Method for producing L-amino acids by fermentation

Details Method for producing L-amino acids by fermentation Method for producing L-amino acids by fermentation

2000-09-18

2002-02-05

Lilling, Herbert J. (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing alpha or beta amino acid or substituted amino acid...

C435S106000

Reexamination Certificate

active

06344347

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a method for producing an L-amino acid by fermentation at high industrial efficiency.
As a direct fermentation method for producing and accumulating an L-amino acids directly from saccahride, there have been known methods in which mutant strains derived from wild-type strains of microorganism belonging to the genus Corynebacterium, Brevibacterium, Escherichia, Serratia or Arthrobacter are employed For example, the following are known as L-amino acid-producing mutants: auxotrophic mutants which require amino acids, etc. (Japanese Published Examined Patent Application No. 10037/1981), mutants which have resistance to amino acid analogs and vitamins (Japanese Published Unexamined Patent Application Nos. 134993/1981 and 44193/1987), mutants which have both auxotrophic mutation and resistance mutation to amino acid analog(Japanese Published Unexamined Patent Application Nos. 31093/1975 and 134993/1981), mutants which have lowered degradability (Japanese Published Unexamined Patent Application No. 273487/1988, and Japanese Published Examined Patent Application No. 48195/1977), and mutants whose aminoacyl t-RNA-synthesizing enzymes have a decreased substrate affinity (Japanese Published Unexamined Patent Application No. 330275/1992).
It has also been known that the production of an amino acid can be improved by using transformants obtained by transformation with recombinant DNAs carrying genes involved in the biosynthesis of amino acids (Japanese Published Unexamined Patent Application Nos. 893/1983, 12995/1985, 210994/1985, 30693/1985, 195695/1986, 271981/1986, 458/1990 and 42988/1990; Japanese Published Examined Patent Application s. 42676/1989, 11960/1993 and 26467/1993).
For producing L-tryptophan, there has been a report that the productivity of the amino acid was improved by giving resistance to aminoquinoline derivatives or to phenothiazine derivatives (Japanese Published Unexamined Patent Application No. 112795/1992).
There have been a report that the expression of an operon involved in histidine synthesis is increased in a DNA gyrase-deficient strain [
Proc. Natl. Acad. Sci. USA,
84, 517 (1987)] and a report that the levels of some amino acid t-RNA species including His-tRNA are decreased in a DNA gyrase mutant strain [
J. Mol. Biol.,
66, 131 (1972)], however, no report has been made yet about the relation between resistance to DNA gyrase inhibitors and amino acid productivity.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an industrially efficient method for producing an L-amino acid useful as medicament, chemical agent, food material and feed additive.
The present invention relates to the following aspects (1) to (14).
(1) A method for producing an L-amino acid, which comprises:
(a) culturing in a medium a microorganism having an ability to produce an L-amino acid and having resistance to a DNA gyrase inhibitor;
(b) producing and accumulating the L-amino acid in the culture; and
(c) recovering the L-amino acid from the culture.
(2) The method for producing an L-amino acid as described above in (1), wherein the DNA gyrase inhibitor is selected from the group consisting of nalidixic acid, oxolinic acid, coumermycin, novobiocin and the alkali metal salts of these substances.
(3) The method for producing an L-amino acid as described above in (1), wherein the microorganism has resistance to an aminoquinoline derivative.
(4) The method for producing an L-amino acid as described above in (3), wherein the aminoquinoline derivative is selected from the group consisting of chloroquine, amodiaquine, pentaquine, primaquine and the alkali metal salts of these substances.
(5) The method for producing an L-amino acid as described above in any one of (1) to (4), wherein the L-amino acid is L-histidine.
(6) The method for producing an L-amino acid as described above in (1) or (3), wherein the microorganism is selected from the group consisting of genera Serratia, Corynebacterium, Arthrobacter, Microbacterium, Bacillus and Escherichia.
(7) The method for producing an L-amino acid as described above in (6), wherein the microorganism is selected from the group consisting of
Escherichia coli
H-9342 (FERM BP-6675) and
Escherichia coli
H-9343 (FERM BP-6676).
(8) A microorganism having an ability to produce an L-amino acid and having resistance to a DNA gyrase inhibitor.
(9) The microorganism described above in (8), wherein the DNA gyrase inhibitor is selected from the group consisting of nalidixic acid, oxolinic acid, coumermycin, novobiocin, and the alkali metal salts of these substances.
(10) The microorganism described above in (8) or (9), wherein the microorganism has resistance to an aminoquinoline derivative.
(11) The microorganism described above in (10), wherein the aminoquinoline derivative is selected from the group consisting of chloroquine, amodiaquine, pentaquine, primaquine, and the alkali metal salts of these substances.
(12) The microorganism described above in (8), wherein the L-amino acid is L-histidine.
(13) The microorganism described above in any one of (8) to (12), wherein the microorganism is selected from the group consisting of genera Serratia, Corynebacterium, Arthrobacter, Microbacterium, Bacillus, and Escherichia.
(14) A microorganism selected from either
Escherichia coli
H-9342 (FERM BP-6675) or
Escherichia coli
H-9343 (FERM BP-6676).
DETAILED DESCRIPTION OF THE INVENTION
As the microorganism of the present invention, any microorganism can be used, so long as it has an ability to produce an L-amino acid and has resistance to the DNA gyrase inhibitor. Additionally, it is preferable that the microorganism has further resistance to an aminoquinoline derivative. Examples of the microorganism include microorganisms belonging to the genus Serratia, Corynebacterium, Arthrobacter, Microbacterium, Bacillus, or Escherichia, such as
Serratia ficaria, Serratia fonticola, Serratia liquiefaciens, Serratia marcescens, Corynebacterium glutamicum, Corynebacterium mycetoides, Corynebacterium variabilis, Corynebacterium ammoniagenes, Arthrobacter crystallopoietes, Arthrobacter duodecadis, Arthrobacter ramosus, Arthrobacter sulfureus, Arthrobacter aurescens, Arthrobacter citreus, Arthrobacter globiformis, Microbacterium ammoniaphilum, Bacillus subtilis, Bacillus amyloliquefacines
and
Escherichia coli.
As the DNA gyrase inhibitor for use in the present invention, any substance can be used, so long as it inhibits DNA gyrase, one of the type II topoisomerases which are present in bacteria. For example, nalidixic acid, oxolinic acid, coumermycin and novobiocin can be used as the DNA gyrase inhibitor. Additionally, the alkali metal salts of these substances can be used as the DNA gyrase inhibitor. Herein, any alkali metal such as sodium and potassium can be used as the alkali metals.
As the aminoquinoline derivative for use in the present invention, any substance can be used, so long as it has the aminoquinoline skeleton. For example, 4-aminoquinoline derivatives such as chloroquine and amodiaquine and 8-aminoquinoline derivatives such as pentaquine and primaquine can be used as the aminoquinoline derivative. Additionally, the alkali metal salts of these substances can be used as the aminoquinoline derivative. All of these substances are known as antimalarial drugs. Herein, any alkali metal such as sodium and potassium can be used as the alkali metals.
The microorganism of the present invention can be obtained by subjecting a microorganism having an ability to produce an L-amino acid to a conventional mutation treatment including ultraviolet irradiation and the treatment with mutagen such as N-methyl-N′-nitro-N-nitrosoguanidine (NTG), culturing the resulting mutant strains under general conditions on an agar plate medium containing a DNA gyrase inhibitor at a concentration at which the parent strain cannot grow or grow poorly, and selecting colonies which grow more rapidly than that of the parent strain or colonies which are larger than the parent strain among the

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