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Biotechnological Production of D-Pantothenic Acid and its Precursor D-Pantolactone

Maria Kesseler 6.3.1

Introduction

D-Pantolactone (Figure 6.3.1) is an important intermediate in the production of d-pantothenic acid, also called vitamin B5. Deficiency of pantothenic acid can result in symptoms such as pathological changes of the skin and mucosa, disorders in the gastrointestinal tract and nervous system, organ changes, and hormonal disorders. Pantothenic acid is used mainly in feed for chicken and pigs and also as a vitamin supply in human nutrition. Its commercial form, the calcium salt, is produced worldwide on a multi-thousand ton scale.

In principle, the variety of synthetic methods used for production of optically active hydroxy acids can be divided into three types. Some acids are derived from the chiral pool of naturally occurring optically active substances. For example about 30,000 tons of L-tartaric acid are prepared from tartar; D-gluconic acid is produced by biocatalytic oxidation of D-glucose via gluconolactone in high yield, e.g. in an Aspergillus submers process [1]. Considering the diversity of optically active intermediates and products in the chemical and pharmaceutical industries, the chiral pool obviously gives access to only a limited number of compounds, so chemical processes were developed to overcome this limitation. These include the well known methods of asymmetric synthesis and the fractionated crystallization of diastereomeric salts of the acid. Examples are the hydrogenation of a-keto esters, for example acyl 2-oxo-4-phenylbutyrate (Ciba Geigy, see Ref. [2]) and the resolution of racemic mandelic acid by crystallization of R-mandelic acid with R-1-phenylethylamine by Yamakawa, Japan.

D-Pantothenic acid is also traditionally produced by chemical processes which involve efficient but troublesome and costly crystallization of diastereomeric salts of pantoate and chiral amines. After lactonization of the isolated D-pantoate, d-pantolactone is reacted with ^-alanine to give D-pantothenate. Because the monovalent salts of pantothenic acid are highly hygroscopic, conversion into the calcium salt is essential for convenient formulation. The third class of synthetic processes for optically active compounds makes use of biotechnology. For natural com-

D-Pantothenic acid D-Pantolactone

Fig. 6.3.1. d-Pantothenic acid and its chemical precursor d-pantolactone.

D-Pantothenic acid D-Pantolactone

Fig. 6.3.1. d-Pantothenic acid and its chemical precursor d-pantolactone.

pounds, strains are generated that overproduce the desired metabolite (e.g. amino acids such as L-glutamate) during growth. For unnatural compounds, one or few biocatalytic steps are used to transform a precursor by isolated enzymes or whole cell catalysts into the desired product. In recent years, such new biotechnological preparation methods have arisen for the production of D-pantothenic acid. Here we review these reactions with a special focus on characteristics of the development of a typical biocatalyst.

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