EP1220904A2 - Nouveaux micro-organismes, leur utilisation et procede de production d'acides amines de configuration d - Google Patents

Nouveaux micro-organismes, leur utilisation et procede de production d'acides amines de configuration d

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Publication number
EP1220904A2
EP1220904A2 EP00969041A EP00969041A EP1220904A2 EP 1220904 A2 EP1220904 A2 EP 1220904A2 EP 00969041 A EP00969041 A EP 00969041A EP 00969041 A EP00969041 A EP 00969041A EP 1220904 A2 EP1220904 A2 EP 1220904A2
Authority
EP
European Patent Office
Prior art keywords
micro
amino acids
organism
production
acids
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00969041A
Other languages
German (de)
English (en)
Inventor
Stephanie G. Dept of Biochem. & Microbio. BURTON
Rosemary A Dept of Biochem. & Microb. DORRINGTON
Carol Janet Dept of Bioche. & Microbio. HARTLEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RHODES UNIVERSITY
SA BIOPRODUCTS (PROPRIETARY) LIMITED
Original Assignee
Rhodes University
AECI Ltd
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 Rhodes University, AECI Ltd filed Critical Rhodes University
Publication of EP1220904A2 publication Critical patent/EP1220904A2/fr
Withdrawn legal-status Critical Current

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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
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • 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
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • 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
    • 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
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • C12P41/009—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving hydantoins or carbamoylamino compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

