Author:
Adak Sanjoy,Ye Naike,Calderone Logan A.,Schäfer Rebecca J. B.,Lukowski April L.,Pandelia Maria-Eirini,Drennan Catherine L.,Moore Bradley S.
Abstract
AbstractNitriles are uncommon in nature and are typically constructed from oximes via the oxidative decarboxylation of amino acid substrates or from the derivatization of carboxylic acids. Here we report a third strategy of nitrile biosynthesis featuring the cyanobacterial nitrile synthase AetD. During the biosynthesis of the ‘eagle-killing’ neurotoxin, aetokthonotoxin, AetD converts the alanyl side chain of 5,7-dibromo-L-tryptophan to a nitrile. Employing a combination of structural, biochemical, and biophysical techniques, we characterized AetD as a non-heme diiron enzyme that belongs to the emergingHeme Oxygenase-likeDiironOxidase and Oxygenase (HDO) superfamily. High-resolution crystal structures of AetD together with the identification of catalytically relevant products provide mechanistic insights into how AetD affords this unique transformation that we propose proceeds via an aziridine intermediate. Our work presents a new paradigm for nitrile biogenesis and portrays a substrate binding and metallocofactor assembly mechanism that may be shared among other HDO enzymes.
Publisher
Cold Spring Harbor Laboratory
Reference41 articles.
1. Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore
2. Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies;RSC Med. Chem,2021
3. Pollak, P. , Romeder, G. , Hagedorn, F. & Gelbke, H.-P. in Ullmann’s Encyclopedia of Industrial Chemistry (2000).
4. Nitrile-containing natural products;Nat. Prod. Rep,1999
5. Isocyanides and cyanides as natural products
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献