Please note that these documents are being included by direct request from our administrative review process as they are marked as required by NIH Assist. These project summaries are the same as included in the Research Summary. Please disregard if not needed! Project Summaries PROJECT 1: Synthetic biology approaches to new fluorinated pharmaceuticals (1R01GM123181- 01): Fluorinated pharmaceuticals represent a rapidly expanding class of small molecule drugs that have become important in the treatment of diverse human health conditions ranging from cancer to high cholesterol. The focus of this project is to develop synthetic biology approaches to engineering enzymatic and living systems for the production of complex fluorinated compounds with bioactivity, with the long- term goal of developing new approaches to fluorinated drug discovery.
Specific aims of this proposal include: (i) elucidating the molecular mechanism of naturally-occurring fluorine selectivity in enzymes from Streptomyces cattleya, one of the few known native organofluorine-producing organisms, in order to build a knowledgebase for engineering fluorine-selective enzymes, (ii) studying the mechanism of fluorinated extender unit usage in polyketide synthases, which produce a large family of medicinally- important natural products, and (iii) developing in vitro and in vivo methods for production of fluorinated natural products in the polyketide family. PROJECT 2: Discovery and application of new halogenases (R01GM134271): The rapid and modular generation of molecular diversity is key to the search for new chemical functions. One particularly useful functional group is the halogen (X = Cl, Br, I), which enables many selective and effective downstream strategies for creating structural complexity. In this regard, halogenase enzymes have provided an important and complementary approach to synthetic catalysts for regio- and stereoselective introduction of a halogen substituent on a complex scaffold. While many families of halogenases exist, the radical halogenases provide the greatest potential for reaction diversity, as they are competent to replace unactivated C-H bonds with a halogen unlike those that operate by electrophilic or nucleophilic mechanisms. However, the substrate scope of these enzymes has been limited to date to either protein- bound substrates or large late-stage natural product intermediates. Our group has discovered a new clade of radical halogenases capable of reacting with small molecule substrates. We now seek to take advantage of this discovery to develop new tools for in vitro and in vivo synthesis.
Specific aims of this proposal include: (i) elucidating the structure and mechanism of these new radical halogenases, which will provide important insight into their engineering, (ii) investigating and engineering selectivity in halogenases.
Please note that these documents are being included by direct request from our administrative review process as they are marked as required by NIH Assist. Please disregard if not needed! Project Narratives (Public Health Relevancy Statement) PROJECT 1: Synthetic biology approaches to new fluorinated pharmaceuticals (1R01GM123181- 01): Fluorinated small molecules have become a key class of structurally diverse compounds with high effectiveness in treating a broad range of human health conditions, such as cancer, bacterial and fungal infections, depression, allergies, pain, and high cholesterol. Indeed, approximately 30% of pharmaceuticals contain a fluorine atom, including over half of the top five drugs sold in the last year. Our long-term goal is to develop new methods to discover and prepare fluorinated pharmaceuticals using biological approaches that will be complementary to existing chemical methods. PROJECT 2: Discovery and application of new halogenases (R01GM134271): The creation of new chemical diversity has long driven the discovery and development of compounds to treat a broad range of human health conditions. Our long-term goal is advance our ability to produce novel structures by working at the interface of biological and chemical catalysis. In this proposal, we seek to identify and generate new diversity in radical halogenases, which are capable of installing the particularly useful halogen handle on small molecules at unactivated positions with regio- and stereo-selectivity to enable rapid generation of new and complex small molecule targets.
| Weeks, Amy M; Wang, Ningkun; Pelton, Jeffrey G et al. (2018) Entropy drives selective fluorine recognition in the fluoroacetyl-CoA thioesterase from Streptomyces cattleya. Proc Natl Acad Sci U S A 115:E2193-E2201 |
| Thuronyi, Benjamin W; Privalsky, Thomas M; Chang, Michelle C Y (2017) Engineered Fluorine Metabolism and Fluoropolymer Production in Living Cells. Angew Chem Int Ed Engl 56:13637-13640 |
| McMurry, Jonathan L; Chang, Michelle C Y (2017) Fluorothreonyl-tRNA deacylase prevents mistranslation in the organofluorine producer Streptomyces cattleya. Proc Natl Acad Sci U S A 114:11920-11925 |
