WO2007120198A2 - Matériaux et procédés de production améliorée de composés organiques - Google Patents

Matériaux et procédés de production améliorée de composés organiques Download PDF

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Publication number
WO2007120198A2
WO2007120198A2 PCT/US2006/043380 US2006043380W WO2007120198A2 WO 2007120198 A2 WO2007120198 A2 WO 2007120198A2 US 2006043380 W US2006043380 W US 2006043380W WO 2007120198 A2 WO2007120198 A2 WO 2007120198A2
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Prior art keywords
betaine
glucose
lactate
pyruvate
mineral salts
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PCT/US2006/043380
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English (en)
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WO2007120198A3 (fr
Inventor
Lonnie O'neal Ingram
Keelnatham T. Shanmugam
Shengde Zhou
Thomas B. Causey
Lorraine P. Yomano
Tammy B. Grabar
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University Of Florida Research Foundation, Inc.
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Priority claimed from US11/501,137 external-priority patent/US7629162B2/en
Application filed by University Of Florida Research Foundation, Inc. filed Critical University Of Florida Research Foundation, Inc.
Publication of WO2007120198A2 publication Critical patent/WO2007120198A2/fr
Publication of WO2007120198A3 publication Critical patent/WO2007120198A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C12P7/56—Lactic acid
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids

