JACS: flavin dependent oxygenase promotes the rearrangement of five membered rings of indole

Flavin dependent oxygenase is a kind of oxidoreductase, which takes flavin adenine dinucleotide or flavin mononucleotide as coenzyme It is widely involved in various biochemical reactions related to redox in various stages of life Recently, Liu Wen group and Guo Yinlong group of Shanghai Institute of organic sciences have worked together to study thiostrepton (TSR), a typical representative of thiopeptide antibiotics, and reported a case of flavin dependent oxygenase, which promotes the ring expansion and rearrangement of indole five membered ring through the stereospecific oxidation of substrate, revealing a new enzymatic mechanism of quinoline unit formation in nature The formation mechanism of quinoline units in the synthesis of TSR (source: Shanghai organic Research Institute) thiopeptide antibiotics are a kind of cyclic peptide antibiotics rich in elemental sulfur and highly modified in structure, most of which have good antibacterial activity In addition to its anti drug activity, it has also been found to have anticancer, antimalarial, anti mycoplasma and immunosuppressive activities, such as the representative member of thiostreptomycin TSR Liu Wen research group of Shanghai Institute of organic sciences has been engaged in the research on the biosynthesis mechanism and molecular transformation of thiopeptide antibiotics for a long time, and confirmed in the previous work that the modification of QA part is very important for the improvement of the biological activity and physical and chemical properties of thiopeptide antibiotics (chem Biol 2015, 22, 1002; curr Opin Biotechnology 2017) The biosynthesis of QA originated from L-tryptophan, but it is not clear how to get into quinoline ketone, the key intermediate, through the intramolecular rearrangement and ring expansion reaction Combined with biotransformation in vivo and biochemical verification in vitro, the researchers found that tsre, a flavin dependent oxygenase, can utilize O2 with reduced flavin FADH2 as a cofactor The stereospecific oxidation of 2-methylindole-3-pyruvic acid to form a highly active hydroxyl intermediate with s-configuration at C3 induced hydrolysis ring opening, cyclization and aromatization reactions including C-N bond breaking and tight coupling, which promoted the conversion of indole to quinoline unit After modification and activation, the latter was modified and activated to form a core skeleton of thiopeptide from precursor peptide Integration to form the side ring system unique to the members of TSR type bicyclic thiopeptide (chem Biol 2012, 19, 443; ACS chem Biol 2016, 11, 2673; proc Natl Acad SCI U S A 2016, 113, 14318) Zhang Fang, an associate researcher of Guo Yinlong's research group, used mass spectrometry to capture and identify the highly active intermediate produced in this unusual ring expanding rearrangement process These findings represent a new strategy for the functionalization of tryptophan and enrich the cognition of the side ring construction of TSR type dicyclothiothiopeptide The catalytic selective oxidation reaction has potential application value in organic chemical synthesis Interestingly, this indole ring expanding mechanism may be widespread in nature For example, the formation of quinine natural products, an antimalarial drug from plants, also undergoes a similar ring expanding process induced by selective oxidation Paper link: http://pubs.acs.org/doi/abs/10.1021/jacs.7b05337