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High yield microbial biosynthesis of the anticoagulant precursor 4-hydroxycoumarin (4HC)


Project TitleHigh yield microbial biosynthesis of the anticoagulant precursor 4-hydroxycoumarin (4HC)
Track Code2058
Short Description

The invention includes genetically modified strains of E. coli which were designed to express 4-hydroxycoumarins (a vitamin K antagonist) in high yields from fermentative process. 4-Hydroxycoumarin is an important fungal metabolite from the precursor coumarin, and its production leads to further fermentative production of the natural anticoagulant dicoumarol. This happens in the presence of naturally occurring formaldehyde, which allows attachment of a second 4-hydroxycoumarin molecule through the linking carbon of the formaldehyde, to the 3-position of the first 4-hydroxycoumarin molecule, to give the semi-dimer the motif of the drug class. One commercial drug in this family is warfarin. Warfarin is one of the most prescribed oral anticoagulants worldwide with a $300 million global market in 2008. Besides, acenocoumarol and phenprocoumon are commonly administered in Europe. These drugs share the 4HC core structure and can be chemically synthesized using 4HC as an immediate precursor. While 4HC and its derivatives can be prepared from petrochemicals, these routes are often associated with the formation of polluting by-products and with precursors of very variable price. In addition to pharmaceutical use, 4HC is an important precursor to compounds used in the pharmaceutical, veterinary, agricultural, chemical and cosmetic industries.


Organism: E. coli.

Target Products and Synonyms: 4-hydroxycoumarin, dicoumarol.  

Target Identifiers: CAS [1076-38-6], [66-76-2]

UGA scientists have designed and constituted of a novel biosynthetic mechanism affording the de novo biosynthesis of 4HC. Remarkably, incorporation of a single enzyme eliminated the bottleneck of the biosynthetic mechanism. Preliminary optimization via metabolic engineering demonstrated its scale-up potential, leading to efficient biosyn-thesis of 4HC and in situ semi-synthesis of warfarin. The methods described herein may also be used to produce other compounds for which 4HC is a precursor, such as the pharmaceuticals acenocoumarol, dicumarol, warfarin, phenprocoumon pesticides such as d-Con, coumatetralyl, difenacoum, and others. The pathway can be implemented in both prokaryotes and eukaryotes.

References and Intellectual Property


Tagshydroxycoumarin, coumarin, anticoagulant
Posted DateNov 14, 2017 1:03 PM


Cheryl Junker


File Name Description
2058 Yan CJ.doc None Download