Definitions

  • the subject invention was made with government support under research projects supported by US DOE-DE FG02-96ER20222 and USDA 00-52104-9704. The government has certain rights in this invention.
  • Kealey, 2002 Metal engineering of a methylmalonyl-CoA mutase - epimerase pathway for complex polyketide biosynthesis in Escherichia coli.” Biochem. 41:5193-5201) and carotenoids (Wang, Chia-wei, Min-Kyu Oh, J. C. Liao, 2000 "Directed evolution of metabolically engineered Escherichia coli for carotenoid production” Biotechnol. Prog. 16:922-926).
  • Pyruvate and acetate are central intermediates for biosynthesis and energy metabolism in plants, animals and microorganisms. Both compounds are commercially produced and used in a variety of products. Pyruvate serves as a starting material for production of amino acids (L-tryptophan, L-tyrosine and others), pharmaceuticals such as L-DOPA, and agrichemicals (Li et al. 2001). Acetate is an important component of many solvents and plastics, in food products, and as a road de-icer (Berraud 2000, Cheryan et al. 1997, Freer 2002).
  • strain W3110 Derivatives of Escherichia coli K- 12 (strain W3110) have been developed for acetate (strain TC36; Causey et al. 2003) and pyruvate (strain TC44; Causey et al. 2004) production from glucose in mineral salts medium.
  • further improvements are desirable in both the biocatalysts and lactate purification (Narayanan et al. 2004; Ohara et al. 2001; Vaidya et al. 2005; Wasewar 2005).
  • Strain SZ 132 is an Escherichia coli B strain capable of rapid D-lactate production in complex medium with 10% (w/v) glucose (Zhou et al, 2005). However, this strain was unable to complete the fermentation of 10% (w/v) glucose in mineral salts medium even after prolonged incubation. Maximum fermentation rates in mineral salts medium with 10% (w/v) glucose were roughly half of those observed with 5% (w/v) glucose, while differences between 5% (w/v) and 10% (w/v) sucrose were less pronounced. Osmotic stress associated with 10% (w/v) sucrose is half that of 10% (w/v) glucose.
  • E. coli is known to adapt to osmotic stress by increasing intracellular levels of potassium glutamate and trehalose, and accumulating other protective osmolytes such as betaine from the environment when available (Csonka 1989; Kempf & Bremer 1998; Purvis et al. 2005).
  • Osmotic stress activates native pathways for the production of glutamate.
  • the increase in acetyl ⁇ P pools in acetate kinase-deficient cells appears to phosphorylate NR 1 , a transcriptional activator that increases production of glutamine synthetase (Feng et al. 1992).
  • Underwood et al. (2004) reported that volumetric rates of ethanol production were increased in mineral salts medium containing 9% (w/v) xylose by supplementing with large amounts of central metabolites or small amounts of protective osmolytes.
  • Osmotic stress due to high concentrations of sugars and fermentation products limits the performance of E. coli in simple batch fermentation, creating a leaky nutritional requirement.
  • This stress-related nutrient requirement can be satisfied, according to the subject invention, by adding an osmoprotectant.
  • an osmoprotectant as described herein reduces the need for complex nutrients.
  • betaine as the osmoprotectant. Addition of betaine allows, for example, E. coli strains to produce increased yields of desired products as a result of the fermentation of 10% (w/v) sugar in mineral salts medium.
  • betaine or other osmoprotectant as described herein, as a supplement for mineral salts media offers advantages over the use of complex additives including a reduction in cost associated with nutrients, product purification, and waste disposal.
  • Figure IA- ID shows the effect of betaine (1 mM) on the growth-inhibition of W3110 by high concentrations of glucose and organic acids in mineral salts medium.
  • Culture tubes (13x100 mm) containing 4 ml of mineral salts medium with glucose or with glucose (2% w/v) and salts of organic acids were inoculated to an initial density of 0.1 mg dry wt I '1 . After incubation at 37 0 C for 24 h, cell mass (growth) was estimated by measuring optical density. Symbols for all: W3110 without betaine, o; W3110 with 1 mM betaine, •.
  • Figure 2A-2C shows the effect of betaine on the aerobic fermentation of glucose to acetate by TC36 in mineral salts medium containing 10% (w/v) glucose. Fermentations were maintained at pH 7 (37 0 C, 350 rpm).
  • Figure 3A-3C shows the effect of betaine on the aerobic fermentation of glucose to pyruvate by TC44 in mineral salts medium containing 10% (w/v) glucose. Fermentations were maintained at pH 7 (37 0 C, 350 rpm).
  • Figure 4A-4C shows the effect of betaine on growth and fermentation in mineral salts medium containing 10% (w/v) sugar (glucose or sucrose). Luria broth containing 10% (w/v) glucose was included for comparison in A and B. Fermentations were maintained at pH 7 (37 0 C, 150 rpm).
  • B Cell mass during fermentation with glucose.
  • C Cell mass and organic acids during the sucrose fermentation.
  • a and B no betaine, o ; 0.25 mM betaine, ⁇ ; 0.50 mM betaine, * • ; 1 niM betaine, • ; 2 mM betaine, D ; and Luria broth, ⁇ .
  • C cell mass without betaine, D ; lactate without betaine, o ; cell mass with 1 mM betaine, ⁇ ; lactate with 1 mM betaine, • .
  • Figure 5A-5B shows the effect of betaine (1 mM) on glucose and lactate tolerance in mineral salts medium.
  • A Glucose.
  • B Potassium lactate (with 2% w/v glucose).
  • Culture tubes 13x100 mm) containing 4 ml of mineral salts medium with glucose or with glucose (2% w/v) and potassium lactate were inoculated to an initial density of 0.1 mg dry wt I "1 . After incubation at 37 0 C for 24 h, cell mass (growth) was estimated by measuring optical density at 550 nm. Symbols for all: SZ132 without betaine, o; SZ132 with 1 mM betaine, •.
  • osmoprotectants such as betaine
  • Betaine serves as a protective osmolyte, during fermentations with high concentrations of sugars or products, replacing the need to divert carbon and energy into native osmoprotectants such as glutamate and trehalose.
  • betaine and/or other osmoprotectants can be added to media and improve the rates of biological conversion of sugars into chemicals such as organic acids.
  • Osmoprotectants are well known to those skilled in the art and include such compounds as betaine, choline, dimethylsulfoniopropionate, mannitol, inositol, proline, fructan, trehalose, and D-ononitol.
  • the methods of the subject invention can be used, as discussed below for the efficient production or organic compounds such as, for example, lactate and pyruvate.
