Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Bacteria or actinomycetales; media therefor
Reexamination Certificate
1996-04-03
2004-02-17
Slobodyansky, Elizabeth (Department: 1652)
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Bacteria or actinomycetales; media therefor
C435S254110, C435S320100, C536S023200
Reexamination Certificate
active
06692950
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a new intermediate involved in the synthesis of clavulanic acid and an enzyme useful in the synthesis of clavulanic acid from intermediates involved in its biosynthesis. The present invention also relates to processes for preparation of the enzyme and intermediate. The present invention further relates to DNA molecules carrying a gene coding for an enzyme involved in clavulanic acid biosynthesis.
BACKGROUND
The biosynthetic route to the important product clavulanic acid, a key ingredient of the antibiotic AUGMENTIN (Trade Mark of SmithKline Beecham plc) has been the subject of considerable study with a view to increasing the yield (titre) of clavulanic acid in fermentation processes. Clavulanic acid has been shown to be derived biosynthetically from clavaminic acid.
It has been reported (J. Chem. Soc., Chem. Commun. 1987, 1737 and 1990, 617) that clavaminic acid is formed by the action of an enzyme on a precursor known as proclavaminic acid (see also EP-A-0213914). Earlier steps in the biosynthetic pathway have been more difficult to elucidate.
We have now established that the final reaction in the biosynthesis of clavulanic acid involves the reduction of a side chain aldehyde to the hydroxyl group, using NADPH as the hydrogen donor.
The involvement of an aldehyde in the biosynthetic pathway has been suggested previously (Townsend et al. 1988, J Chem Soc Chem Commun, 18, 1234-36; Iwata-Reuyl, D and Townsend, C. A. 1992, J AM Chem Soc 114, 2762-4), however the present work represents the first isolation and proof of the existence of such a compound.
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Copy of EP Search Report (EP 02 07 7067, Jun. 28, 2002).
Brown, et al., “Clavulanic Acid and its Derivatives. Structure Elucidation of Clavulanic Acid and the Preparation of Dihydroclavulanic Acid, Isoclavulanic Acid, Esters and Related Oxidation Products”,Journal of the Chemical Society, Perkin Transactions 1, pp. 635-650 (1984).
Nicholson, et al., “Evidence that the Immediate Biosynthetic Precursor of Clavulanic Acid is its N-aldehyde Analogue”,Journal of the Chemical Society, Chemical Communicationspp. 1281-1282 (1994).
Reuyl, et al., “Common Origin of Clavulanic Acid and Other Clavam Metabolites inStreptomyces ”, Journal of the American Chemical Society, 114, No. 7, pp. 2762-2763 (1992).
Arnell Janice
Elson Stephen William
Nicholson Neville Hubert
Woroniecki Stefan Roland
Gimmi Edward R.
Kinzig Charles M.
Lockenour Andrea V.
Slobodyansky Elizabeth
SmithKline Beecham plc
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