The protection of human health depends on the continued discovery of biologically active compounds and their development into useful pharmaceuticals. Historically, synthetic chemistry has enabled medicinal chemists to create and optimize novel lead compounds and has empowered process chemists to produce compounds at the scale necessary for the treatment of a population. The processes of drug discovery and drug production are undergoing a dramatic change with the development of efficient enzyme catalysts as practical tools for synthesis. Medicinal chemists are now harnessing the promiscuous activities of enzymes to access in a single step medicinally relevant compounds that otherwise require multiple-step chemical syntheses. Further, process chemists are starting to leverage the unrivalled efficiency and inherent sustain- ability of enzymes to replace the expensive catalysts and the toxic reagents and solvents that characterize many current production routes. As a result, enzymes are rapidly becoming important tools for pharmaceu- tical synthesis. These transformative developments are unfortunately limited by the relative dearth of useful synthetic reactions in the ?biocatalytic toolbox?. Our group has made fundamental advances to expanding this toolbox by using directed evolution to obtain new, useful biocatalysts starting from enzymes whose activities may have been low or even undetectable for the desired substrate or reaction. This proposal seeks to expand and generalize a powerful biocatalytic platform for the synthesis of chiral amines. Such compounds are prevalent as building blocks for pharmaceuticals that encompass all realms of human health such as antibacterial, antifungal, and anticancer drugs. The ability to improve upon these compounds is dependent on access to suitable building blocks. We have identified the enzyme TrpB as a unique biocatalyst for the synthesis of chiral amines. This enzyme mediates a bond-forming reaction be- tween two substrates, one nucleophilic and one electrophilic. Previous work has almost exclusively focused on the activity of this enzyme with diverse nucleophilic substrates, for which TrpB has modest promiscuity. The research proposed here, by contrast, aims to expand the electrophilic substrate scope of the enzyme to make highly functionalized ?-amino acids, as well as other classes of chiral amine such as amino alcohols and ?-amino acids. The result of this research will be a new suite of biocatalysts that can be used to syn- thesize a wide range of chiral amine building blocks for the novel medicinal compounds essential for ad- vancing the diagnosis and treatment of human diseases.

Public Health Relevance

The naturally occurring enzyme TrpB will be engineered to synthesize amino acids and chiral amines, which are ubiquitous precursors for bioactive compounds, both natural and synthetic. The results of this pro- ject will allow chemists and biologists direct access to these useful medicinal building blocks using a simple, efficient, and sustainable biocatalytic platform.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Fabian, Miles
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California Institute of Technology
Schools of Arts and Sciences
United States
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Almhjell, Patrick J; Boville, Christina E; Arnold, Frances H (2018) Engineering enzymes for noncanonical amino acid synthesis. Chem Soc Rev 47:8980-8997