  • Strain TC44 did not grow well in mineral salts medium containing 10% (w/v) glucose in comparison to strains TC36 and W3110 although all three strains grew well in the same media containing a lower glucose concentration. Addition of 1 mM betaine caused a modest 2-fold increase in cell mass after 24 h for the latter strains and 10-fold increase in cell mass for strain TC44 (pyruvate production).
  • Strain W3110 (ATCC 27325) is a wild-type K- 12 strain and is the parent used to construct TC44(A(focA-pflB) Afrd ⁇ ldhA AatpFH AsucA adhEv.FRT AackA ApoxB) and TC36(A(focA-pflB) Afrd AldhA AatpFH AsucA adhEv.FRT ).
  • Strain TC36 was engineered for acetate production by introducing a series of mutations and deletions in W3110.
  • Strain TC44 was constructed from TC36 by deleting the genes ⁇ AackA and ApoxB) essential for each of the two major acetate producing pathways. These strains do not contain any foreign genes and can be regarded as non GMO organisms. Cultures were grown at 37 0 C in NBS mineral salts medium (pH 7) containing 10% glucose (Causey et al. 2004). Betaine (1 mM) was added as a supplement where indicated.
  • Tube cultures were prepared with NBS mineral salts medium (2% glucose, with or without 1 mM betaine) and various concentrations of glucose, potassium pyruvate, or potassium acetate. After inoculation with W3110 (parent) and incubation for 24 h, growth was compared by measuring optical density at 550 nm (Purvis et al. 2005). In some experiments, medium was adjusted from pH 7 to pH 8 prior to inoculation.
  • NBS mineral salts medium 2% glucose, with or without 1 mM betaine
  • Fermentations were carried out in 6.6-liter vessels with a 5-liter initial liquid volume (37 0 C, dual Rushton impellers, 350 rpm) using New Brunswick Bioflow 3000 fermentors (Causey et al. 2004). Dissolved oxygen was maintained above 5 % of air saturation by altering the proportion of O 2 and air at a constant flow rate of 1.0 L min "1 (0.2 wm). Broth was maintained at pH 7 or pH 8 by automatic addition of 11.4 M KOH. Seed cultures were prepared by inoculating colonies from a fresh plate into NBS mineral salts medium containing 3% glucose and 0.1 M MOPS (Causey et al. 2004). Cells harvested from flask cultures were used to provide an inoculum of 16.5 mg dry cell weight I "1 .
  • volumetric rates and maximum specific rates were estimated from measured values for glucose and acetate or pyruvate using GraphPad Prism (GraphPad Software, San Diego, CA). A smooth curve was generated with 10 points per min (Lowess method) to fit measured results. The first derivative (acetate or glucose versus time) of each curve served as an estimate of volumetric rate. Specific rates (mmol I "1 h "1 mg "1 dry cell weight) were calculated by dividing volumetric rates by respective values for cell mass.
  • Betaine increases the growth of WSIlO (parent) in media containing high concentrations of glucose, pyruvate and acetate
  • the final acetate titer with TC36 (685 mM; 41.1 g I "1 ) was 6-fold higher than the pyruvate titers with TC44 (114 mM; 10.6 g 1 " '). Since TC44 is an isogenic derivative of TC36, the poor performance of TC44 in 10% glucose can be presumed to result from loss of function mutations (ackA mdpoxB).
  • Figure 1 shows that betaine reduced growth-inhibition by high concentrations of glucose and pyruvate at pH 7, and by acetate (pH 8 only).
  • betaine was of limited value for the fermentation of 10% (w/v) glucose to acetate by strain TC36 at either pH (Tables 1 and 2; Figure 2).
  • Betaine increased the initial rates of growth and fermentation but also increased unwanted co-products (Figure 2; Table 2).
  • Co-product accumulation (2-oxoglutarate and succinate) began at the end of the growth phase ( Figure 2C), decreasing acetate yield (Table 2).
  • Betaine had little effect on volumetric and specific rates of acetate production or glycolytic flux (Table 1).
  • Table 2 Effect of betaine on fermentation products and yield a
  • Strain SZ132 (A(focA-Z. mobilis pdc-adhB-pflB) adhEv.FRT ⁇ ackA::FRT t ⁇ dr.K. oxytoca casAB lacYr.E. chrysanthemi celY ) (Zhou et al. 2005) was previously constructed from E. coli KOI l, an ethanologenic derivative of E. coli B (ATCC 11303). Strain SZ132 produces D-lactate as the primary fermentation product from hexose and pentose sugars, and has the native ability to ferment sucrose. Cultures were grown at 37 0 C in NBS mineral salts medium (Causey et al. 2004) or Luria broth (per liter: 1O g tryptone, 5 g yeast extract, and 5 g NaCl) supplemented with 2%-10% (w/v) glucose or sucrose.
  • Seed cultures were prepared as described previously (Shukla et al. 2004; Zhou et al. 2003; Zhou et al. 2005) and used to inoculate small fermentation vessels (350 ml working volume, 37 0 C, 150 rpm agitation, inoculum dry wt of 33 mg I "1 ).
  • Broth was maintained at pH 7.0 by the automatic addition of 6 M KOH.
  • Plotted data represent an average of 2 or more replicates. Bars denoting the S ⁇ M are included for averages of 3 or more experiments.
  • Specific growth rate was estimated from the steepest region of the curve, the initial 6 h period in most cases.
  • D-lactate volumetric productivity (maximum) was calculated for the initial 12 h period of fermentation in most cases. Specific productivity was calculated by dividing this rate by the average cell mass. Since D-lactate is the primary fermentation product, specific rates of lactate production are representative of glycolytic flux. Analyses
  • Acid production (primarily lactate) was measured by base (KOH) usage to maintain pH 7.0. Acidic products were analyzed at the end of fermentation by HPLC (Zhou et al. 2003). Ethanol was measured by GC (Ohta et al.1991).
  • Betaine decreased the time required to ferment of 10% (w/v) glucose by SZl 32 in mineral salts medium
  • Betaine improved growth and fermentation performance of SZl 32 in mineral salts medium containing 10% (w/v) glucose. To determine the basis of this effect, growth inhibition by glucose and lactate were compared in the presence and absence of betaine. Supplementing with 1 mM betaine was beneficial for glucose and lactate tolerance (Figure 5). Betaine increased the growth of SZl 32 in all glucose concentrations above 400 mM, and increased the MIC for glucose from approximately 800 mM to 1000 mM. With 10% (w/v) glucose (556 mM), cell mass after 24 h was only 30% of that with 2% (w/v) glucose. Smaller but significant benefits were observed for betaine during growth in the presence of 100-400 mM potassium lactate (Figure 5B). Betaine addition caused a small increase in the MIC for lactate.
  • Betaine (1 mM) increased the rate and extent of sucrose fermentation in mineral salts medium

