Auxiliary Phase Guidelines for Microbial Biotransformations of Toxic Substrate into Toxic Product

When an industrial process is developed using the microbial transformation of a precursor into a desired chemical compound, high concentrations of substrate and product will be involved. These compounds may become toxic to the cells. In situ product removal (ISPR) may be carried out, using auxiliary phases such as extractants or adsorbents. Simultaneously, in situ substrate addition (ISSA) may be performed. It is shown that for uncharged substrates and products, the aqueous solubilities of substrate and product can be used to predict if ISPR might be required. When a particular auxiliary phase is selected and the distribution coefficients of substrate and product are known, it is possible to estimate a priori if this auxiliary phase might be good enough and how much of it might be needed for an efficient (fed‐)batch biotransformation process. For biotransformation products of intermediate polarity (aqueous solubility of about 1–10 g/L) there seems to be a lack of extractants and adsorbents with the capacity to raise the product concentrations to commercially more interesting levels.

[1]  A. Schmid.  Two-liquid phase bioprocess development , 1997 .

[2]  F. Molinari,et al.  Continuous production of isovaleraldehyde through extractive bioconversion in a hollow-fiber membrane bioreactor , 1997 .

[3]  B. Sonnleitner,et al.  Extractive Bioconversion of 2‐Phenylethanol from l‐Phenylalanine by Saccharomycescerevisiae , 2002, Biotechnology progress.

[4]  R. Bar.  Phase toxicity in a water-solvent two-liquid phase microbial system , 1987 .

[5]  John M. Woodley,et al.  In Situ Product Removal as a Tool for Bioprocessing , 1993, Bio/Technology.

[6]  W. M. Haynes.  CRC Handbook of Chemistry and Physics , 1990 .

[7]  F. Molinari,et al.  Aldehyde production by alcohol oxidation with Gluconobacter oxydans , 1995, Applied Microbiology and Biotechnology.

[8]  Marty,et al.  Extractive fermentation of aroma with supercritical CO2 , 1999, Biotechnology and bioengineering.

[9]  H. Heipieper,et al.  Mechanisms of resistance of whole cells to toxic organic solvents , 1994 .

[10]  J J Heijnen,et al.  Fundamental bottlenecks in the application of continuous bioprocesses. , 1992, Journal of biotechnology.

[11]  W. Meylan,et al.  Atom/fragment contribution method for estimating octanol-water partition coefficients. , 1995, Journal of pharmaceutical sciences.

[12]  H. Heipieper,et al.  Determination of the toxicity of several aromatic carbonylic compounds and their reduced derivatives on Phanerochaete chrysosporium using a Pseudomonas putida test system. , 2001, Biotechnology and bioengineering.

[13]  W. Bluemke,et al.  Biotechnological production of 2-phenylethanol , 2002, Applied Microbiology and Biotechnology.

[14]  F. Malcata,et al.  How performance of integrated systems of reaction and separation relates to that of parallel and sequential configurations , 2000 .

[15]  Urs von Stockar,et al.  In situ product removal (ISPR) in whole cell biotechnology during the last twenty years. , 2003, Advances in biochemical engineering/biotechnology.

[16]  Luuk A M van der Wielen,et al.  In situ product removal using a crystallization loop in asymmetric reduction of 4‐oxoisophorone by Saccharomyces cerevisiae , 2004, Biotechnology and bioengineering.

[17]  M. Lilly,et al.  Process design for the oxidation of fluorobenzene to fluorocatechol by Pseudomonas putida , 1997 .

[18]  Karel Ch. A. M. Luyben,et al.  Integrated product formation and recovery in fermentation , 1992 .

[19]  J. Tramper,et al.  Toxicity of homologous series of organic solvents for the gram‐positive bacteria Arthrobacter and Nocardia Sp. and the gram‐negative bacteria Acinetobacter and Pseudomonas Sp. , 1993, Biotechnology and bioengineering.

