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WO1998018937A1 - Preparation microbienne de substances a partir d'un metabolisme aromatique - Google Patents

Preparation microbienne de substances a partir d'un metabolisme aromatique Download PDF

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Publication number
WO1998018937A1
WO1998018937A1 PCT/NL1997/000583 NL9700583W WO9818937A1 WO 1998018937 A1 WO1998018937 A1 WO 1998018937A1 NL 9700583 W NL9700583 W NL 9700583W WO 9818937 A1 WO9818937 A1 WO 9818937A1
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WO
WIPO (PCT)
Prior art keywords
gene
activity
process according
sugar
genes
Prior art date
Application number
PCT/NL1997/000583
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English (en)
Inventor
Georg Sprenger
Ruth Siewe
Hermann Sahm
Martin Karutz
Theodorus Sonke
Original Assignee
Holland Sweetener Company V.O.F.
Forschungszentrum Jülich GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Holland Sweetener Company V.O.F., Forschungszentrum Jülich GmbH filed Critical Holland Sweetener Company V.O.F.
Priority to AU47278/97A priority Critical patent/AU4727897A/en
Publication of WO1998018937A1 publication Critical patent/WO1998018937A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1022—Transferases (2.) transferring aldehyde or ketonic groups (2.2)
    • 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
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • 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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/22—Tryptophan; Tyrosine; Phenylalanine; 3,4-Dihydroxyphenylalanine
    • 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
    • C12P7/42—Hydroxy-carboxylic acids

