Fermentation of bile

Details Fermentation of bile Fermentation of bile

1984-04-09

1985-07-09

Tanenholtz, Alvin E.

Chemistry: molecular biology and microbiology

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

Preparing compound containing a...

435874, 435872, C12P 3316, C12R 138, C12R 1365

Patent

active

045282722

DESCRIPTION:

BRIEF SUMMARY
This invention relates to the conversion of animal bile to compounds of value as intermediates for the production of pharmaceuticals.
Currently the corticosteroids and other steroid pharmaceuticals are synthesised by lengthy and expensive chemical processes. Materials isolated from bile, such as the bile acids, cholic acid and deoxycholic acid, may be used as intermediates in such processes. Also, it has been reported that the bile acids and their conjugates with taurine and glycine may be microbially transformed into certain steroids. Both the chemical and microbial prior art concerns the treatment of bile components per se. Surprisingly, it has now been found that, as regards microbial transformations, the use of pure compounds as starting materials is unnecessary and, moreover, there are significant advantages in employing unfractionated bile as a substrate for steroid production.
Accordingly, a major aspect of the present invention is the provision of a process for the preparation of steroids which comprises the microbial fermentation of unfractionated bile.
In this specification the term `unfractionated bile` means bile from which components such as bile acids, bile acid conjugates, proteins and lipids have not been extracted, but it does not exclude bile concentrated by the evaporation of water.
Accordingly, the invention provides a process for the fermentation of bile which includes the step of cultivating one or more aerobic microorganism(s) which has or have the ability to selectively degrade bile acids or bile acid conjugates contained in bile in a cultivation medium containing or consisting of unfractionated bile under aerobic conditions to prepare a compound of the formula ##STR3## wherein .about. is a bond chosen from one which is alpha or beta to the ring, X is chosen from hydrogen hydroxyl or oxo, may be either a double or single bond, and R is selected from oxo, hydroxy, or a propionic acid residue attached at the 2-position ##STR4## Any suitable aerobic microorganism characterised by its ability to grow aerobically in bile can be used in the process of the invention. Typically, suitable organisms will be adapted to the presence of bile and so, for example, may be found in the vicinity of bile-processing plants or in faeces; they may, however, be adapted to bile utilisation by well known techniques such as mutation, and gene or plasmid transfer.
Species of the genus Pseudomonas have been found to be particularly effective in selectively degrading bile acid conjugates. Thus, under certain conditions Pseudomonas sp. ATCC 31752 can accumulate compounds I-III (as designated in Table I hereinafter) in a cattle or sheep bile fermentation liquor; under other conditions compounds XIII-XV in Table I hereinafter will accumulate, while with different conditions again, other conditions shown in Table I can be obtained. Another Pseudomonas sp. ATCC 31753 is seen to be characterised by its ability to produce mainly acidic compounds such as some of those in Table II.
Most of the compounds shown in Table II hereinafter can be obtained from a cattle or sheep bile fermentation liquor when the active microorganism is Nocardia sp. ATCC 31754 (or the revised genus Rhodococcus sp. ATCC 31754, see Goodfellow and Alderson, J. Gen. Microbiol. 100, 99-122, 1977). Other species of the genera Rhodococcus, Nocardia, Mycobacterium, Arthrobacter, Corynebacterium, Streptomyces, Actinomyces, mutants thereof and any other aerobic microorganisms are within the scope of this invention, provided they possess the ability to selectively degrade the bile acid conjugates of bile in the presence of other bile components.
The invention also includes within its scope novel compounds that may be prepared by the process of the invention. These compounds with reference to Tables I and II hereinafter referred to are compounds V, VI, VIII, IX, X, XI, XIII, XIV, XV and XIX.
As previously intimated, the microbial transformation of sterols is not an unknown art. However, the prior art is distinguished by its reference only to the treatment o

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