Bio-compatible molecules used in the production of pharmaceuticals often require unique molecular structures that can only be readily made in pure form by the use of biological catalysts known as enzymes. The goal of the present study is to engineer a class of enzymes known as amine dehydrogenases (AmDHs) so that they can convert a common ketone into a specific compound known as a chiral amine. The resulting uniquely-structured nitrogen-containing chiral compound can potentially be used as a building block for a wide range of new pharmaceutical products through simpler and less costly routes than by conventional (non-biological) chemical synthesis. This collaboration between Georgia Tech and Armstrong State University (a predominantly undergraduate institution) will provide research opportunities for Armstrong State students while also providing teaching and learning opportunities for graduate students from Georgia Tech.
The PI recently designed three (R)-specific amine dehydrogenases (AmDHs) from the corresponding amino acid dehydrogenases (AADHs) via protein engineering. These AmDHs catalyze the reductive amination of prochiral ketones into chiral amines. The present proposal extends this line of research to create variations of the same enzymes to achieve (S)-amines synthesis. In support of this effort, the research will increase substrate specificity by broadening the ketone and co-factor binding pockets, and by tightening ammonia binding. The main tool used for these modifications is site-directed or site-saturated mutagenesis on key residues, the latter being identified by crystal structures determined by neutron scattering. The study is likely to yield results that will be of commercial significance, especially to the pharmaceutical industry for which the chiral amines are important intermediates. The reductive amination of ketones to produce chiral amines is an important transformation in the production of pharmaceutical intermediates. Therefore, industrially applicable enzymatic methods that enable the selective synthesis of chiral amines could be very useful. Exchanges in students at both the undergraduate and graduate levels between the two universities are planned. These will not only aid the research, but also provide educational and outreach opportunities at both institutions.
