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Parameters influencing the productivity of recombinant E. coli cultivations

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Bioprocess Design and Control

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 48))

Abstract

In the past 10 to 15 years, many of the promises of microbial genetic engineering have been realized: the use of recombinant Escherichia coli has moved from the laboratory to the production facility, and the manufacture of therapeutic recombinant proteins such as human growth hormone and interleukins is a rapidly growing industry.

Along with this progress, however, have come new problems to solve: bioreactor operators have discovered that large-scale cultivations of plasmid-containing bacteria do not behave in exactly the same way as those of plasmid-free cells, plasmid stability has been recognized as a major hurdle, and the protein product might not be present in a soluble form but rather as intracellular granules that resist solubilization. These and other difficulties represent a new generation of challenges for genetic engineering.

However, genetic engineering can do more than solve these problems. Molecular biological techniques also have the ability to create new opportunities: to produce new compounds, to use cheaper substrates, to facilitate downstream processing, and to optimize production in new ways.

The productivity of a cultivation can generally be expressed as the product of the cell density and the specific biological activity. Both of these parameters are influenced by a variety of factors. For recombinant cultivations, though, the level of biological activity, a reflection of the plasmid copy number and expression efficiency, is the more interesting and important consideration and will therefore be given more attention in our review. In this contribution, our general goal is to discuss the factors that influence the productivity of recombinant E. coli cultivations, covering

  • -parameters relating to DNA;

  • -parameters relating to protein synthesis;

  • -parameters relating to proteins; and

  • -parameters relating to downstream processing.

The object is not to tell the reader how to choose the perfect plasmid, host, and cultivation conditions, but to make known the many variables involved in designing a recombinant process and to point out recent and potential advances made possible by genetic engineering. The discussion focuses on the production of a protein, but many of the same concepts apply to other cultivations of recombinant E. coli, including cases in which the desired product is not a protein or the cells have been designed for a special metabolic capability such as pollutant biodegradation.

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References

  1. Dennis K, Srienc F, Bailey JE (1985) Biotechnol Bioeng 27:1490

    Google Scholar 

  2. Twigg AJ, Sherratt D (1980) Nature (London) 283:216

    Google Scholar 

  3. Lacatena RM, Cesareni G (1981) Nature (London) 294:623

    Google Scholar 

  4. Tacon WCA, Bonass WA, Jenkins B, Emtage JS (1983) Gene 23:255

    Google Scholar 

  5. Terawaki Y, Itoh Y (1985) J Bacteriol 162:72

    Google Scholar 

  6. Sherratt D (1986) Control of plasmid maintenance. In: Booth IR, Higgins CF (eds) Regulation of gene expression — 25 years on. Cambridge University Press, Cambridge, p 239 (39th Symp Soc Gen Microbiol)