Definitions

  • the invention relates to a process for the microbial preparation of substances, in particular aromatic amino acids, in accordance with Claims 1-20, 36 and 37, gene structures in accordance with Claims 21-29, and transformed cells in accordance with Claims 30-35.
  • L- phenylalanine for example, is used for preparing medicaments and, in particular, also in the preparation of the sweetener aspartame ( ⁇ -L-aspartyl-L-phenylalanine methyl ester) .
  • L-tryptophan is required as a medicament and as an additive to animal feeds; there is likewise a need for L- tyrosine as a medicament and also as a raw material in the pharmaceutical industry.
  • biotechnological preparation is a very important method for obtaining amino acids in the desired optically active form under economically justifiable conditions.
  • Biotechnological preparation is effected either using enzymes or using microorganisms.
  • the latter, microbial, preparation enjoys the advantage that simple and inexpensive raw materials can be employed.
  • amino acid analogs for example, have been employed in order to switch off the regulation of biosynthesis.
  • mutants of Escherichia coli permitting an increased production of L-phenylalanine were obtained by selecting for resistance to phenylalanine analogs (GB- 2,053,906).
  • PEP is an activated precursor of the glycolysis product pyruvate; Ery4P is an intermediate in the pentose phosphate pathway.
  • PEP carboxylase Miller J.E. et al . , J. Ind. Microbiol. 2 (1987) 143-9; EP-0, 140, 606
  • PEP synthase Cho Y.P. et al . , J. Biol . Chem. 269 (1994) 5122-26; Patniak R. et al . , Biotechnol . Bioeng. 46 (1995) 361-70) .
  • PPS sugar phosphotransferase system
  • the object of the invention is, therefore, to make available an alternative process for producing substances, in particular aromatic amino acids, which process is characterized by an increased provision of PEP for the synthesis of these substances.
  • bacterial cells e.g. Escherichia coli
  • hexoses such as glucose or fructose
  • PEP:hexose phosphotransferase systems and phosphorylated, with PEP being consumed.
  • the effect of sugar-phosphorylating kinases is therefore restricted to activating those sugars which are present in the cell in a non-phosphorylated state because they were taken up by means of a PEP- independent transport system.
  • Sugars of this nature can result, for example, from reactions in which intracellular disaccharides and oligosaccharides, such as trehalose, lactose, maltose or maltodextrin, are hydrolyzed.
  • glucokinase has a subordinate function in Escherichia coli which is growing on glucose (Curtis and Epstein, J. Bacteriol . 122, (1975), 1189-
  • the inventors assume that overexpression of the kinase leads to an increase in the proportion of intracellular sugar phosphates whose activation takes place on the basis of ATP functioning as the energy donor. As a result, the quantity of PEP employed for this purpose decreases, something which is beneficial for the synthesis of secondary products of PEP. Despite many years of detailed studies on the preparation of substances from aromatic metabolism, simply increasing the activity of a kinase has never hitherto been postulated in the state of the art.
  • substances are to be understood as being, for example, fine chemicals such as aromatic amino acids, indigo, indoleacetic acid, adipic acid, melanin, quinones and benzoic acid, as well as their potential derivatives and secondary products - or, generally, derivatives of intermediates of the pentose phosphate pathway.
  • fine chemicals such as aromatic amino acids, indigo, indoleacetic acid, adipic acid, melanin, quinones and benzoic acid, as well as their potential derivatives and secondary products - or, generally, derivatives of intermediates of the pentose phosphate pathway.
  • all these substances are also regarded as being substances from aromatic metabolism.
  • other genetic alterations to the microorganisms producing the substances are required, in addition to the novel interventions, in order to prepare indigo, adipic acid and other unnatural secondary products .
  • the process for the microbial preparation of substances is therefore particularly advantageous when substances in whose synthesis PEP is involved are being prepared.
  • a sugar-phosphorylating kinase When a sugar-phosphorylating kinase is being employed, it is advisable to use a hexose-phosphorylating kinase, preferably a kinase from Zymomonas mobilis, in particular glucokinase (Glk) from Zymomonas mobilis .
  • the protein-encoding gene, glk is derived, for example, from Z . mobilis ATCC 10988, ATCC 29191 or ATCC 31821.
  • genes for hexose-phosphorylating kinases from bacteria whose gene products phosphory- late hexoses while consuming ATP are likewise suitable for the novel process.
  • genes for, for example, kinases from eukaryotic microorganisms, such as Saccharomyces cerevisiae, or, in a general manner, genes for sugar- phosphorylating kinases from other organisms are also suitable, provided they can be expressed in a functional manner in the microorganisms, in particular amino acid- producing microorganisms (amino acid producers) and can operate without using PEP to phosphorylate the sugars.
  • the sugar-phosphorylating kinases in amino acid producers .
  • the glucokinase gene glk for phosphorylating glucose, which gene is isolated from Z . mobilis ATCC 29191, is particularly suitable for preparing aromatic amino acids in accordance with the novel process.
  • Overexpressing the sugar-phosphorylating kinase in accordance with the present invention makes available an alternative process which decreases the consumption of PEP for activating sugars in the cell by increasing the use of alternative energy donors, such as ATP as the energy donor. As a result, an increased quantity of PEP is available for the microbial synthesis of substances in whose synthesis PEP is involved.
  • This embodiment also includes increasing the activity of a transport protein for the PEP-independent uptake of such a sugar in a substance-producing microorganism which is able to take up the relevant sugar by means of a PEP-dependent transport system.
  • the additional integration of a PEP-independent transport system makes it possible to increase the provision of non- phosphorylated sugars in the substance-producing microorganism. These sugars can be converted into activated sugar phosphates by the kinases which are in each case relevant, with consumption of ATP, and then subjected to further metabolism.
  • PEP is not required as an energy donor for these reactions and is consequently available in increased quantity, assuming a constant metabolic flux in glycolysis and the pentose phosphate pathway, for condensing with Ery4P to form the primary metabolite in the general pathway for biosynthesizing aromatic compounds, i.e. deoxy-D-arabinoheptulosonate-7- phosphate (DAHP) , and consequently for producing substances such as aromatic compounds.
