Industrial enzymes

Details Industrial enzymes Industrial enzymes

1997-04-25

1999-07-06

Patterson, Jr., Charles L.

Chemistry: molecular biology and microbiology

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

Preparing compound having a 1-thia-5-aza-bicyclo

435195, 43525233, 4353201, 435874, 435 691, 536 232, C12P 3500, C12N 914, C12N 120, C12N 1500

Patent

active

059196483

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to an enzyme process for the one step conversion of cephalosporin C or a derivative thereof into 7-aminocephalosporanic acid or a corresponding derivative thereof The one step conversion is effected using a cephalosporin C amidohydrolase enzyme derived from Pseudomonas vesicularis B965, or from any cephalosporin C amidohydrolase producing or potentially producing descendants thereof, or from any expression of DNA, particularly a recombinant DNA molecule, derived from Pseudomonas vesicularis B965 as described herein, or any cephalosporin C amidohydrolase producing or potentially producing descendants thereof.
Cephalosporin C is the fermentation product of the cephalosporin biosynthesis pathway and although it has been shown to have some activity against gram-negative microorganisms as an antibiotic itself, the major commercial use of cephalosporin C is as a building block for other cephalosporin-like antibiotics. In particular, the D-.alpha.-aminoadipoyl side chain may be removed to give the highly useful intermediate 7-aminocephalosporanic acid (7-ACA) which is a precursor to a wide range of semi-synthetic cephalosporin antibiotics including cephalothin, cephaloridine and cefuroxime.
The current industrial process for producing 7-ACA from cephalosporin C is a chemical cleavage of the D-.alpha.-aminoadipoyl side chain. There are several different methods in use (see for instance A Smith in "Comprehensive Biotechnology: the Principles, Applications and Regulations of Biotechnology in Industry, Agriculture and Medicine", Volume 3 ( "The Practice of Biotechnology: Current Commodity Products"), Eds. H W Blanch et.al., esp. pp.163-185, Pergamon Press, Oxford, UK, 1985), but all are essentially imino-halide processes with appropriate protection of amino and carboxyl groups. See, for example, the nitrosyl chloride cleavage developed by Morin et al (J. Am. Chem. Soc., 84, 3400 (1962)) now superseded by the imino ether method developed by Ciba Geigy (Fechtig et al, Helv. Chim. Acta., 51, 1108 (1968)).
These chemical processes have several disadvantages which include: the cost of the chemical reagents for protection and cleavage; the expense of providing the required low operating temperatures (e.g. -20.degree. C.); the cost of the complex, often multi-step plant; the cost of the measures to contain the toxic chemical reagents (e.g. trimethyl silyl chloride, phosphorous pentachloride and chloroacetyl chloride); and the need to purify the highly impure cephalosporin C (or a derivative) starting material.
There is therefore a need to provide a means of converting cephalosporin C (or a derivative thereof) to 7-ACA (or a corresponding derivative thereof) which is cheap, involves simple technology, is environmentally friendly and is safe. Such criteria are met herein using an enzyme process.
The search for efficient microbiological or enzyme processes for converting cephalosporin C (or a derivative thereof) into 7-ACA (or a corresponding derivative thereof) has been largely unsuccessful. There have been reports in the literature of two-stage enzymatic processes for converting cephalosporin C to 7-ACA. These require the initial conversion of cephalosporin C into glutaryl-7-ACA using a D-amino acid oxidase (see for instance U.S. Pat. Nos. 3,658,649 or 3,801,458) followed by cleavage of the glutaryl side chain to give 7-ACA- Two-stage enzymatic processes have, for example, been described by Shibuya et al, Agric. Biol. Chem.,45, 1561-1567 (1981), but all suffer from the disadvantage of reduced efficiency and increased complexity compared with the one step conversion.
There have also been reports of low activity single-step enzyme reactions. For example, EP0283218, EP0322032, and EP0405846, describe one step conversion of cephalosporin C to 7-ACA using enzymes derived from Arthrobacter viscosus, Bacillus Megaterium, and another Bacillus species respectively. EP0474652 describes an enzyme capable of a one step conversion of cephalosporin C to 7-ACA which is derived from Pseudomonas diminuta. Despit

REFERENCES:
patent: 5320948 (1994-06-01), Iwami et al.

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