    Google Scholar 

  7. Scott JR (1984) Microbiol Rev 48:1

    Google Scholar 

  8. Shibui T, Kamizono M, Teranishi Y (1988) Agric Biol Chem 52:2235

    Google Scholar 

  9. Uhlin BE, Molin S, Gustafsson P, Nordstrom K (1979) Gene 6:91

    Google Scholar 

  10. Yarranton GT, Wright E, Robinson MK, Humphreys GO (1984) Gene 28:293

    Google Scholar 

  11. Seo J-H, Bailey JE (1985) Biotechnol Bioeng 27:1668

    Google Scholar 

  12. Jones IM, Primrose SB, Robinson A, Ellwood DC (1980) Mol Gen Genet 180:579

    Google Scholar 

  13. Edler C, Friehs K, Schügerl K (1989) DECHEMA Biotechnol Conf 3:549

    Google Scholar 

  14. Summers DK, Sherratt DJ (1984) Cell 36:1097

    Google Scholar 

  15. Imanaka T, Aiba S (1981) Ann NY Acad Sci 369:1

    Google Scholar 

  16. Ensley BD (1986) CRC Crit Rev Biotechnol 4:263

    Google Scholar 

  17. Kumar PKR, Maschke H-E, Friehs K, Schügerl K (1991) Trends Biotechnol 9:279

    Google Scholar 

  18. Anderson DM, Herrrmann KM, Somerville RL (1983) US Patent No. 4371614

    Google Scholar 

  19. Skogman SG, Nilsson J (1984) Gene 31:117

    Google Scholar 

  20. Porter RD, Black S, Pannuri S, Carlson A (1990) Bio/Technology 8:47

    Google Scholar 

  21. Gerdes K, Rasmussen PB, Molin S (1986) Proc Natl Acad Sci USA 83:3116

    Google Scholar 

  22. Rosteck Jr PR, Hershberger CL (1983) Gene 25:29

    Google Scholar 

  23. Siegel R, Ryu DYD (1985) Biotechnol Bioeng 27:28

    Google Scholar 

  24. Chen J, Morrison DA (1987) Gene 55:179

    Google Scholar 

  25. Nishimura N, Taniguchi T, Komatsubara S (1989) J Fermentation Bioeng 67:107

    Google Scholar 

  26. Meacock PA, Cohen SN (1980) Cell 20:529

    Google Scholar 

  27. Chambers SP (1989) PhD Thesis, University of Warwick

    Google Scholar 

  28. Ryan W, Parulekar SJ (1991) Biotechnol Bioeng 37:415

    Google Scholar 

  29. Naock D, Roth M, Geutner R, Muller G, Undisz K, Hoffmieir C, Gaspar S (1981) Mol Gen Genet 184:121

    Google Scholar 

  30. Jones SA, Melling J (1984) FEMS Microbiol Lett 22:239

    Google Scholar 

  31. Brownlie L, Stephenson JR, Cole JA (1990) J Gen Microbiol 136:2471

    Google Scholar 

  32. Hopkins DJ, Betenbaugh MJ, Dhurjati P (1987) Biotechnol Bioeng 29:85

    Google Scholar 

  33. Caunt P, Impoolsup A, Greenfield PF (1989) Biotechnol Lett. 11:5

    Google Scholar 

  34. Wouters JTM, Driehuis FL, Polaczek PJ, Van Oppenraag MLHA, Van Andel JG (1980) Antonie van Leeuwenhoek 37:311

    Google Scholar 

  35. Impoolsup A, Caunt P, Greenfield PF (1989) Biotechnol Lett 11:605

    Google Scholar 

  36. Stephens ML, Lyberatos G (1985) Biotechnol Bioeng 31:464.

    Google Scholar 

  37. Di Pasquantonio VM, Betenbaugh MJ, Dhurjati P (1987) Biotechnol Bioeng 29:513

    Google Scholar 

  38. Henry KL, Davis RH, Taylor AL (1990) Biotechnol Prog 6:7

    Google Scholar 

  39. Berry F, Sayadi S, Nasri M, Thomas D, Barbotin JN (1990) J Biotechnol 16:199

    Google Scholar 

  40. Godwin D, Slater H (1979) J Gen Microbiol 111:201

    Google Scholar 

  41. Hawley DK, McClure R (1983) Nuc Acd Res 11:2237

    Google Scholar 

  42. Horwitz MSZ, Loeb LA (1990) Prog. Nuc. Acd. Res. Mol. Biol. 38:137

    Google Scholar 

  43. Kobayashi M, Nagata K, Ishihama A (1990) Nue Acd Res 18:7367

    Google Scholar 

  44. Reinikainen P, Lähde M, Karp M, Suominen I, Markkanen P, Mäntsälä P (1988) Biotechnol Lett 10:149

    Google Scholar 

  45. Botterman J, Höfte H, Zabeau M (1987) J Biotechnol 6:71

    Google Scholar 

  46. Elvin CM, Thompson PR, Argall ME, Hendry P, Stamford NPJ, Lilley PE, Dixon NE (1990) Gene 87:123

    Google Scholar 

  47. Shapira SK, Chou J, Richaud FV, Casadaban MJ (1983) Gene 25:71

    Google Scholar 

  48. Amann E, Brosius J, Ptashne M, (1983) Gene 25:167

    Google Scholar 

  49. Makoff AJ, Oxer MD (1991) Nuc Acd Res 19:2417

    Google Scholar 

  50. Perez L, Vega J, Chuay C, Menendez A, Ubieta R, Montero M, Padron G, Silva A, Santizo C, Besada V, Herrera L (1990) Appl Microbiol Biotechnol 33:429

