Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Patent
1989-09-29
1993-03-09
Robinson, Douglas W.
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
435106, 435139, C12P 702, C12P 1304, C12P 756
Patent
active
051926873
DESCRIPTION:
BRIEF SUMMARY
The present invention relates, in a general way, to the use of reactions of oxidation and of reduction of organic molecules, in a process combining electrochemical reactions and enzyme catalysis and, in particular, an electroenzymatic process for producing a compound of controlled enantiomeric purity.
In living organisms electron exchanges are catalyzed by enzymes called oxidoreductases. These enzymes are of particular interest in enzyme technology, because they catalyze partial oxidation or reduction reactions. As an example of these enzymes there may be mentioned dehydrogenases and especially dehydrogenases with a cosubstrate of the type of nicotinamide adenine dinucleotide (denoted hereinafter by the abbreviation NAD) or nicotinamide adenine dinucleotide phosphate (denoted hereinafter by the abbreviation NADP), which are catalysts of high performance in their specificity and their selectivity. They catalyze reversible reactions of the type: ##STR1##
As a general rule the concerned substrates carry more or less oxygenated groups which are modified by the reaction.
The practical application of any process of the abovementioned type assumes that it is possible to recycle the cosubstrate, namely, in the abovementioned example, the NAD(P) if it is desired to employ direction 1 of the above reaction, the result being an oxidation of the reduced substrate, or else the NAD(P)H, if it is desired to employ direction 2 of the above reaction, the result being a reduction of the oxidized substrate. In fact, NAD and NADP are molecules whose cost is such that it is necessary to be able to regenerate them cyclically several thousand times for the process to be economically acceptable.
Among the various methods of regeneration (chemical, enzymatic, microbiological and electrochemical), enzymatic regeneration, according to which a second enzyme, as well as other substrates, are employed to perform the regeneration, is currently considered to give the highest performance in respect of recycling capacity. However, it presents the disadvantage of complicating the process, in particular because it involves various separation stages. On the other hand, electrochemical regeneration is particularly attractive from this point of view, because no by-product is formed; however, electrochemical regeneration is still considered in the literature to give relatively poor performance.
Within the scope of the studies which have led to the present invention it was found that, contrary to this prejudice, electrochemical oxidation of NADH to NAD can be obtained with a very high yield (higher than 99.99%), and this makes it possible to obtain at least 10,000 regeneration cycles. Consequently the direct route for oxidizing a substrate (direction 1 of the above reaction scheme), employing dehydrogenases, can be applied industrially using tho enzyme process.
On the other hand, direct electrochemical reduction of NAD to NADH leads to a very low number of regeneration cycles, fewer than 10, and, as a result, it is not possible to make use of this technique in an application performed on the industrial scale. Now, from the point of view of economy, it is precisely the reduction direction (direction 2 of the above reaction scheme) which is of interest, because it produces optically active compounds which are of a high purity and which are difficult to prepare by purely chemical methods.
By way of example there may be mentioned the chemical or electrochemical reduction of an unsymmetrical ketone, which produces a racemic mixture, difficult to purify, of D and L stereoisomers, as a general rule, in equimolar quantities.
As indicated above, the present invention is concerned with the production of these optically active compounds. In what follows, S will denote a starting substrate and P the end product, which carries an asymmetric carbon. P can be present in two optically active isomeric forms, written D-P and L-P, respectively. The (racemic) mixture of the two forms is written D/L-P.
The problem to be solved is that of obtaining, from S (or from D/
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Laane et al, Israel J. of Chem. 28:17-22 (1987/1988).
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Bartalits et al, Clin. Chem. 30:1780-1783 (1984).
Bourdillon, "Biotechnology and Bioengineering", vol. 31, pp. 553-558, 1988.
Luisi, "TIBTECH", 153 to 161, Jun. 1986.
Laane, "Biotechnology and Bioengineering", vol. 30, pp. 81-87, 1987.
Biade, J.A.C.S., "Complete Conversion of L. Lactate into D-Lactate." (in publication).
Bonnefoy Jacques P. B.
Bourdillon Christian
Laval Jean-Marc
Moiroux Jacques
Centre National de la Recherche Scientifique "CNRS"
Robinson Douglas W.
Saucier S.
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