Microbial biosynthesis of the anticoagulant precursor 4-hydroxycoumarin

Yuheng Lin, Xiaolin Shen, Qipeng Yuan and Yajun Yan ()
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Yuheng Lin: College of Engineering, University of Georgia
Xiaolin Shen: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology
Qipeng Yuan: State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology
Yajun Yan: BioChemical Engineering Program, College of Engineering, University of Georgia

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: Abstract 4-Hydroxycoumarin (4HC) type anticoagulants (for example, warfarin) are known to have a significant role in the treatment of thromboembolic diseases—a leading cause of patient morbidity and mortality worldwide. 4HC serves as an immediate precursor of these synthetic anticoagulants. Although 4HC was initially identified as a naturally occurring product, its biosynthesis has not been fully elucidated. Here we present the design, validation, in vitro diagnosis and optimization of an artificial biosynthetic mechanism leading to the microbial biosynthesis of 4HC. Remarkably, function-based enzyme bioprospecting leads to the identification of a characteristic FabH-like quinolone synthase from Pseudomonas aeruginosa with high efficiency on the 4HC-forming reaction, which promotes the high-level de novo biosynthesis of 4HC in Escherichia coli (~500 mg l−1 in shake flasks) and further in situ semisynthesis of warfarin. This work has the potential to be scaled-up for microbial production of 4HC and opens up the possibility of biosynthesizing diverse coumarin molecules with pharmaceutical importance.

Date: 2013
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DOI: 10.1038/ncomms3603

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