Expanding the scope of organofluorine biochemistry through the study of natural and engineered systems

摘要: Fluorination has become a very useful tool in the design and optimization of bioactive small molecules ranging from pesticides to pharmaceuticals. Its size allows sterically conservative substitution for hydrogen or hydroxyl, thus maintaining overall shape molecule. However, extreme electronegativity fluorine can dramatically alter other properties As result, development new methods incorporation is currently major focus synthetic chemistry. It our goal use complementary biosynthetic approach enzymes regio-selective into complex natural product scaffolds through fluoroacetate building block.Towards this goal, we initiated study only known genetic host carbon-fluorine bond forming enzyme, fluoroacetate- fluorothreonine-producing bacterium Streptomyces cattleya . Sequencing analysis genome identified several paralogs predicted be on fluorothreonine pathway whose function were probed by vitro biochemistry knock-out studies. We sought further explore how S. manages fluoroacetate, which potential block but also potent toxin that operates shutting down tricarboxylic acid (TCA) cycle. Coordinated transcriptional changes genes involved central metabolism organofluorine suggest control may serve as mechanism management toxicity. This hypothesis supported biochemical toxicity, showed they no more selective against than orthologs non-producing bacteria. To possibility incorporating fluorinated blocks products, turned type I polyketide synthases their modular assembly line nature would make them ideal candidates engineering site-selective subunits. first developed enzymatically synthesize fluoromalonyl-CoA, congener malonyl-CoA extender unit. With hand, able observe triketide polyketide. then it possible site-selectively incorporate tetraketide products. These results production products allow us medicinal chemistry these compounds using fluorination.