Production of new bioactive compounds by plants and bacteria using new and improved halogenases

Lead Research Organisation: John Innes Centre
Department Name: Contracts Office

Abstract

Natural products produced by plants and microorganisms exhibit a wealth of agriculturally and medicinally significant activities. Over the past three decades more than 60% of anticancer agents and over 70% of antibiotics entering clinical trials were based on natural products. The introduction of a halogen into a natural product has frequently been demonstrated to improve bioactivity and bioavailability. Furthermore, the incorporation of chlorine or bromine into a natural product provides a reactive handle that may be utilised for further site-specific functionalisation. The inherent complexity of many natural products renders them and their analogues hard to access synthetically. A more expeditious approach is to harness the processes that generate them. Using flavin-dependent halogenases regioselective incorporation of halogen atoms (chloride and bromide) can be achieved. Flavin-dependent halogenases are two-component systems consisting of a flavin reductase producing FADH2 and the halogenase. The halogenase does not require a specific flavin reductase enabling the convenient possibility of using flavin reductases from different bacteria at will. The genes of flavin-dependent halogenases accepting different substrates have been cloned, over-expressed, and some of the enzymes were characterised. Using such enzymes, members of this consortium have demonstrated the suitability of tryptophan halogenases to modify biosynthetic pathways in bacteria and plants to obtain new compounds and showed that it is possible to modify the regioselectivity and substrate specificity of these enzymes. These results underpin the success of the proposed project.

Publications

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