Definitions

  • the invention relates to novel micro-organisms and their use in the production of D- amino acids
  • micro-organisms suitable for the production of D-amino acids from corresponding hydantoins or N-carbamoylamino acids are simple to cultivate and make possible high D-amino acids yields from different substrates
  • optically pure amino acids are p ⁇ ma ⁇ lv due to the use of D-amino acids, e g D-/?-hydroxyphenylglyc ⁇ ne, as side chains in semi-synthetic penicillins and cephalospo ⁇ ns (Syldatk et al, 1990)
  • Optically pure amino acids also have applications in the production of other pharmaceuticals and flavourants (e g D- alanine in sweetners), pesticides (D-vahne in the synthesis of insecticide fluvamlate), and as additives in animal feedstock (Polastro, 1989)
  • D, L-5- substituted hvdantoins have been used as starting materials for the chemical synthesis of D-ammo acids This process is cumbersome and inefficient since chemical synthesis results in an equimolar mixture of D- and L-ammo acids requiring racemate resolution to obtain optically pure D-ammo acids (Syldatk et al , 1990)
  • hydantoinases catalyses the ring-opening hydrolysis of the 5-substituted hydantoin to produce an N-carbamylarmno acid in a reversible reaction Classified as cyclic amidases (E C 3 5 2)
  • hydantoinases may be D-, L- or non-stereoselective
  • the N-carbamylamino acid is converted to its corresponding amino acid either chemically, or through the action of a second enzyme, an N-carbamylamino acid amidohydrolase (E C 3 5 1 6), which is usually stereoselective (Olivieri et al , 1979)
  • an N-carbamylamino acid amidohydrolase (E C 3 5 1 6), which is usually stereoselective (Olivieri et al , 1979)
  • racemization of the hydantoins occurs spontaneously at alkaline pH, certain microbial systems include a D-racemas
  • D-selective hydantoin-hydrolysing enzyme systems have been identified in a variety of bacteria, including a Pseudomonas isolate (Ikenaka et al , 1998), Bacillus stearothermophilus (Lee et al , 1996), Bacillus circulans (Luksa et al , 1997) and several Agrobacterium strains (Olivieri et al , 1981 , Runser et al , 1990, Hartley et al , 1998, ⁇ anba et al , 1998) The genes encoding one hydantoinase and three N- carbamylamino acid amidohydrolase enzymes from the Agrobacterium strains have been cloned and over-expressed in Eschenchia coli (Durham and Weber, 1995, Buson et al 1996, Grifantini et al , 1998, ⁇ anba et al , 1998)
  • the word “constitutive” is to be understood to mean unregulated expression of enzymes
  • the word “expression” is understood to mean the production of a protein from a DNA template via transcription and translation
  • the word “activity” is understood to mean the ability of the hydantoinase and N-carbamylamino acid aminohydrolase enzymes to hydrolyse hydantoins to N-carbamylamino acids and amino acids and vice versa, respectively
  • the phrase “over-express” to mean levels of enzyme production in excess of those under the same conditions in the original isolate
  • the phrase “enzyme system” is to be understood to include hydantoinase, N-carbamylamino acid amidohydrolase and hydantoin racemase enzymes which are capable of converting D- or L- or D,L-5-monosubstituted hydantoins or D- or L- or D,L- N-carbamoylamino acids to their
  • An object of the invention is the isolation of micro-organisms able constitutively to produce enzymes which convert racemic mixtures of 5-subst ⁇ tuted hydantoins or N- carbamyl amino acids to D-amino acids and thereby, at least partially, to alleviate the problems associated with chemical synthesis of D-amino acids
  • micro-organisms which are able to constitutively produce enzymes which convert racemic mixtures of N-carbamylamino acids to D-amino acids
  • an isolated and purified enzyme system able to convert racemic mixtures of 5-subst ⁇ tuted hydantoins to D- ammo acids
  • micro-organism for use in the production of D-amino acids for the production ot pharmaceuticals, alternatively agrochemicals, further alternatively for use in the production of D-amino acids for the production of pesticides, and still further alternatively for use in the production of D-amino acids for the production of feedstock additives.
  • the invention also extends to a growth medium to achieve over-expressed levels of hydantoinase and/or NCAAH enzyme activity during optimum culture conditions.
  • the invention also provides for a N-carbamylamino acid produced in accordance with the invention.
  • the invention also provides for a D-amino acid produced in accordance with the invention.
  • Figure 1 shows the DNA sequence of the 16S rRNA gene i Agrobacterium RTJ-OR
  • Figure 2 shows hydantoinase and N-carbamylamino acid amidohydrolase activity in Agrobacterium RU-OR cells during mid-logarithmic phase during growth in HMM;
  • Figure 3 shows the effect of carbon and nitrogen source on hydantoinase and N- carbamylamino acid amidohydrolase activities in RU-OR cells;
  • Figure 4 shows that ammonia shock represses enzyme activity in wild-type Agrobacterium RU-OR cells
  • Figure 5 shows that RU-ORP ⁇ 1 cells constitutively express hydantoinase enzyme, but that the hydantoinase enzyme is inactive due to repression by ammonium in the growth medium;
  • Figure 6 shows that RU-ORP ⁇ 1 cells constitutively express active N-carbamylamino acid amidohydrolase enzyme, while the wild type enzyme is repressed;
  • Figure 7 shows that hydantoinase activity in RU-ORPN l F9 cells is not sensitive to ammonia shock,
  • Figure 8 shows the levels of hydantoinase activity in RU-ORPNl F9 cells during mid- logarithmic growth phase compared with the levels in the wild-type RU-OR and mutant RU-ORPNl , when cells are grown under optimal growth conditions
  • Figure 9 shows the levels of N-carbamylamino acid amidohydrolase activity in both RU-ORP ⁇ 1 and RU-ORP ⁇ 1F9 cells during mid-logarithmic growth phase compared with the levels in the wild-type RU-OR, when cells are grown under optimal growth conditions, and
  • Figure 10 shows the increase in specific hydantoinase activity per unit biomass in RU-ORPNl F9 cells in mid-logarithmic growth phase, with D,L-p- hydroxyphenylhydantoin as substrate, as compared with the specific hydantoinase activity in the wild-type RU-OR cells and RU-ORPNl cells achieved during stationary phase
  • Agrobacterium tumefaciens 47 C Agrobacterium radiobacter B 1 1291 and Agtobacterinm sp IP 1-671 Agrobacterium radiobacter B11291 and Agrobacterium sp IP 1-671 also have N-carbamylamino acid and amidohydrolase activity
  • RU-OR novel Agrobacterium species
