Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing a...
Patent
1998-09-29
1999-11-23
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing a...
435 52, 4352563, 435911, C12N 114, C12P 3306
Patent
active
059898550
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a microorganism producing a bile acid having a 7.beta.-hydroxyl group such as 3.alpha., 7.beta.-dihydroxy-5.beta.-cholanic acid (hereinafter, referred to as ursodeoxycholic acid) or the like, which is useful as a cholagogue, and to a process for preparing ursodeoxycholic acid or a bile acid having a 7.beta.-hydroxyl group, which is an intermediate for preparing the former, utilizing the microorganism.
BACKGROUND ART
For introducing a 7.beta.-hydroxyl group into a 7-unsubstituted bile acid utilizing the conversion by a microorganism, the following methods have been known:
1) A process for preparing 3.alpha., 7.beta., 12.alpha.-trihydroxy-5.beta.-cholanic acid (hereinafter, referred to as ursocholic acid) from 3.alpha., 12.alpha.-dihydroxy-5.beta.-cholanic acid (hereinafter, referred to as deoxycholic acid) using one or more microorganisms belonging to the genus Pleurotus, the genus Coriolus, the genus Daedaleopsis, the genus Panaeolus, the genus Marasmius, the genus Crinipellis, the genus Pholiota or the genus Fusarium. (Japanese Patent Publication No. 34038 of 1989)
2) A process for preparing ursodeoxycholic acid from 3.alpha.-hydroxy-5.beta.-cholanic acid (hereinafter, referred to as lithocholic acid) using a microorganism belonging to the genus Fusarium. (Japanese Patent Publication No. 29397 of 1991)
3) A process for preparing a conjugated form of ursodeoxycholic acid from a conjugated form of lithocholic acid using a microorganism belonging to the genus Mortierella. (Japanese Patent Publication No. 29438 of 1993)
When a 7.beta.-hydroxyl group was introduced using these microorganisms, however, it was necessary to adjust the concentration of a substrate at a level as low as approximately 0.02-0.1% v/w. Therefore, a great technical problem arose that a colossal apparatus for production was required when production at an industrial scale was carried out.
On the other hand, microorganisms of the genus Penicillium have been known having a bile acid-converting capacity by introducing a 1.beta.-hydroxyl group and a 15.beta.-hydroxyl group (Journal of Lipid Research, Vol. 22, p. 1225 (1981) ); no microorganism of the genus Penicillium, however, has been known to have a bile acid-converting capacity by introducing a 7.beta.-hydroxyl group.
DISCLOSURE OF INVENTION
The purpose of the present invention is to provide an industrially useful process for preparing a bile acid having a 7.beta.-hydroxyl group by obviating the defect in the conventional art where it requires a low concentration for a substrate. After conducting extensive studies for attaining this purpose, the present inventors have found a novel microorganism having a bile acid-converting capacity by introducing a 7.beta.-hydroxyl group, having confirmed that this microorganism introduces a hydroxyl group to the 7.beta.-position of a bile acid at a substrate concentration higher than the conventional one, that is, even at a substrate concentration as high as 0.5% v/w or above, and thus have completed the present invention.
The present invention provides Penicillium sp. TTUR 422 belonging to the genus Penicillium and having a capability of introducing a 7.beta.-hydroxyl group into a 7-unsubstituted bile acid (hereinafter, referred to as TTUR 422), and a process for the preparation of a bile acid having a 7.beta.-hydroxyl group which comprises bringing TTUR 422 into contact with a 7-unsubstituted bile acid to convert the acid to a bile acid having a 7.beta.-hydroxyl group. As shown by the Chemical Reaction 1, deoxycholic acid is converted into ursocholic acid and 12-keto-ursodeoxycholic acid, intermediates for preparing ursodeoxycholic acid, and lithocholic acid is converted into ursodeoxycholic acid, by bringing TTUR 422 into contact with deoxycholic acid or lithocholic acid.
Chemical Reaction 1
##STR1##
Ursocholic acid obtained by the present invention is converted into 12-keto-ursodeoxycholic acid by oxidizing the hydroxyl group at the 12-position according to a chemical process using an oxidiz
REFERENCES:
patent: 4579819 (1986-04-01), Sawada et al.
patent: 4604353 (1986-08-01), Sawada et al.
Carlstrom et al, "Microbial synthesis of 1.beta.- and 15.beta.-hydroxylated bile acids," Journal of Lipid Research, vol. 22, pp. 1225-1234 (1981).
Joannou et al, "Identification of 15.beta.-hydroxylated C.sub.21 steriods in the neo-natal . . . ," Journal of Steroid Biochemistry, vol. 14, pp. 901-912 (1981).
Computer JPOABS 60-228500 Kimura et al, Nov. 13, 1985.
Matsui Hiroyuki
Okamura Akio
Lilling Herbert J.
Tokyo Tanabe Company Limited
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