Biocatalytic Synthesis of Chiral Pharmaceutical Intermediates

Abstract

SummaryThe production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand from both the pharmaceutical and agrochemical industries for the preparation of bulk drug substances and agricultural products. The enormous potential of microorganisms and enzymes for the transformation of synthetic chemicals with high chemo-, regio-and enantioselectivities has been demonstrated. In this article, biocatalytic processes are described for the synthesis of chiral pharmaceutical intermediates.

Protein Engineering Applications on Industrially Important Enzymes: Candida methylica FDH as a Case Study

“…FDH catalyzes the oxidation of formate to carbon dioxide coupled with reduction of NAD + to NADH (Thiskov & Popov, 2004, 2006: The FDH enzyme was first discovered in 1950 (Uversky, 2003) but it has attracted attention in recent years due to its practical application in the regeneration of NAD(P)H in the enzymatic processes of chiral synthesis. FDH is widely used for coenzyme regeneration with enzymes used for optically pure product synthesis in the pharmaceutical, food, cosmetic and agriculture industries (Patel, 2004;Jormakka et al, 2003). The FDH catalysed reaction is also a suitable model for investigating the general mechanism of hydride ion transfer because of direct transfer of hydride ion from the substrate onto the C4-atom of the nicotinamide moiety of NAD + without stages of acid-base catalysis (Serov et al, 2002a).…”

“…It is possible to recover used coenzymes via recycling reactions, but existing methods for regenerating NAD(P)H are still a significant expense and are not costeffective in the manufacturing process. Therefore, there is a need for a low-priced method of coenzyme regeneration (Liu and Wang, 2007;Patel, 2004;Vrtis, 2002).…”

Site Saturation Mutagenesis Applications onCandida methylicaFormate Dehydrogenase

“…From NADH regeneration point of view the site saturation mutagenesis approach is applied to improve the properties of NAD + -dependent Candida methylica formate dehydrogenase ( cm FDH) which is a critical enzyme in pharmaceutical industry [5]. Although there are many dehydrogenases that can carry out the necessary chemistry, the NAD + -dependent FDH offers several advantages over any of the other dehydrogenases.…”

Influence of the hydrostatic pressure and pH on the asymmetric 2‐hydroxyketone formation catalyzed by Pseudomonas putida benzoylformate decarboxylase and variants thereof

“…Asymmetric syntheses play an important role in the production of fine chemicals as building blocks for the pharmaceutical and agricultural industries (Hilterhaus and Liese, 2007;Liese et al, 2006;Panke and Wubbolts, 2005;Patel, 2004;Ran et al, 2008). The amount of biocatalytic steps in chemical synthesis routes thereby increased significantly during the last decades, whereas the selectivity of the catalyzed reactions is mainly dependent on the nature of the applied enzymes.…”