  • DAHP deoxy-D-arabinoheptulosonate-7- phosphate
  • the transport protein activity is to be understood, in this context, as being the rate of protein-mediated uptake.
  • the PTS can be eliminated and the gene for the transport protein can be introduced in one step.
  • a strategy of this nature can be implemented by inserting the gene, for exampi-e, into a gene of the p ⁇ sHI-crr operon, e.g. into the ptsl gene or into another pts locus, and makes it easier to obtain the desired mutants.
  • This approach completely abolishes vectorial sugar transport through . the cell membrane and the PEP-dependent process for phosphorylating sugars which is coupled to it.
  • other functions of the PTS can be preserved.
  • Inserting the gene for the transport protein downstream of a PTS promoter is also advantageous since there is then no need to introduce a separate gene structure and the expression of the protein does not, due to the natural level of expression, destabilize the recombinant cell .
  • a facilitator as the transport protein for the PEP-independent uptake of a sugar, that is a transport protein which acts in accordance with the principle of protein-mediated facilitated diffusion.
  • a facilitator is a transport protein which acts in accordance with the principle of protein-mediated facilitated diffusion.
  • the glucose facilitator protein (Glf) from Zymomonas mobilis .
  • the protein-encoding gene, glf is obtained, for example, from Z . mobilis ATCC 10988, ATCC 29191 or ATCC 31821.
  • other bacterial sugar transport genes whose gene products transport glucose, fructose or sucrose, for example, and in doing so do not use any PEP, for example the GalP system from Escherichia coli , are also suitable for the novel process.
  • the facilitator gene gl f isolated from Z . mobilis ATCC 31821, for taking up sugars such as glucose, fructose or mannose when preparing aromatic amino acids in accordance with the novel process.
  • the glf gene in particular, should preferably be inserted at a low gene copy number in order to avoid harmful effects on the cell due to excessive expression of membrane proteins.
  • a gene copy number of from 2 to 5 is preferred, for example, for the glf gene. It is particularly advantageous, as already mentioned above, for the glf gene to be inserted into one of the genes of the ptsHI-crr operon.
  • the activity of a transaldolase and/or the activity of a transketolase is increased in addition to increasing the activity of a sugar-phosphorylating kinase or to increas- ing the activity of a sugar-phosphorylating kinase and of a PEP-independent transport protein.
  • the additional increase in the activity of one of these proteins makes it possible to achieve an even higher production of substances, in particular aromatic amino acids, due to the fact that Ery4P is provided in increased quantity for the condensation with PEP to form the primary metabolite in the general pathway for biosynthesizing aromatic compounds, i.e. deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) .
  • DAHP deoxy-D-arabinoheptulosonate-7-phosphate
  • transaldolase preference is given to increasing the activity of a transaldolase from Escherichia coli and, in par- ticular, . to increasing the activity of Escherichia coli transaldolase B (TalB) .
  • TalB Escherichia coli transaldolase B
  • this gene preferably originates from Escherichia coli K12 or from a strain derived therefrom.
  • any other gene is also suitable whose gene product catalyzes a reaction which corresponds to that of transaldolase, that is the conversion of sedoheptulose-7- phosphate plus glyceraldehyde-3 -phosphate to Ery4P and fructose-6-phosphate .
  • transketolase With regard to increasing the activity of a transketolase, preference is given to increasing the activity of a transketolase from Escherichia coli and, in particular, the activity of Escherichia coli transketolase A (TktA) .
  • TktA Escherichia coli transketolase A
  • this gene preferably originates from Escherichia coli K12 or from a strain which is derived therefrom.
  • any other gene is also suitable whose gene product catalyzes a reaction which corresponds to that of transketolase, that is the conversion of ribose-5-phos- phate plus xylulose-5-phosphate to sedoheptulose-7- phosphate plus glyceraldehyde-3-phosphate or to the conversion of xylulose-5-phosphate plus Ery4P to fructose- 6-phosphate plus glyceraldehyde-3-phosphate .
  • PEP for producing the first intermediate of aromatic amino acid metabolism
  • PEP sugar phosphotransferase system
  • a decrease of this nature can be effected either at the enzymic level or by using genetic methods, for example by using alternative, highly repressible promoters for expressing the pts genes or by inserting a gl f gene and/or a glk gene into the chromosome and, in particular, into the locus of the pfcsl gene, a procedure which simultaneously stabilizes the recombinant DNA in the chromosome (segregation stability) and consequently means that the use of a vector can be dispensed with.
  • a regulatable promoter influence can also be exerted on the activity of the PTS, during culture, by adding inducers or inhibitors of the corresponding promoter.
  • measures for increasing the activity are to be understood as being all measures which are suitable for increasing the activity of the kinase, of the transport protein, of the transaldolase and of the transketolase.
  • measures for this purpose - introduction of genes, for example using vectors or temperate phages;
  • - increasing gene expression for example by increasing the rate of transcription, for example by using promoter elements such as Ptac, Ptet or other regulatory nucleotide sequences, and/or by increasing the rate of translation, for example by using a consensus ribosome binding site;
  • Combinations of the abovementioned methods and other, analogous methods can also be employed for increasing the activity.
  • the endogeneous activity of transport proteins can be increased, for example, by cloning the gene using the abovementioned methods, for example, or by selecting mutants which exhibit an increased transport of substrates.
  • the harvested cells were washed in 100 mM tris/HCl buffer (pH 8.0) containing 1.2 mM ATP and 11.2 mM MgCl 2 .
  • the cells in the sediment were disrupted by ultrasonic treatment (Branson 250 Sonifier fitted with a microtip) in a sonication cycle of 25% and at an intensity of 40 watts for 4 min per ml of cell suspension.
  • the supernatant was used for measuring the activity of the glucokinase.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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Abstract

