title: Aliphatic Halogenase Enables Late-Stage C-H Functionalization: Selective Synthesis of a Brominated Fischerindole Alkaloid with Enhanced Antibacterial Activity.
abstract: The anion promiscuity of a newly discovered standalone aliphatic halogenase WelO5 was probed and enabled the selective synthesis of 13R-bromo-12-epi-fischerindole U via late-stage enzymatic functionalization of an unactivated sp(3) C-H bond. Pre-saturating the WelO5 active site with a non-native bromide anion was found to be critical to the highly selective in vitro transfer of bromine, instead of chlorine, to the target carbon center and also allowed the relative binding affinity of bromide and chloride towards the WelO5 enzyme to be assessed. This study further revealed the critical importance of halogen substitution on modulating the antibiotic activity of fischerindole alkaloids and highlights the promise of WelO5-type aliphatic halogenases as enzymatic tools to fine-tune the bioactivity of complex natural products.
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hillwig
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh School of Medicine, 3550 Terrace St, Pittsburgh, PA, 15261, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Doi
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260, USA. xinyuliu@pitt.edu.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001966:Bromine / Q000737:chemistry*; D004798:Enzymes / Q000737:chemistry*; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry*; D013058:Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D004798:Enzymes; D026121:Indole Alkaloids; D007211:Indoles; C491991:fischerindole; D001966:Bromine
keywords: C−H activation; alkaloid biogenesis; antibiotics; halogenases; non-heme iron enzymes