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Abstract

L'invention fait appel à des éléments protecteurs contre le stress osmotique, tels que la bétaïne, pour augmenter la productivité et le titre de fermentation anaérobie et aérobie de E. coli. et d'autres microbes. La bétaïne sert d'osmolyte protecteur au cours de fermentations en présence de concentrations élevées de sucres ou produits, supprimant la nécessité de transformer le carbone et l'énergie en éléments protecteurs natifs tels que le glutamate et le tréhalose. On peut par conséquent, selon l'invention, ajouter de la bétaïne et/ou d'autres éléments protecteurs contre le stress osmotique à des milieux afin d'améliorer la vitesse de conversion biologique des sucres en substances chimiques telles que des acides organiques.
PCT/US2006/043380 2005-11-08 2006-11-07 Matériaux et procédés de production améliorée de composés organiques WO2007120198A2 (fr)

Applications Claiming Priority (8)

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US73444305P 2005-11-08 2005-11-08
US60/734,443 2005-11-08
US76157606P 2006-01-24 2006-01-24
US60/761,576 2006-01-24
US79961906P 2006-05-11 2006-05-11
US60/799,619 2006-05-11
US11/501,137 2006-08-08
US11/501,137 US7629162B2 (en) 2005-08-10 2006-08-08 Materials and methods for efficient lactic acid production

