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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Tee, Kang Lan Hans, Marcus Meijrink, Ben Van Scheppingen, Wibo B. Van Der Laan, Jan-metske Van Den Berg, Marco A. Vollebregt, Aad Leys, David Munro, Andrew W. Mclean, Kirsty J. |
| Description | Author Affiliation: McLean KJ ( Manchester Institute of Biotechnology, Faculty of Life Sciences, The University of Manchester, Manchester M1 7DN, United Kingdom); Hans M ( DSM Biotechnology Center, 2613 AX, Delft, The Netherlands.); Meijrink B ( DSM Biotechnology Center, 2613 AX, Delft, The Netherlands.); van Scheppingen WB ( DSM Biotechnology Center, 2613 AX, Delft, The Netherlands.); Vollebregt A ( DSM Biotechnology Center, 2613 AX, Delft, The Netherlands.); Tee KL ( Manchester Institute of Biotechnology, Faculty of Life Sciences, The University of Manchester, Manchester M1 7DN, United Kingdom); van der Laan JM ( DSM Biotechnology Center, 2613 AX, Delft, The Netherlands.); Leys D ( Manchester Institute of Biotechnology, Faculty of Life Sciences, The University of Manchester, Manchester M1 7DN, United Kingdom); Munro AW ( Manchester Institute of Biotechnology, Faculty of Life Sciences, The University of Manchester, Manchester M1 7DN, United Kingdom); van den Berg MA ( DSM Biotechnology Center, 2613 AX, Delft, The Netherlands andrew.munro@manchester.ac.uk marco.berg-van-den@dsm.com.); |
| Abstract | The cholesterol-lowering blockbuster drug pravastatin can be produced by stereoselective hydroxylation of the natural product compactin. We report here the metabolic reprogramming of the antibiotics producer Penicillium chrysogenum toward an industrial pravastatin production process. Following the successful introduction of the compactin pathway into the ß-lactam-negative P. chrysogenum DS50662, a new cytochrome P450 (P450 or CYP) from Amycolatopsis orientalis (CYP105AS1) was isolated to catalyze the final compactin hydroxylation step. Structural and biochemical characterization of the WT CYP105AS1 reveals that this CYP is an efficient compactin hydroxylase, but that predominant compactin binding modes lead mainly to the ineffective epimer 6-epi-pravastatin. To avoid costly fractionation of the epimer, the enzyme was evolved to invert stereoselectivity, producing the pharmacologically active pravastatin form. Crystal structures of the optimized mutant P450(Prava) bound to compactin demonstrate how the selected combination of mutations enhance compactin binding and enable positioning of the substrate for stereo-specific oxidation. Expression of P450(Prava) fused to a redox partner in compactin-producing P. chrysogenum yielded more than 6 g/L pravastatin at a pilot production scale, providing an effective new route to industrial scale production of an important drug. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 9 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cytochrome P-450 Enzyme System Fungal Proteins Penicillium Chrysogenum Pravastatin Biosynthesis Crystallography, X-Ray Chemistry Genetics Metabolism Molecular Sequence Data Mutation Enzymology Stereoisomerism Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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