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Method for Producing L-Leucine Verfahren Zur Herstellung Von L-Leucin Procédé De Préparation De L-Leucine

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Method for Producing L-Leucine Verfahren Zur Herstellung Von L-Leucin Procédé De Préparation De L-Leucine Europäisches Patentamt *EP000913466B1* (19) European Patent Office Office européen des brevets (11) EP 0 913 466 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C12N 1/20, C12P 13/06 of the grant of the patent: // (C12N1/20, C12R1:19) 07.04.2004 Bulletin 2004/15 (21) Application number: 98120261.7 (22) Date of filing: 26.10.1998 (54) Method for producing L-leucine Verfahren zur Herstellung von L-Leucin Procédé de préparation de L-leucine (84) Designated Contracting States: • Arkadievich, Livshits Vitaly (VNIIGenetika) DE FR NL SE 113545, Moscow (RU) • Ivanovich, Kozlov Yury (VNIIGenetika) (30) Priority: 29.10.1997 RU 97117875 113545, Moscow (RU) • Georgievich, Debabov Vladimir (VNIIGenetika) (43) Date of publication of application: 113545, Moscow (RU) 06.05.1999 Bulletin 1999/18 (74) Representative: Strehl Schübel-Hopf & Partner (73) Proprietor: Ajinomoto Co., Inc. Maximilianstrasse 54 Tokyo (JP) 80538 München (DE) (72) Inventors: (56) References cited: • Markovich, Gusyatiner Mikhail (VNIIGenetika) EP-A- 0 530 803 EP-A- 0 698 668 113545, Moscow (RU) US-A- 3 970 519 • Grigorievna, Lunts Maria (VNIIGenetika) 113545, Moscow (RU) • CALHOUN D H: "Threonine deaminase from • Valerievna, Ivanovskaya Lirina (VNIIGenetika) Escherichia coli: feedback- hypersensitive 113545, Moscow (RU) enzyme from a genetic regulatory mutant." • Georgievna, Rostova Yulia (VNIIGenetika) JOURNAL OF BACTERIOLOGY, (1976 APR) 126 113545, Moscow (RU) (1) 56-63. , XP002122210 • Aleksandrovna, Bachina Tatiana (VNIIGenetika) 113545, Moscow (RU) Remarks: • Zavenovich, Akhverdyan Valery (VNIIGenetika) The file contains technical information submitted 113545, Moscow (RU) after the application was filed and not included in this • Moiseevich, Khurges Evgeny (VNIIGenetika) specification 113545, Moscow (RU) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 913 466 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 0 913 466 B1 2 Description and the productivity of L-leucine. [0009] But EP-A-0 698 668 discloses a process for Technical Field producing L-leucine comprising culturing a microorgan- ism belonging to the genus Escherichia having resist- [0001] The present invention relates to a method for 5 ance to a leucine analogue and an ability to produce L- producing L-leucine, especially to a method for produc- leucine. ing L-leucine using a bacterium belonging to the genus Escherichia. L-leucine is an essential amino acid which DISCLOSURE OF THE INVENTION can be used as a nutritious additive for food or feed, reagent or material for medical treatment, pharmaceu- 10 [0010] The present invention has been made from the tical or chemical industry, or a growth factor used for pro- aforementioned viewpoint, an object of which is to im- duction of other amino acids such as lysine. prove the productivity of L-leucine of bacteria belonging to the genus Escherichia and to provide an efficient 'and Background Art cost-effective method for producing L-leucine. 15 [0011] As a result of diligent investigation in order to [0002] In the past, L-leucine has been produced by a achieve the aforementioned object, the present inven- method of fermentation primarily using microorganisms tors have found that conferring L-leucine resistance to belonging to the genus Brevibacterium, Corynebacteri- a bacterium belonging to the genus Escherichia im- um or Serratia or mutants thereof which produce L-leu- proves the productivity of L-leucine, and completed the cine (Amino acid fermentation, JAPAN SCIENTIFIC SO- 20 present invention. CIETY'S PRESS, pp.397-422, 1986). [0012] In a first aspect, the present invention provides [0003] US 3,970,519 for example discloses microor- a process for selecting an L-leucine producing bacteri- ganisms of the genus Brevibacterium or Corynebacte- um belonging to the genus of Escherichia which com- rium which resist feedback inhibition by leucine or its prises selecting a strain of a bacterium belonging to the analogs and require at least one of isoleucine, threonine 25 genus of Escherichia that is capable of producing L-leu- or methionine as a growth nutriment and which produce cine and selecting a strain of said bacterium that can L-leucine under aerobic culture conditions. grow in a medium containing 15 g/l of L-leucine. [0004] The highest level of L-leucine accumulation [0013] In a second aspect, the present invention pro- was obtained when using Brevibacterium flavum VKPM vides a bacterium obtainable by the process of the first B-2736: this strain produces L-leucine at a concentra- 30 aspect. tion up to 26 g/L on sucrose-containing media for 72 h [0014] In a third aspect, the present invention pro- of fermentation in a laboratory