N‐Heterocyclization in Gliotoxin Biosynthesis is Catalyzed by a Distinct Cytochrome P450 Monooxygenase. (5th October 2020) - Scharf, Daniel H.
Abstract: Gliotoxin and related epidithiodiketopiperazines (ETP) from diverse fungi feature highly functionalized hydroindole scaffolds with an array of medicinally and ecologically relevant activities. Mutation analysis, heterologous reconstitution, and biotransformation experiments revealed that a cytochrome P450 monooxygenase (GliF) from the human‐pathogenic fungus Aspergillus fumigatus plays a key role in the formation of the complex heterocycle. In vitro assays using a biosynthetic precursor from a blocked mutant showed that GliF is specific to ETPs and catalyzes an unprecedented heterocyclization reaction that cannot be emulated with current synthetic methods. In silico analyses indicate that this rare biotransformation takes place in related ETP biosynthetic pathways. Abstract : Odd skills : Mutational analysis, in silico studies, and in vitro reconstitution revealed that GliF from A. fumigatus is a novel cytochrome P450 monooxygenase catalyzing an unprecedented N‐heterocyclization reaction to form the hydroindole ring scaffold of the important virulence factor gliotoxin.