    Google Scholar 

  51. Vidal-Ingigliardi D, Raibaud O (1985) Nuc Acd Res 13:1163

    Google Scholar 

  52. Pistillo, JM, Vishwanatha JK (1990) Biochem Biophys Res Comm 169:1129

    Google Scholar 

  53. Lukacsovich T, Orosz A, Baliko G, Venetianer P (1990) J Biotechnol 16:49

    Google Scholar 

  54. Pharmacia (1991) Pharmacia LKB Biotechnology, Uppsala, Sweden

    Google Scholar 

  55. Deng T, Noel JP, Tsai MD (1990) Gene 93:229

    Google Scholar 

  56. Yasukawa K, Saito T (1990) Biotechnol Lett 12:419

    Google Scholar 

  57. Owolabi JB, Rosen BP (1990) J Bacteriol 172:2367

    Google Scholar 

  58. Flores N, de Anda R, Guerec L, Cruz N, Antonio S, Balbas P, Bolivar F, Valle F (1986) Appl Microbiol Biotechnol 25:267

    Google Scholar 

  59. Dikshit KL, Dikshit RP, Webster DA (1990) Nuc Acd Res 18:4149

    Google Scholar 

  60. Scanlan DJ, Bloye SA, Mann NH, Hodgson DA, Carr NG (1990) Gene 90:43

    Google Scholar 

  61. Berg BL, Stewart V (1990) Genetics 125:691

    Google Scholar 

  62. Su TZ, Schweizer H, Oxender DL (1990) Gene 90:129

    Google Scholar 

  63. Metcalf WW, Steed PM, Wanner BL (1990) J Bacteriol 172:3191

    Google Scholar 

  64. Claverie-Martin F, Magasanik B (1991) Proc Natl Acad Sci USA 88:1631

    Google Scholar 

  65. Bingham RJ, Hall KS, Slonczewski JL (1990) J Bacteriol 172:2184

    Google Scholar 

  66. Poindexter K, Gayle III RB (1991) Gene 97:125

    Google Scholar 

  67. Repoila F, Gutierrez C (1991) Mol Micorbiol 5:747

    Google Scholar 

  68. Lucht JM, Bremer E (1991) J Bacteriol 173:801

    Google Scholar 

  69. Unden G, Trageser M, Duchene A (1990) Mol Microbiol 4:315

    Google Scholar 

  70. Terasawa N, Masayuki I, Uchida Y, Kobayashi M, Kurusu Y, Yukawa H (1991) Appl Microbiol Biotechnol 34:623

    Google Scholar 

  71. Fischer M, Fytlovich S, Amit B, Wortzel A, Beck Y (1990) Appl Microbiol Biotechnol 33:424

    Google Scholar 

  72. Mott JE, Grant RA, Ho Y, Platt T (1985) Proc Natl Acad Sci USA 82:88

    Google Scholar 

  73. Iijima S, Kawai S, Mizutani S, Taniguchi M, Kobayashi T (1987) Appl Microbiol Biotechnol 26:542

    Google Scholar 

  74. Stanley KK, Luzio JP (1984) EMBO J 3:1429

    Google Scholar 

  75. Chan WKY, Belfort G, Belfort M (1988) Gene 73:295

    Google Scholar 

  76. Chan WKY, Belfort G, Belfort M (1991) J Biotechnol 18:225

    Google Scholar 

  77. Claverie-Martin F, Diaz-Torres MR, Yancey SD, Kushner SR (1991) J Biol Chem 266:2843

    Google Scholar 

  78. Donovan WP, Kushner SR (1986) Proc Natl Acad Sci USA 83:120

    Google Scholar 

  79. Schmucker R, Gülland U, Will M, Hillen W (1989) Appl Microbiol Biotechnol 30:509

    Google Scholar 

  80. Olsen MK, Rockenbach SK, Curry KA, Tomich C-SC (1989) J Biotechnol 9:179

    Google Scholar 

  81. Surek B, Wilhelm M, Hillen W (1991) Appl Microbiol Biotechnol 34:488

    Google Scholar 

  82. Spanjaard RA, van Dijk MCM, Turion AJ, van Duin J (1989) Gene 80:345

    Google Scholar 

  83. Bröker M, Amann E (1986) Appl Microbiol Biotechnol 23:294

    Google Scholar 

  84. Ernst JF (1988) Trends Biotechnol 6:196

    Google Scholar 

  85. Maurizi MR, Trisler P, Gottesman S (1985) J Bacteriol 164:1124

    Google Scholar 

  86. Boss MA, Kenton JH, Wood CR, Emtage JS (1984) Nucl Acids Res 12:3791

    Google Scholar 

  87. Simon LD, Randolph B, Irwin N, Binowski G (1983) Proc Natl Acad Sci USA 80:2059

    Google Scholar 

  88. Kadokura H, Yoda K, Mitsunobu I, Yamasaki M (1990) Appl Environ Microbiol 56:2742

    Google Scholar 

  89. Wittliff JL, Wenz LL, Dong J, Nawaz Z, Butt TR (1990) J Biol Chem 265:35

    Google Scholar 

  90. Quaas R, McKeown Y, Stanssens P, Frank R, Blöcker H, Hahn U (1988) Eur J Biochem 173:617

    Google Scholar 

  91. Hartley DL, Kane JF (1988) Biochem Soc Trans 16:101

    Google Scholar 

  92. Langley KE, Berg TF, Strickland TW, Fenton DM, Boone TC, Wypych J (1987) Eur J Biochem 163:313

    Google Scholar 

  93. Georgiou G, Bowden GA (1991) Inclusion body formation and the recovery of aggregated recombinant proteins. In: Prokop A, Bajpai RK, Ho CS (eds) Recombinant DNA technology and applications. McGraw-Hill, New York, p 333

