Recuperado a partir de



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