[20]  Andreas Schmid,et al.  The production of fine chemicals by biotransformations. , 2002, Current opinion in biotechnology.

[21]  F. Malcata,et al.  Cascading Reactor-Separator Sets Reduces total Processing Time for Low Yield Michaelis-Menten Reactions: Model Predictions , 1998 .

[22]  Yingqing Ran,et al.  Prediction of the aqueous solubility: comparison of the general solubility equation and the method using an amended solvation energy relationship. , 2002, Journal of pharmaceutical sciences.

[23]  M. Turner,et al.  Correlation of biocatalytic activity in an organic-aqueous two-liquid phase system with solvent concentration in the cell membrane. , 1990, Enzyme and microbial technology.

[24]  M. Wubbolts,et al.  Efficient production of optically active styrene epoxides in two-liquid phase cultures , 1994 .

[25]  D. Maass,et al.  Integrated L-phenylalanine separation in an E. coli fed-batch process: from laboratory to pilot scale , 2002, Bioprocess and biosystems engineering.

[26]  Ana Alba Pérez.  Enhanced microbial production of natural flavors via in-situ product adsorption , 2001 .

[27]  H Baldascini,et al.  Effect of mass transfer limitations on the enzymatic kinetic resolution of epoxides in a two-liquid-phase system. , 2001, Biotechnology and bioengineering.

[28]  M. Wubbolts,et al.  An integrated process for the production of toxic catechols from toxic phenols based on a designer biocatalyst. , 1999, Biotechnology and bioengineering.

[29]  R. Zell,et al.  SYNTHESIS OF OPTICALLY ACTIVE NATURAL CAROTENOIDS AND STRUCTURALLY RELATED COMPOUNDS. I. SYNTHESIS OF THE CHIRAL KEY COMPOUND (4R,6R)-4-HYDROXY-2,2,6-TRIMETHYLCYCLOHEXANONE , 1976 .

[30]  P. Fernandes,et al.  Whole-cell biocatalysis in organic media , 1998 .

[31]  G J Lye,et al.  Application of in situ product-removal techniques to biocatalytic processes. , 1999, Trends in biotechnology.

[32]  H. Tsai,et al.  Amplification of the tryptophan operon gene in Escherichia coli chromosome to increase l-tryptophan biosynthesis , 1993, Applied Microbiology and Biotechnology.

[33]  T. V. Van Dooren,et al.  Factors relevant to the production of (R)-(+)-glycidol (2,3-epoxy-1-propanol) from racemic glycidol by enantioselective oxidation with Acetobacter pasteurianus ATCC 12874. , 1994, Enzyme and microbial technology.

[34]  Jorge A. Marrero,et al.  Group-contribution based estimation of pure component properties , 2001 .

[35]  P. Marler,et al.  Enantioselective reduction of 3,4-methylene-dioxyphenylacetone using Candida famata and Zygosaccharomyces rouxii , 1997, Applied Microbiology and Biotechnology.

[36]  A. Straathof,et al.  Effect of High Product Concentration in a Dual Fed-batch Asymmetric 3-oxo Ester Reduction by Baker's Yeast , 2002 .

[37]  C. Laane,et al.  Rules for optimization of biocatalysis in organic solvents , 1987, Biotechnology and bioengineering.

[38]  N. Ruiz-Ordaz,et al.  Degradation kinetics of phenol by immobilized cells of Candida tropicalis in a fluidized bed reactor , 2001 .

[39]  K. Luyben,et al.  Integrated product formation and recovery in fermentation , 1992, Current Biology.

[40]  M. Zmijewski,et al.  Large-scale stereoselective enzymatic ketone reduction with in situ product removal via polymeric adsorbent resins , 1997 .

[41]  Graham,et al.  Nitrile biotransformations using free and immobilized cells of a thermophilic Bacillus spp. , 2000, Enzyme and microbial technology.

[42]  F. Xavier Malcata,et al.  Integration of reaction and separation with lipases: An overview☆ , 1997 .