Research Interests   Stereoselective Enzymatic Reactions

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Research Description

Biocatalysis uses enzymes for synthesis of drugs, chemical intermediates & biofuels. Enzymes are nature’s catalysts evolved for efficient biochemistry. Applying these enzymes to current chemical problems minimizes pollution and the use of toxic and non-selective chemical reagents.

The scientific challenge is to understand why enzymes are such selective and efficient catalysts. For example, enzymes can distinguish molecules with only subtle differences in shape, such as enantiomers (mirror-image molecules). Chemical catalysts can make such distinctions only in limited cases. This ability to distinguish enantiomers - enantioselectivity - is needed to make drugs because drugs must be enantiopure to avoid side effects. The challenge is to find or redesign enzymes that accept drug precursors, yet show high enantioselectivity. We have developed rules and computer modeling methods that allow chemists to choose enzymes. In addition, we used directed evolution methods to modify existing enzymes (lipases and esterases) for higher enantioselectivity.

Another scientific challenge is getting enzymes to catalyze new chemical reactions, that is reactions needed for synthesis, but not available in natural biochemistry. Designing a completely new enzyme is still impossible, so we adapt existing enzymes using several strategies. One way is to find additional reactions that an existing enzyme can catalyze (catalytic promiscuity). For example, esterases catalyze hydrolysis, but many can also catalyze perhydrolysis to make peroxycarboxylic acids, useful reagents for synthesis and removal of lignin from biomass. Another way to find additional reactions is to replace the catalytic metal center in an enzyme with a one that catalyzes new reactions. For example, we’ve replaced the zinc in carbonic anhydrase with manganese, thus turning it into a peroxidase. A third way to find new reaction is to modify existing enzyme reaction mechanisms, for example to use enzymes in water free environments to make biodegradable polymers.

Practical results from this research are more efficient preparations of enantiopure chemical intermediates, collections of more enantioselective esterases and lipases and more efficient enzymes to make peroxycarboxylic acids.

Research may involve travel to collaborating laboratories in Greifswald, Germany or Nara, Japan. Students can join NIH Training Grants in Chemical Biology or in Biotechnology.

Q. Jing, K. Okrasa, R. J. Kazlauskas "Stereoselective hydrogenation of olefins using rhodium-substituted carbonic anhydrase – a new reductase" Chem. Eur. J., 2008, accepted.

Qing Jing, Krzysztof Okrasa, Romas J. Kazlauskas “Manganese-substituted a-carbonic anhydrase as an enantioselective peroxidase” Topics Organometall. Chem. 2008, in press.

K. Okrasa, R. J. Kazlauskas, “Manganese carbonic anhydrase as an enantioselective epoxidation of olefins with hydrogen peroxide” Chem. Eur. J. 2006, 11, 1587-1596. more...

C. K. Savile, V. P. Magloire, R. J. Kazlauskas, “Subtilisin-catalyzed resolution of N-acyl arylsulfinamides” J. Am. Chem. Soc. 2005, 127, 2104-2113. more...

S. Park, K. Morley, G. P. Horsman, M. Holmquist, K. Hult, R. J. Kazlauskas, “Focusing mutations into the P. fluorescens esterase binding site increases enantioselectivity more effectively than random mutagenesis” Chem. Biol., 2005, 12, 45-54. more...

U. T. Bornscheuer, R. J. Kazlauskas, “Catalytic promiscuity in biocatalysis: using old enzymes to form new bonds and follow new pathways” Angew. Chem. Intl. Ed. 2004, 43, 6032-6040. more...

S. Park, R. J. Kazlauskas “Biocatalysis in ionic liquids – advantages beyond green technology” Curr. Opin. Biotechnol. 2003, 14, 432-437. more...