Identification of Cyclopropane Formation in the Biosyntheses of Hormaomycins and Belactosins: Sequential Nitration and Cyclopropanation by Metalloenzymes. Issue 7 (27th December 2021)

• Record Type: Journal Article
• Authors: Li, Xiaojun; Shimaya, Ryo; Dairi, Tohru; Chang, Wei‐chen; Ogasawara, Yasushi
• Is Part Of: Angewandte Chemie international edition. Volume 61:Issue 7(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-27
• Subjects: Biosynthesis -- Cyclopropane -- Metalloenzymes -- Natural products -- Peptides; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202113189
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Hormaomycins and belactosins are peptide natural products that contain unusual cyclopropane moieties. Bioinformatics analysis of the corresponding biosynthetic gene clusters showed that two conserved genes, hrmI / belK and hrmJ / belL, were potential candidates for catalyzing cyclopropanation. Using in vivo and in vitro assays, the functions of HrmI/BelK and HrmJ/BelL were established. HrmI and BelK, which are heme oxygenase‐like dinuclear iron enzymes, catalyze oxidation of the ϵ‐amino group of l ‐lysine to afford l ‐6‐nitronorleucine. Subsequently, HrmJ and BelL, which are iron‐ and α‐ketoglutarate‐dependent oxygenases, effectively convert l ‐6‐nitronorleucine into 3‐( trans ‐2‐nitrocyclopropyl)‐alanine through C4−C6 bond installation. These observations disclose a novel pathway of cyclopropane ring construction and exemplify the new chemistry involving metalloenzymes in natural product biosynthesis. Abstract : The biosynthetic pathway of amino/nitro‐cyclopropylalanine moieties in hormaomycin and belactosin was fully elucidated. The pathway involves six‐electron oxidation of the ϵ‐amino group of l ‐lysine by heme oxygenase‐like dinuclear iron enzymes (HrmI/BelK) and C−C bond formation by iron‐ and α‐ketoglutarate‐dependent oxygenases (HrmJ/BelL). This is the first example of Fe/α‐KG oxygenase‐catalyzed cyclopropane formation.