Abstract: 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. Owing to its unique chemical properties, functionalization of molecules with fluorine has allowed chemists to rationally tune the bioactivity and pharmacokinetics of small molecules and turn a lead compound into an effective treatment. However, these same chemical properties limit our ability to specifically incorporate fluorine into molecules and consequently our ability to fully exploit the potential that fluorine provides as a design element in the pipeline of drug design and discovery. Although much interest has focused on new synthetic methods to make carbon-fluorine bonds, fluorination remains a challenging chemical problem with regard to specificity and selectivity. Our group is exploring the ability of living systems to incorporate fluorine into small molecules with specificity, with the long-term goal of developing alternative synthetic biology approaches for the design and production of novel fluorinated natural products. Towards this goal, we have focused on studying Streptomyces cattleya, the only known native organofluorine-producing organism, to develop a basic picture of how living systems have evolved to manage this unique element. With a more fundamental understanding of fluorine biochemistry in hand, we can begin to expand the narrow scope of fluorine biochemistry in nature and work towards developing new methods for drug design and discovery. Public Health Relevance: Fluorinated small molecules have been tapped relatively recently as a class of compounds with great utility in treating diverse conditions in human health, such as cancer, bacterial and fungal infections, depression, allergies, and high cholesterol. Indeed over half of the top five drugs sold in the last year contain fluorine. The long-term goal of our proposed work is to expand methods used to incorporate fluorine into new small-molecule compounds using biological approaches that are complementary to more traditional chemical methods.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2OD008696-01
Application #
8146802
Study Section
Special Emphasis Panel (ZGM1-NDIA-S (01))
Program Officer
Basavappa, Ravi
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2011-09-30
Budget End
2016-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$2,302,500
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Ad, Omer; Thuronyi, Benjamin W; Chang, Michelle C Y (2017) Elucidating the mechanism of fluorinated extender unit loading for improved production of fluorine-containing polyketides. Proc Natl Acad Sci U S A 114:E660-E668
Thuronyi, Benjamin W; Chang, Michelle C Y (2015) Synthetic biology approaches to fluorinated polyketides. Acc Chem Res 48:584-92
Chang, Michelle C Y; Zhao, Huimin (2015) Editorial overview: Opportunities and challenges in synthetic biology. Curr Opin Chem Biol 28:v-vi
Walker, Mark C; Chang, Michelle C Y (2014) Natural and engineered biosynthesis of fluorinated natural products. Chem Soc Rev 43:6527-36
Weeks, Amy M; Keddie, Neil S; Wadoux, Rudy D P et al. (2014) Molecular recognition of fluorine impacts substrate selectivity in the fluoroacetyl-CoA thioesterase FlK. Biochemistry 53:2053-63
Walker, Mark C; Thuronyi, Benjamin W; Charkoudian, Louise K et al. (2013) Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways. Science 341:1089-94
Weeks, Amy M; Chang, Michelle C Y (2012) Catalytic control of enzymatic fluorine specificity. Proc Natl Acad Sci U S A 109:19667-72
Walker, Mark C; Wen, Miao; Weeks, Amy M et al. (2012) Temporal and fluoride control of secondary metabolism regulates cellular organofluorine biosynthesis. ACS Chem Biol 7:1576-85
Weeks, Amy M; Chang, Michelle C Y (2011) Constructing de novo biosynthetic pathways for chemical synthesis inside living cells. Biochemistry 50:5404-18
Weeks, Amy M; Coyle, Scott M; Jinek, Martin et al. (2010) Structural and biochemical studies of a fluoroacetyl-CoA-specific thioesterase reveal a molecular basis for fluorine selectivity. Biochemistry 49:9269-79