Development of a multi-enzymatic desymmetrization and its application for the biosynthesis of l-norvaline from dl-norvaline.

Perindopril is an effective antihypertensive drug in strong demand used to treat hypertension. l -norvaline is a vital intermediate of Perindopril production mainly produced by chemical synthesis with low purity. We developed an environmentally friendly method to produce l -norvaline with high purity based on a desymmetrization process. d -Norvaline was oxidized to the corresponding keto acid by d -amino acid oxidase from the substrate dl -norvaline. Asymmetric hydrogenation of the keto acid to l -norvaline was carried out by leucine dehydrogenase with concomitant oxidation of NADH to NAD + . A NADH regeneration system was introduced by overexpressing a formate dehydrogenase. The unwanted H 2 O 2 by-product generated during d -norvaline oxidation was removed by adding catalase. A total of 54.09 g/L of l -norvaline was achieved, with an enantiomeric excess over 99% under optimal conditions, with a 96.7% conversion rate. Our desymmetrization method provides an environmental friendly strategy for the production of enantiomerically pure l -norvaline in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]