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012013025A1 (fr) * 2010-07-27 2012-02-02 南京工业大学 Procédés d'amélioration du rendement de fermentation d'acide gras polyinsaturés
NL2007353C2 (en) * 2011-09-05 2013-03-07 Kwr Water B V Solution comprising an osmotic agent and method of extracting water using said solution.
WO2016146633A1 (fr) 2015-03-18 2016-09-22 Basf Se Micro-organisme recombinant pour la production améliorée de produits chimiques fins
WO2016193351A2 (fr) 2015-06-04 2016-12-08 Basf Se Micro-organisme recombinant pour la production améliorée de produits chimiques fins
WO2016198529A1 (fr) 2015-06-12 2016-12-15 Basf Se Micro-organisme de recombinaison pour la production améliorée d'alanine
US10208323B2 (en) 2013-12-13 2019-02-19 Basf Se Recombinant microorganism for improved production of fine chemicals
US10731186B2 (en) 2014-07-23 2020-08-04 Purac Biochem Bv Genetically modified (R)-lactic acid producing thermophilic bacteria

Citations (1)

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Patent Citations (1)

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US4818268A (en) * 1985-09-16 1989-04-04 Spawn Mate, Inc. Osmoprotectant

Non-Patent Citations (5)

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Title
CAYLEY S. ET AL.: 'Origins of the osmoprotective properties of betaine and proline in Escherichia coli K-12' J. BACTERIOL. vol. 174, no. 5, 1992, pages 1586 - 1595 *
PURVIS J.E. ET AL.: 'Enhanced trehalose production improves growth of Escherichia coli under osmotic stress' APPL. ENVIRON. MICROBIOL. vol. 71, no. 7, July 2005, pages 3761 - 3769 *
UNDERWOOD S.A. ET AL.: 'Lack of protective osmolytes limits final cell density and volumetric productivity of ethanologenic Escherichia coli KO11 during xylose fermentation' APPL. ENVIRON. MICROBIOL. vol. 70, no. 5, 2004, pages 2734 - 2740 *
ZHOU S. ET AL.: 'Betaine tripled the volumetric productivity of D(-)-lactate by Escherichia coli strain SZ132 in mineral salts medium' BIOTECHNOL. LETT. vol. 28, no. 9, May 2006, pages 671 - 676 *
ZHOU S. ET AL.: 'Production of optically pure D-lactic acid in mineral salts medium by metabolically engineered Escherichia coli W3110' APPL. ENVIRON. MICROBIOL. vol. 69, no. 1, 2003, pages 399 - 407 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012013025A1 (fr) * 2010-07-27 2012-02-02 南京工业大学 Procédés d'amélioration du rendement de fermentation d'acide gras polyinsaturés
NL2007353C2 (en) * 2011-09-05 2013-03-07 Kwr Water B V Solution comprising an osmotic agent and method of extracting water using said solution.
WO2013036111A1 (fr) * 2011-09-05 2013-03-14 Kwr Water B.V. Solution comprenant un agent osmotique et procédé d'extraction d'eau au moyen de ladite solution
US10208324B2 (en) 2013-12-13 2019-02-19 Basf Se Recombinant microorganism for improved production of fine chemicals
US10731188B2 (en) 2013-12-13 2020-08-04 Basf Se Recombinant microorganism for improved production of fine chemicals
US10208323B2 (en) 2013-12-13 2019-02-19 Basf Se Recombinant microorganism for improved production of fine chemicals
US10731186B2 (en) 2014-07-23 2020-08-04 Purac Biochem Bv Genetically modified (R)-lactic acid producing thermophilic bacteria
WO2016146633A1 (fr) 2015-03-18 2016-09-22 Basf Se Micro-organisme recombinant pour la production améliorée de produits chimiques fins
US10717998B2 (en) 2015-03-18 2020-07-21 Basf Se Recombinant microorganism for improved production of fine chemicals
US10519474B2 (en) 2015-06-04 2019-12-31 Basf Se Recombinant microorganism for improved production of fine chemicals
WO2016193351A2 (fr) 2015-06-04 2016-12-08 Basf Se Micro-organisme recombinant pour la production améliorée de produits chimiques fins
WO2016198529A1 (fr) 2015-06-12 2016-12-15 Basf Se Micro-organisme de recombinaison pour la production améliorée d'alanine
US10837034B2 (en) 2015-06-12 2020-11-17 Basf Se Recombinant microorganism for improved production of alanine

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