Biotransformations large-scale

The growth of industrial scale biotransformation processes has increased significantly over recent years with more than 130 reported in 2002 [1]. Major activity is focussed on the production of chiral pharmaceuticals although a number of large scale industrial processes have been developed for the food and agricultural industries. 

The biotransformation process has been improved by significant advances in biochemical engineering advances in genetic and protein engineering, microbiological manipulations for the production of enzymes, and the use of biocatalysts in immobilized form and large-scale purification methods. 

The latter part of the book is dedicated to redox biotransformation application, with Chapter 9 disclosing several methods for the synthesis of chiral secondary alcohols using a range of commercially available ketoreductases (alcohol dehydrogenases) which are now being applied regularly on a large scale. 

J )-Mandelic acid 3 is a useful chiral synthon for the production of pharmaceuticals such as semi-synthetic penecillins, cephalosporins and antiobesity agents and many methods have been reported for the preparation of the optically pure material. A method to deracemize the racemate which is readily available on a large scale was developed by Ohta et al. using a combination of two biotransformations. The method consists of enantioselective oxidation of (S)-... 

The use of bacteria for preparative biotransformations is particularly attractive for the following reasons (i) they do not tend to form dense mycelia, which may impede agitation of large-scale reactions when whole-cell (fungal) systems are employed and (ii) cloning of bacterial enzymes is generally less problematic. 

Similarly, sulfides 19 and 21 were biooxidized to the corresponding enantiomerically enriched sulfoxides, (-)-pantoprazole 20 and (-)-lansoprazole 22, respectively. These biotransformation processes are still at the exploratory stage. The concentration of the substrate is generally minute — in the ppm range. As a result, this method is not suitable for large-scale processes. 

The biotransformations of sulfur compounds by microorganisms can have large-scale impacts on global chemistry. As an example, sulfate-reducing bacteria have, throughout histoiy, formed major deposits of elemental sulfur and iron sulfides on Earth, and these processes are continuing today (1). Contemporary sulfate-reduction coupled with the oxidation of reduced inorganic sulfur... 

In addition to the identification of the appropriate biosynthetic enzyme, the feasibility of all biotransformation processes depends heavily on other criteria, such as the availability of inexpensive starting materials, the reaction yield, and the complexity of product recovery, hi the case of transaminase processes, the reversible nature of the reaction (Scheme 3.1) and the presence of a keto acid by-product is a concern that limits the overall yield and purity of product and has led to efforts to increase the conversion beyond the typical 50% yield of product.99 100 Additionally, there are cost considerations in the large-scale preparation of keto acid substrates such as 2-ketobutyrate, which are not commodity chemicals. 

Lonza is a major custom manufacturer of intermediates for the life science industries, and uses biocatalysis in many of its processes. Some of the products for which a biotransformation is used are achiral, however, an important characteristic of enzymes is their chirality, and this characteristic is used by Lonza to produce a number of chiral synthons. Biotransformations for the synthesis of asymmetric compounds can be divided into two types of reactions those where an achiral precursor is converted into a chiral product (true asymmetric synthesis) and those involving the resolution of a racemic mixture. Both types of reaction are used at Lonza, and several examples of each type of reaction are described for large-scale syntheses of chiral molecules that use a biotransformation in one or more of the steps. 

The following examples illustrate Lonza s activities in large-scale biocatalysis for asymmetric synthesis. There are more examples of resolutions than true asymmetric syntheses, and this reflects the general current situation in the field of large-scale biotransformations. However, considerable research work is underway, both in universities and industry, to broaden the types of biocatalytic reactions that can be applied on a commercial scale. 

When we want to use biofunctional molecules practically in agriculture or medicine, of course we have to provide them in quantity. Organic synthesis is a method of choice for their large-scale production together with biotransformation and fermentation. More importantly, organic synthesis can provide useful... 

The application of isolated enzymes to preparative organic synthesis on an industrial scale is a matter of active research worldwide. Since the late sixties, immobilized enzymes have been used in amino acid production in continuous processes on a large scaled 2. In the late seventies, the use of soluble enzymes, especially in membrane reactors, broadened the scope of enzyme technology13, 41 and opened the way to simultaneous use of more than one enzyme for complex conversions -especially coenzyme-dependent biotransformations[5-7. In the early 1980s the use of enzymes was extended further to involve organic solvents[8, 9 ... 

A new industrial avenue to oligosaccharide synthesis may be opened by an approach using whole-cell biotransformations. Researchers from Kyowa Hakko Co. (Japan) have developed systems for the large-scale production of UDP-Gal and globotriose (Fig. 11) from inexpen-... 

Gbewonyo G,Buckland BC, Lilly MD (1991) Development of a large-scale continuous substrate feed process for the biotransformation of simvastatin by Nocardia sp. Biotechnol Bioeng 37 1101-1107... 

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