    Google Scholar 

  94. Spalding BJ (1991) Bio/Technology 9:229

    Google Scholar 

  95. Orsini G, Brandazza A, Sarmientos P, Molinari A, Lansen J, Cauet G (1991) Eur J Biochem 195:691

    Google Scholar 

  96. Gatenby AA, Viitanen PV, Lorimer GH (1990) Trends Biotechnol 8:354

    Google Scholar 

  97. Horwich AL, Neupert W, Hartl F-U (1990) Trends Biotechnol 8:126

    Google Scholar 

  98. Burton SJ, Quirk AV, Wood PC (1989) Eur J Biochem 179:379

    Google Scholar 

  99. Kane JF, Hartley DL (1988) Trends Biotechnol 6:95

    Google Scholar 

  100. Kopetzki E, Schumacher G, Buckel P (1989) Mol Gen Genet 216:149

    Google Scholar 

  101. Takagi H, Morinaga Y, Tsuchiya M, Ikemura H, Inouye M (1988) Bio/Technology 6:948

    Google Scholar 

  102. Claassen LA, Ahn B, Koo H-S, Grossman L (1991) J Biol Chem 266:11380

    Google Scholar 

  103. Bowden GA, Georgiou G (1988) Biotechnol Prog 4:97

    Google Scholar 

  104. Kenealy WR, Gray JE, Ivanoff LA, Tribe DE, Reed DL, Korant BD, Petteway SR (1987) Dev Ind Microbiol 28:45

    Google Scholar 

  105. Lee S-M (1989) J Biotechnol 11:103

    Google Scholar 

  106. Mota MJ, Teixeira JA (1990) Current Microbiol 20:209

    Google Scholar 

  107. Harrison STL (1991) Biotechnol Adv 9:217

    Google Scholar 

  108. Kula MR, Schütte H (1987) Biotechnol Prog 3:31

    Google Scholar 

  109. Scawen MD, Hammond PM, Sherwood RF, Atkinson T (1990) Biochem Soc Trans 18:231

    Google Scholar 

  110. Sampson BA, Benson A (1987) J Ind Microbiol 1:335

    Google Scholar 

  111. Altieri M, Suit JL, Fan M-LJ, Luria SE (1986) J Bacteriol 168:648

    Google Scholar 

  112. Luria SE, Suit JL, Jackson JA (1991) US Patent 4948735

    Google Scholar 

  113. Dabora RL, Eberiel DT, Cooney CL (1989) Biotechnol Lett 11:845

    Google Scholar 

  114. Rasched I, Oberer-Bley E (1990) Chem Lab Biotech 41: 36

    Google Scholar 

  115. Hsiung MH, Becker GW (1988) Biotechnol Genet Eng Rev 6:43

    Google Scholar 

  116. Lee C, Li P, Inouye H, Brickman ER, Beckwith J (1989) J Bacteriol 17:4609

    Google Scholar 

  117. Alexander P, Oriel PJ, Glassner DA, Grulke EA (1989) Biotechnol Lett 11:609

    Google Scholar 

  118. Emerick AW, Bertolani BL, Ben-Bassat A, White TJ, Konrad MW (1984) Bio/Technology 2:165