fermenter (USSR Author vides bacteria having the accession numbers VKPM- Certificate 1394711). And Brevibacterium lactofermen- 7386, VKPM-7387 and VKPM-7388. tum 34 produces L-leucine up to 34 g/L on a medium [0015] In a fourth aspect, the present invention pro- with glucose (Appl. Environ. Microbiol., 51, p.1024 35 vides a method for producing L-leucine, comprising the (1986)). step of culturing the bacteria of the first aspect. [0005] As described above, the productivity of L-leu- [0016] In a fifth aspect, the present invention provides cine has been improved to some extent, however, the a method for producing L-leucine, comprising the steps development of a more efficient and cost-effective meth- of: od for producing L-leucine is required in order to meet 40 increasing demand for L-leucine in the future. a) selecting a bacterium by a process as defined in [0006] On the other hand, microorganisms belonging the first aspect, to the genus Escherichia are potentially utilized as po- b) culturing the bacterium obtained in step a), and tent L-leucine-producing bacteria due to their rapid c) recovering L-leucine from the medium. growth rate, prominent data obtained from genetic anal- 45 ysis and plentiful genetic materials. However, there are [0017] Preferred embodiments of the present inven- few reports which disclose the production of L-leucine tion are defined in the independent claims. using bacteria belonging to the genus Escherichia. [0018] The present invention will be explained in de- [0007] As L-leucine-producing bacterial strains of the tail below. genus Escherichia, a strain which is resistant to β- 50 thienylalanine, strain which is resistant to β-thienyla- <1> Bacterium belonging to the genus Escherichia of lanine and β-hydroxyleucine (Japanese Patent Publica- the present invention tion No.62-34397 for two) and a strain which is resistant to 4-azaleucine or 5,5,5-trifluoroleucine (Japanese [0019] A bacterium of the present invention is a bac- Laid-Open Publication No. 8-70879) are known. 55 terium belonging to the genus Escherichia, which has [0008] However, there have been known neither L- an ability to produce L-leucine and is resistant to L-leu- leucine-resistant bacteria belonging to the genus Es- cine. The bacterium belonging to the genus Escherichia, cherichia nor a relation between L-leucine resistance may be exemplified by Escherichia coli (E. coli). A bac- 2 3 EP 0 913 466 B1 4 terium belonging to the genus Escherichia which has an pathway, which includes a common pathway among the ability to produce L-leucine is exemplified, for example, L-valine biosynthesis and L-leucine biosynthesis. by bacteria having a resistance to leucine analogs such [0022] Of above-mentioned reactions in the L-leucine as β-2-thienylalanine, 3-hydroxyleucine, 4-azaleucine biosynthetic pathway, the rate determining step is the and 5,5,5-trifluoroleucine, which are described in Japa- 5 synthetic reaction from α-ketoisovalerate to α-isopro- nese Patent Publication No. 62-34397 and Japanese pylmalate catalyzed by α-isopropylmalate synthase Patent Laid-Open Publication No. 8-70879, and by bac- which suffers feedback inhibition by L-leucine. Also, the terium which can be bred by genetic engineering tech- expression of leuABCD operon is repressed by L-leu- niques as described in WO96/06926. The bacterium be- cine. Expression of ilvBN gene encoding acetohydroxy longing to the genus Escherichia of the present inven- 10 acid synthase I suffers concerted repression by L-valine tion can be obtained by selecting a strain which is re- and L-leucine, expression of ilvGM gene encoding ace- sistant to L-leucine from bacteria belonging to the genus tohydroxy acid synthase II suffers concerted repression Escherichia having an ability to produce L-leucine. Al- by L-isoleucine, L-valine and L-leucine, and expression ternatively, the bacterium belonging to the genus Es- of ilvIH gene encoding acetohydroxy acid synthase III cherichia of the present invention can be also obtained 15 suffers repression by L-leucine. by selecting a strain which has an ability to produce L- [0023] α-Isopropylmalate synthase which is inhibited leucine from bacteria belonging to the genus Es- as well as leuABCD operon which is repressed only con- cherichia being resistant to L-leucine. The most pre- cern the biosynthesis of L-leucine. Therefore the above ferred embodiment is a bacterium belonging to the ge- inhibition and repression do not cause cutting the route nus Escherichia, which is further resistant to leucine an- 20 for supplying any nutrient substance, even if there exists alog(s). an excess amount of L-leucine. Furthermore, although [0020] In a bacterium belonging to the genus Es- expression of ilvIH gene is repressed, expression of il- cherichia, L-leucine is synthesized through biosynthetic vBN gene and ilvGM gene encoding the other isozymes pathway inherent to L-leucine which diverges from the are not effected.
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