  • Agrobacterium RU-OR and RU-ORPNl cells grown to saturation in hydantoin minimal medium (HMM) broth, are diluted to OD ⁇ oo n 0 02 in standard minimal medium (MM) (MM per litre l Og glucose, O Ol lg CaC l 2 , 0 02g M g Cl 2 , 60g Na 2 HP0 4, 30g KH 2 P0 4 , 5g NaC l , 0 04g boric acid, 0 04g MnS0 4 , 0 02g (NH 4 ) 6 Mo 2 0 24 4H 2 o, O Olg KI, 0 004g CuS0 4 ) supplemented with 1% hydantoin (HMM), 0 01% casamino acids (SMM), or (NH 4 ) 2 S0 4 (AMM) Strain RU-ORPN1F9 cells are grown in HMM or SMM or AMM supplemented with 0 002% glutamine.
  • MM standard minimal
  • Hydantoinase activity is measured as the sum of the concentration of N-carbamylglycine ( ⁇ mol/ml) and glycine ( ⁇ mol/ml) produced from 50 ⁇ mol/ml hydantoin in a 5 ml reaction volume after 6 h, shaking, at 40°C N- carbamylamino acid amidohydr
  • Soil samples from the Eastern Cape environment were inoculated into hydantoin minimal medium (HMM) broth (per litre l Og glucose, 0 01 lg CaCl 2 , 0 02g MgCl 2 , 60g Na 2 HP0 4 , 30g KH 2 P0 4 , 5g NaCl, 0 04g boric acid, 0 04g MnS0 4 0 02g (NH 4 ) 6 Mo 2 0 24 4H 2 0, 0 Olg KI, 0 004g CuS0 4 , 1% hydantoin) and incubated, shaking at 25°C for 24 hours, after which serial dilutions were plated onto HMM agar and incubated for 5 days at 25°C Resulting colonies, which utilised hydantoins as a sole nitrogen source, were purified by re-streaking onto HMM agar Isolated strains were examined for the presence of hydantoinase and N-
  • Mutant RU-ORP ⁇ 1 was selected as follows Agrobacterium RU-OR cells were cultured in HMM broth to mid-log phase and then subjected to mutagenesis using ethylmethane sulfonate (EMS) according to the method described in Miller (1992) Mutated cells were plated onto MM agar supplemented with 0 1% (NH 4 ) S0 and 0 1% 5-fluorouracil Strain RU-ORPNl was isolated from these plates and evaluated under standard culture and assay conditions for enzyme activity in the absence of inducer Strain RU-ORPNl F9 was isolated by mutagenizing RU-ORPNl cells as described above and after penicillin-enrichment for glutamine-dependent growth, cells were plated onto HMM agar supplemented with 0 002% glutamine Gin mutants were selected by relica plating to HMM without supplementation with glutamine
  • EMS ethylmethane sulfonate
  • Total glutamine synthetase activity was measured using the ⁇ -glutamyl transferase assay Cells were prepared by treatment with 0 01% cetyl-trimethylammonium bromide for 10 minutes before harvesting. The cells were then washed twice with 0.1M phosphate buffer pH 9 0 before being suspended in 50 times less volume of resuspension buffer, and assayed according to the method of Bender et al (1977). Protein concentration was determined by the method of Bradford (1976). Activity is expressed as ⁇ moles of ⁇ -glutamyl hydroxamate generated per minute per milligram protein The percentage adenylation of the glutamine synthetase enzyme subunits was measured using the method of Magasanik et al.
  • the nutritional factors responsible for regulating enzyme activity were identified by establishing standard culture conditions under which enzyme activity was not limited to stationary phase Hydantoinase and NCAAH activities were measured during growth of RU-OR cells in a chemically defined minimal medium containing hydantoin and glucose as sole nitrogen and carbon sources, respectively (MM plus 0 1 % hydantoin) Activity of both enzymes was low in early exponential phase and after the cells reached stationary phase, with highest activity detected during mid to late exponential phase (Figure 2)
  • RU-ORP ⁇ 1 cells grown in minimal medium with ( ⁇ H 4 ) 2 S0 4 as nitrogen source had repressed levels of hydantoinase activity, as observed in the wild-type, RU-OR cells ( Figure 5), but, in contrast to the RU-OR, FIFAH activity in RU-ORPNl cells was elevated to wild-type, induced levels ( Figure 6) After growth in SMM for 60 minutes, hydantoinase activity in mutant RU-ORPNl cells recovered to levels normally observed in induced wild-type cells (see table 2) while there was no increase in hydantoinase activity in the wild-type Agrobacterium RU-OR cells after growth in SMM Thus, unlike the wild-type, the mutant strain expresses both hydantoinase and N-carbamylamino acid amidohydrolase enzymes even under nitrogen repression conditions, but the hydantoinase enzyme is inactive in the presence of ( ⁇ H 4 ) 2 S0 4
  • Glutamine synthetase assays of all three strains before and after ammonia shock showed that glutamine synthesis was reduced by 60% in RU-ORPN1F9 when compared to that in Agrobacterium RU-OR and RU-ORPN 1 cells
  • a reduction in glutamine synthesis when RU-ORPN 1F9 cells are grown in (NH 4 ) S ⁇ 4 results in insensitivity of hydantoinase activity to ammonia shock HYDANTOINASE AND GeorgiaH ACTIVITY IN REGULATORY MUTANTS DURING GROWTH IN (NH 4 )?SO. ⁇ .
  • RU-ORPN l and RU-ORPN1F9 cells were assessed during batch culture in SMM and compared with enzyme activity of the wild-type Agrobacterium RU-OR grown in the same medium, supplemented with 2- thiouracil
  • Hydantoinase activity in mutant strain RU-ORPNl followed the same trend as in the wild-type Agrobacterium RU-OR ( Figure 8), but high levels of activity were detected in exponential growth phase in RU-ORPN 1F9 cells
  • NCAAH activities in strains RU-ORPNl and RU-ORPN 1F9 were highest in exponential growth phase and these levels declined during stationary phase.
  • RU-ORPN 1F9 cells achieved the highest overall hydantoin-hydrolyzing activity of all three strains during exponential growth phase ( Figures 8 and 9) indicating that the gin phenotype does not have a deleterious effect upon hydantoinase or NCAAH production in this strain
  • Strain Agrobacterium RU-OR was selected for its efficient conversion of D,L-p-hydroxyphenylhydantoin to D-/?-hydroxyphenylglycine High levels of D,L- ?-hydroxyphenylhydantoin- hydrolysis were also achieved The highest D,L-/?-hydroxyphenylhydantoin conversion by the wild-type Agrobacterium RU-OR and RU-ORPNl cells was detected during stationary growth phase In strain RU-ORPN 1F9 both hydantoinase and NCAAH activity during exponential growth phase exceeded that detected in either Agrobacterium RU-OR or RU-ORPNl cells Up to 45 % of D,L
  • Figure 10 depicts the specific hydantoinase activity per milligram dry cell mass with D,L- -hydroxyphenylhydantoin as substrate
  • Strain RU-ORPNl shows an overall increase of 50% in hydantoinase activity compared with wild-type Agrobacterium RU-OR
  • Mutant RU-ORPN 1F9 showed the highest specific hydantoinase activity with a 300%> and 200%> increase over the wild-type Agrobacterium RU-OR and mutant RU-ORPNl respectively Most important, the highest specific hydantoinase activity per unit biomass was observed in RU- ORPN 1F9 cells during mid-logarithmic growth phase (0 015 units) versus 0.002 units and 0 003 units of activity in RU-OR and RU-ORPNl cells, respectively, during the same growth phase