    Google Scholar 

  119. Zemel-Dreasen O, Zamir A (1984) Gene 27:315

    Google Scholar 

  120. Georgiou G, Shuler ML, Wilson DB (1988) Biotech Bioeng 32:741

    Google Scholar 

  121. Ohagi H, Kumakura T, Komoto S, Matsuo Y, Oshiden K, Koide T, Yanaihara C, Yanaihara N (1989) J Biotechnol 10:151

    Google Scholar 

  122. Summers RG, Knowles JR (1989) J Biol Chem 264:20074

    Google Scholar 

  123. Blondel A, Bedouelle H (1990) Eur J Biochem 193:325

    Google Scholar 

  124. Bedouelle H, Duplay P (1988) Eur J Biochem 171:541

    Google Scholar 

  125. Libby RT, Braedt G, Kronheim SR, March CJ, Urdal DL, Chiaverotti TA, Tushinski RJ, Mochizuki DJ, Hopp TP, Cosman D (1987) DNA 6:221

    Google Scholar 

  126. Takahara M, Sagai H, Inouye S, Inouye M (1988) Bio/Technology 6:195

    Google Scholar 

  127. Barbero JOL, Buesa JM, Penalva MA, Perez-Aranda A, Garcia JL (1986) J Biotechnol 4:255

    Google Scholar 

  128. Habuka N, Akiyama KJ, Hideaki T, Miyano M, Matsumoto T, Noma M (1990) J Biol Chem 265:10988

    Google Scholar 

  129. Henze P-PC, Hahn U, Erdmann VA, Ulbrich N (1990) Eur J Biochem 192:127

    Google Scholar 

  130. Shibui T, Matsui R, Uchida-Kamizono M, Okazaki H, Kondo J, Nagahari K, Nakanishi S, Teranishi Y (1989) Appl Microbiol Biotechnol 31:253

    Google Scholar 

  131. Sherwood R (1991) Trends Biotechnol 9:1

    Google Scholar 

  132. Marks CB, Vasser M, Ng P, Henzel W, Anderson S (1986) J Biol Chem 261:7115

    Google Scholar 

  133. Oka T, Sumi S, Fuwa T, Yoda K, Yamasaki M, Tamura G, Miyake T (1987) Agricult Biolog Chem 5:1099

    Google Scholar 

  134. Ohsuye K, Nomura M, Tanaka S, Kubota I, Nakazato H, Shinagawa H, Nakata A, Noguchi T (1983) Nuc Acd Res 11:1283

    Google Scholar 

  135. Guan C, Li P, Riggs PD, Inouye H (1988) Gene 67:21

    Google Scholar 

  136. Fujimura T, Tanaka T, Kanako O, Morioka H, Uesugi S, Ikehara M, Nishikawa S (1990) FEBS 269:71

    Google Scholar 

  137. Anba J, Baty D, Lloubes R, Pages J-M, Joseph-Liauzum E, Shire D, Roskam W, Lazdunski C (1987) Gene 53:219

    Google Scholar 

  138. Hogset A, Blinsmo OR, Saether O, Gautvik VT, Holmgren E, Hartmanis M, Josephson S, Gabrielsen OS, Gordelaze JO, Alestrom P, Gautvik KM (1990) J Biol Chem 265:7338