La présente invention se rapporte à de nouveaux procédés de préparation microbienne de substances, et notamment d'acides aminés aromatiques tels que la L-phénylalanine, lesdits procédés faisant un usage accru d'intermédiaires métaboliques intracellulaires, et notamment de phosphoénolpyruvate, et lesdits procédés consistant à accroître l'activité d'une kinase de phosphorylation des sucres dans un micro-organisme produisant de telles substances. Dans les réalisations préférées de l'invention, on accroît en outre l'activité d'une protéine de transport conçue pour assurer l'apport, indépendant du phosphoénolpyruvate (PEP), d'un sucre devant être phosphorylé par la kinase ou l'activité d'une transaldolase et/ou d'une transcétolase. L'invention se rapporte également à des structures géniques et à des cellules transformées portant ces structures géniques, qui permettent une mise en oeuvre particulièrement réussie de ces procédés.
PCT/NL1997/000583 1996-10-26 1997-10-17 Preparation microbienne de substances a partir d'un metabolisme aromatique WO1998018937A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47278/97A AU4727897A (en) 1996-10-26 1997-10-17 Microbial preparation of substances from aromatic metabolism/ii

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19644567A DE19644567A1 (de) 1996-10-26 1996-10-26 Mikrobielle Herstellung von Substanzen aus dem aromatischen Stoffwechsel / II
DE19644567.1 1996-10-26

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DE (1) DE19644567A1 (fr)
WO (1) WO1998018937A1 (fr)
ZA (1) ZA979565B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6258554B1 (en) 1998-07-03 2001-07-10 Kyowa Hakko Kogyo Co., Ltd. Method for producing metabolites biologically synthesized via phosphoribosyl pyrophosphate
WO2002029078A3 (fr) * 1999-01-29 2003-02-06 Univ Michigan State Synthese biocatalytique d'acide shikimique
EP1484410A1 (fr) * 2003-06-05 2004-12-08 Ajinomoto Co., Ltd. Procédé de fermentation et bactéries modifiées génétiquement pour une augmentation de l'absorption cellulaire des substrates et des sous-produits
JP2005013229A (ja) * 2003-06-05 2005-01-20 Ajinomoto Co Inc 目的物質の製造法
US6942996B2 (en) 2000-08-02 2005-09-13 Degussa Ag Isolated polynucleotide from Corynebacterium encoding a homocysteine methyltransferase
US7524660B2 (en) 2005-05-05 2009-04-28 E.I. Du Pont De Nemours And Company Utilization of fructose in microbial production strains
US7790431B2 (en) 2003-09-24 2010-09-07 Board Of Trustees Operating Michigan State University Methods and materials for the production of shikimic acid
EP2330184A1 (fr) 2008-09-01 2011-06-08 Shinshu University Procédé pour produire une substance utile