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
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  • General Engineering & Computer Science (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne de nouveaux micro-organismes simples à cultiver et leur utilisation dans la production d'acides aminés de configuration D, et en particulier des micro-organismes convenant pour la production d'acides aminés de configuration D à partir d'hydantoïnes correspondantes de N-carbamoylamino acides.
EP00969041A 1999-09-17 2000-09-18 Nouveaux micro-organismes, leur utilisation et procede de production d'acides amines de configuration d Withdrawn EP1220904A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ZA995981 1999-09-17
ZA9905981 1999-09-17
PCT/ZA2000/000173 WO2001019982A2 (fr) 1999-09-17 2000-09-18 Nouveaux micro-organismes, leur utilisation et procede de production d'acides amines de configuration d

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EP1220904A2 true EP1220904A2 (fr) 2002-07-10

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EP00969041A Withdrawn EP1220904A2 (fr) 1999-09-17 2000-09-18 Nouveaux micro-organismes, leur utilisation et procede de production d'acides amines de configuration d

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EP (1) EP1220904A2 (fr)
JP (1) JP2005518179A (fr)
AU (1) AU7887000A (fr)
CA (1) CA2385241A1 (fr)
HK (1) HK1044173A1 (fr)
WO (1) WO2001019982A2 (fr)

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Publication number Priority date Publication date Assignee Title
JP4504810B2 (ja) * 2002-08-07 2010-07-14 岡山県 微生物由来のポリアミノ酸またはその誘導体

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Publication number Priority date Publication date Assignee Title
FR2620731B1 (fr) * 1987-09-21 1990-03-23 Hoechst France Nouveau systeme enzymatique, son procede de preparation et son application notamment dans la preparation de la d-parahydroxyphenylglycine
IT1274167B (it) * 1994-04-15 1997-07-15 Eniricerche Spa Procedimento per la produzione di d- -amminoacidi
DE19519717C1 (de) * 1995-05-30 1996-08-22 Degussa Neuer Mikroorganismus, dessen Verwendung und Verfahren zur Herstellung von L-alpha-Aminosäuren

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Title
See references of WO0119982A2 *

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Publication number Publication date
CA2385241A1 (fr) 2001-03-22
WO2001019982A2 (fr) 2001-03-22
JP2005518179A (ja) 2005-06-23
WO2001019982A3 (fr) 2001-10-25
HK1044173A1 (zh) 2002-10-11
AU7887000A (en) 2001-04-17

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