    Google Scholar 

  139. Wadenstein H, Ekebacke A, Hammarberg B, Holmgren E, Kalderen C, Tally M, Moks T, Uhlen M, Josephson S, Hartmanis M (1991) Biotechnol Appl Biochem 13:412

    Google Scholar 

  140. Fraser TH, Bruce TJ (1987) Proc Natl Acad Sci USA 75:5936

    Google Scholar 

  141. Kornacker MG, Pugsley AP (1990) Molec Microbiol 4:1101

    Google Scholar 

  142. Talmadge K, Brosius J, Gilbert W (1981) Nature 294:176

    Google Scholar 

  143. Morioka-Fujimoto K, Marumoto R, Fukuda T (1991) J Biol Chem 266:1728

    Google Scholar 

  144. Legoux R, Leptlatois P, Joseph-Liauzun, E (1991) US Patent 4945047

    Google Scholar 

  145. Letoffe S, Delepelaire P, Wandersman C (1991) J Bacteriol 173:2160

    Google Scholar 

  146. van Putten AJ, de Graaf FK, Oudega B (1987) Proc 4th Europ Con Biotechnol 4:593

    Google Scholar 

  147. Mackman N, Nicaud JM, Gray L, Holland IB (1986) Cur Top Microbiol Immunol 125:159

    Google Scholar 

  148. Lazzaroni JC, Portalier RC (1982) Eur J Appl Microb Biotechnol 16:146

    Google Scholar 

  149. Atlan D, Portalier RC (1984) Eur J Appl Microb Biotechnol 19:5

    Google Scholar 

  150. Mosbach K, Birnbaum S, Hardy K, Davies J, Bulow L (1983) Nature (London) 302:543

    Google Scholar 

  151. Murakami Y, Furusato Y, Kato C, Habuka N, Kudo T, Horikoshi K (1989) Appl Microbiol Biotechnol 30:619

    Google Scholar 

  152. Bialy H (1987) Bio/Technology 5:883

    Google Scholar 

  153. Thatcher DR (1990) Biochem Soc Trans 18:234

    Google Scholar 

  154. Fischer G, Schmid FX (1990) Biochem 29:2205

    Google Scholar 

  155. Dill KA (1990) Biochem 29:7133

    Google Scholar 

  156. Jaenicke R (1987) Prog Biophys Molec Biol 49:117

    Google Scholar 

  157. Hanada K, Yamamoto I, Anraku Y (1987) J Bio Chem 262:14100

    Google Scholar 

  158. Maschke H-E, Hebenbrock K, Friehs K (1990) DECHEMA Biotechnol Conf 4:379

    Google Scholar 

  159. Ullman A (1984) Gene 29:27

    Google Scholar 

  160. Maina CV, Riggs PD, Grandea AG, Slatko BE, Moran LS, Tagliamonte JA, McReynolds LA, di Guan C (1988) Gene 74:365

    Google Scholar 

  161. Hochuli E, Bannwarth W, Döbeli H, Gentz R, Stüber D (1988) Bio/Technology 11:1321

    Google Scholar 

  162. Smith JC, Derbyshire RB, Cook E, Dunthorne L, Viney J, Brewer SJ, Sassenfeld HM, Bell LD (1984) Gene 32:321

    Google Scholar 

  163. Persson M, Bergstrand MG, Bülow L, Mosbach K (1988) Anal Biochem 172:330/337

    Google Scholar 

  164. Stiegelmeier C, Friehs K, Schügerl K (1992) Acta Biotechnol (in press)

    Google Scholar 

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Authors and Affiliations

  1. Technische Fakultät, AG Fermentationstechnik, Universität Bielefeld, D-4800, Bielefeld, Germany

    K. Friehs

  2. Department of Agricultural and Chemical Engineering, Colorado State University, 80523, Fort Collins, Colorado, USA

    K. F. Reardon

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Dedicated to Professor Dr. Karl Schügerl on the occasion of his 65th birthday

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Friehs, K., Reardon, K.F. (1993). Parameters influencing the productivity of recombinant E. coli cultivations. In: Bioprocess Design and Control. Advances in Biochemical Engineering/Biotechnology, vol 48. Springer, Berlin, Heidelberg. https://doi.org/10.1007/BFb0007196

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