Organohalogen moieties occur frequently in pharmaceuticals and agrochemical products as halogen insertion can improve compound properties, including bioactivity. However, traditional synthetic halogenation methods are complicated by a lack of specificity and regioselectivity and/or require toxic and environmental-harmful halogen sources. Therefore, methods for the facile, selective, and environmental-friendly installation of halogen-substituents are required. This project addresses this demand: It aims at identifying, characterizing, and utilizing novel halogenase enzymes from secondary metabolism of algae, that way introducing a novel strategy for exploiting natural resources towards halogenating enzymes and leading to the development of novel synthetic methods for the creation of new compounds with enhanced functions. This aim is directly linked to three FocusLabs in that the novel halogenases identified here will expand the toolbox of halogenases to be generated in CombiCom, and the halogenases will be applied in the synthesis of halogenated pyrazolidine-diones for greenRelease, a novel class of selective C4 plant herbicides for application in plant health and sustainable agriculture, and will be utilized for the metabolic stabilization of pharmaceutically relevant metaraminol-derived tetrahydroisochinolines within HyImPact.
The proposed project will identify, characterize, and utilize novel halogenase enzymes from secondary metabolism of macroalgae and, hence, aims at an improved understanding of biological routes towards halogenation, that way leading to the development of novel synthetic methods for the creation of new compounds with enhanced functions. Thus, the project addresses a central element and priority field of the National Research Strategy BioEconomy 2030. Furthermore, it meets our responsibility for providing innovations that foster the efficient and careful use of biological resources, protect our environment, and enhance the supply of raw materials as well as high-value chemicals.
Our research team possesses a broad interdisciplinary expertise, which allows generating an integrated pipeline “from gene to enzyme to synthesis to active compound”. Hallmarks of the interdisciplinary expertise include methods to assemble and analyze complex genomes and to screen gigabytes of sequence data for relevant enzyme candidates, the ability to predict enzyme structures, characterize active sites and enzyme/substrate complexes in a rational, structure-based manner, and to utilize biocatalysts in the synthesis of active agent libraries.
Together with a library of already successfully identified and characterized halogenases identified in the FocusLab CombiCom, this provides an excellent basis to achieve the project’s key objective. This set of advantages is unique with respect to other national and international approaches on the development of halogenase enzymes for use in synthesis. The topic of the HaloEnz project is highly relevant for three FocusLabs, which will be directly addressed by this proposal: In CombiCom, halogenation of prodigionines is a central aspect to diversify the compound class’ bioactivities. In greenRelease, microgel-based formulations for application in plant health and sustainable agriculture will be developed, which will be loaded with inhibitors of C4 photosynthesis. Recently, a novel class of selective C4 plant herbicides has been identified by one of us, the key structural element of which is a bromo-phenyl-pyrazolidinedione core. In HyImPact, the focus is on the production of the high-value pharmaceutical metaraminol, a halogenated tetrahydroisoquinoline. A success of our integrated approach to introduce a strategy for exploiting natural resources towards halogenating specific substrates will place the Bioeconomy Science Center (BioSC) in an elevated position to provide an essential solution for an efficient and careful use of biological resources and an enhanced supply of halogenated high-value chemicals.
Prof. Dr. Holger Gohlke
Computational Pharmaceutical Chemistry and Molecular Bioinformatics
Heinrich Heine University Düsseldorf
phone: +49 211 8113662
Prof. Dr. Jörg Pietruszka & Dr. Thomas Classen, Bioorganic Chemistry, Heinrich Heine University Düsseldorf
Prof. Dr. Björn Usadel, Botany and Molecular Genetics, RWTH Aachen University
01.09.2019 - 31.08.2021
The total budget of HaloEnz is 336,340 €. HaloEnz is is part of the NRW-Strategieprojekt BioSC and thus funded by the Ministry of Culture and Science of the German State of North Rhine-Westphalia.