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19958159A1 (de) * 1999-12-02 2001-06-07 Degussa Neue für das glk-Gen codierende Nukleotidsequenzen
DE10032173A1 (de) 2000-07-01 2002-01-17 Degussa Neue für das plsC-Gen kodierende Nukleotidsequenzen
US6958228B2 (en) 2000-08-02 2005-10-25 Degussa Ag Nucleotide sequence which code for the metH gene
WO2002010209A1 (fr) * 2000-08-02 2002-02-07 Degussa Ag Sequences nucleotidiques codant pour le gene meth
WO2002010208A1 (fr) * 2000-08-02 2002-02-07 Degussa Ag Sequences nucleotidiques codant pour le gene mete
DE10109690A1 (de) * 2000-09-02 2002-03-14 Degussa Neue für das metY-Gen kodierende Nukleotidsequenzen
US6812016B2 (en) 2000-09-02 2004-11-02 Degussa Ag Nucleotide sequences which code for the metY gene

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JPS6178378A (ja) * 1984-09-27 1986-04-21 Ajinomoto Co Inc 芳香族アミノ酸生合成遺伝子を含有する組換えｄｎａ及びそれを有するコリネ型細菌

Patent Citations (1)

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US5602030A (en) * 1994-03-28 1997-02-11 University Of Florida Research Foundation Recombinant glucose uptake system

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PARKER C. ET AL.: "Characterization of the Zymomonas mobilis glucose facilitator gene product (glf) in recombinant Escherichia coli: examination of transport mechanism, kinetics and the role of glucokinase in glucose transport", MOLECULAR MICROBIOLOGY, vol. 15, no. 5, March 1995 (1995-03-01), pages 795 - 802, XP002054312 *
SPRENGER G.A. ET AL.: "Transaldolase B of Escherichia coli K-12: cloning of its gene, talB, and characterization of the enzyme from recombinant strains", JOURNAL OF BACTERIOLOGY, vol. 177, no. 20, October 1995 (1995-10-01), pages 5930 - 5936, XP002053305 *
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6258554B1 (en) 1998-07-03 2001-07-10 Kyowa Hakko Kogyo Co., Ltd. Method for producing metabolites biologically synthesized via phosphoribosyl pyrophosphate
WO2002029078A3 (fr) * 1999-01-29 2003-02-06 Univ Michigan State Synthese biocatalytique d'acide shikimique
US6942996B2 (en) 2000-08-02 2005-09-13 Degussa Ag Isolated polynucleotide from Corynebacterium encoding a homocysteine methyltransferase
EP1484410A1 (fr) * 2003-06-05 2004-12-08 Ajinomoto Co., Ltd. Procédé de fermentation et bactéries modifiées génétiquement pour une augmentation de l'absorption cellulaire des substrates et des sous-produits
JP2005013229A (ja) * 2003-06-05 2005-01-20 Ajinomoto Co Inc 目的物質の製造法
US7335496B2 (en) 2003-06-05 2008-02-26 Ajinomoto Co., Inc. Method for producing target substance
US8372621B2 (en) 2003-09-24 2013-02-12 Board Of Trustees Operating Michigan State University Methods and materials for the production of shikimic acid
US7790431B2 (en) 2003-09-24 2010-09-07 Board Of Trustees Operating Michigan State University Methods and materials for the production of shikimic acid
US7524660B2 (en) 2005-05-05 2009-04-28 E.I. Du Pont De Nemours And Company Utilization of fructose in microbial production strains
EP2330184A1 (fr) 2008-09-01 2011-06-08 Shinshu University Procédé pour produire une substance utile
US8530203B2 (en) 2008-09-01 2013-09-10 Shinshu University Process for producing useful substance
JP5833311B2 (ja) * 2008-09-01 2015-12-16 国立大学法人信州大学 有用物質の製造法
JP2016013141A (ja) * 2008-09-01 2016-01-28 国立大学法人信州大学 有用物質の製造法
EP2330184B1 (fr) * 2008-09-01 2020-11-25 Shinshu University Procédé pour produire une substance utile dans des bactéries coryneformes

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ZA979565B (en) 1998-11-28
AU4727897A (en) 1998-05-22

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