Thursday, July 30, 2009 - 9:00 AM
S129

Enzymatic Process Development Using Transaminases: Greater than 200-fold Activity Improvement Through Process and Enzyme Engineering

Rajesh Kumar1, Katarina Midelfort1, Marie Anderson2, Jeanne Chang2, Dan Gehlhaar3, Seungil Han2, Michael Karmilowicz1, Ravi Kurumbail2, Kevin McConnell3, Anil Mistry2, Van Martin1, and John Wong1. (1) Chemical Research Division-Biocatalysis Center of Emphasis, Pfizer Inc, 140 Eastern point Road, MS 4094, Groton, CT 06340, (2) Structural Biology group, Pfizer Inc, 140 Eastern point Road, Groton, CT 06340, (3) Computational Sciences Group, Pfizer Inc, 140 Eastern point Road, Groton, CT 06340

This presentation will highlight the enzymatic process development for an advanced stage compound in the Pfizer portfolio to make it viable on a commercial manufacturing scale. This was a challenging task since the activity of the wild type enzyme was barely detectable. We undertook a comprehensive enzyme engineering initiative to improve the catalytic efficiency. This included the study of model substrates, rational mutagenesis based on homologous protein structures, crystallographic studies, and bioinformatics approaches. These methods proved to be very complementary and resulted in greater than 200-fold improvement in the catalytic efficiency of the wild type enzyme.

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