@misc{KoenigKiebistKalmbachetal., author = {K{\"o}nig, Rosalie and Kiebist, Jan and Kalmbach, Johannes and Herzog, Robert and Schmidtke, Kai-Uwe and Kellner, Harald and Ullrich, Ren{\´e} and Jehmlich, Nico and Hofrichter, Martin and Scheibner, Katrin}, title = {Novel unspecific peroxygenase from Truncatella angustata catalyzes the synthesis of bioactive lipid mediators}, series = {Microorganisms}, volume = {10}, journal = {Microorganisms}, number = {7}, issn = {2076-2607}, doi = {10.3390/microorganisms10071267}, pages = {1 -- 18}, abstract = {Lipid mediators, such as epoxidized or hydroxylated eicosanoids (EETs, HETEs) of arachidonic acid (AA), are important signaling molecules and play diverse roles at different physiological and pathophysiological levels. The EETs and HETEs formed by the cytochrome P450 enzymes are still not fully explored, but show interesting anti-inflammatory properties, which make them attractive as potential therapeutic target or even as therapeutic agents. Conventional methods of chemical synthesis require several steps and complex separation techniques and lead only to low yields. Using the newly discovered unspecific peroxygenase TanUPO from the ascomycetous fungus Truncatella angustata, 90\% regioselective conversion of AA to 14,15-EET could be achieved. Selective conversion of AA to 18-HETE, 19-HETE as well as to 11,12-EET and 14,15-EET was also demonstrated with known peroxygenases, i.e., AaeUPO, CraUPO, MroUPO, MweUPO and CglUPO. The metabolites were confirmed by HPLC-ELSD, MS1 and MS2 spectrometry as well as by comparing their analytical data with authentic standards. Protein structure simulations of TanUPO provided insights into its substrate access channel and give an explanation for the selective oxyfunctionalization of AA. The present study expands the scope of UPOs as they can now be used for selective syntheses of AA metabolites that serve as reference material for diagnostics, for structure-function elucidation as well as for therapeutic and pharmacological purposes}, language = {en} } @incollection{KiebistHofrichterZuhseetal., author = {Kiebist, Jan and Hofrichter, Martin and Zuhse, Ralf and Scheibner, Katrin}, title = {Oxyfunctionalization of Pharmaceuticals by Fungal Peroxygenases}, series = {Pharmaceutical biocatalysis : chemoenzymatic synthesis of active pharmaceutical ingredients}, booktitle = {Pharmaceutical biocatalysis : chemoenzymatic synthesis of active pharmaceutical ingredients}, editor = {Grunwald, Peter}, edition = {1. Auflage}, publisher = {Jenny Stanford Publishing Pte. Ltd.}, address = {Singapore}, isbn = {978-981-4800-80-8}, pages = {643 -- 673}, abstract = {Throughout drug discovery and development, metabolic studies are driven by an increased interest to understand the potential for side effects and drug-drug interactions. Peroxygenases are a subclass of peroxide-dependent enzymes that catalyze the transfer of a peroxide-borne oxygen to diverse substrates. The selective oxyfunctionalization of organic molecules is one of the major challenges for the chemical community. Benzylic hydroxylation is one of the most frequently observed reactions of unspecific peroxygenases due to the activated nature of benzylic C-H bonds. The hydroxylation of aromatic rings is a common reaction in the formation of drug metabolites by P450s in mammals including humans. In the liver, P450s facilely metabolize secondary and tertiary amines as well as ethers to the corresponding dealkylated metabolites. The regio- and stereoselective direct introduction of oxygen functionalities into complex pharmaceuticals is a great challenge for organic chemists.}, language = {en} }