The incorporation of halogen atoms in organic molecules plays an important role in modulating their physical properties and biological activities. While the selective chemosynthetic installation of halogens is technically challenging and frequently employs toxic reagents and byproducts, Nature has developed efficient enzymatic strategies to introduce halides into chemical scaffolds. Site-specific vanadium-dependent haloperoxidases (VHPOs) are a unique halogenase family that employ a histidine-coordinated vanadate ion and co-substrate hydrogen peroxide to oxidize aqueous halides and install them in a regio- and stereospecific manner on organic substrates. Although only ~15 microbial site-specific VHPOs have been extensively characterized, the majority have been involved in the construction of meroterpenoid antibiotics effective against Gram-positive bacterial pathogens. We have subsequently identified hundreds of novel homologs and will highlight two unique VHPOs that are under active investigation in our research lab; both halogenases putatively modulate the bioactivities of other microbially-produced small molecules. We have implicated a novel actinobacterial VHPO in the putative inactivation and macrocyclization of potent antimicrobial compound napyradiomycin A1 through a cryptic halogenation and cyclization cascade. Preliminary comparative genomic and metabolomic analyses have further supported this biosynthetic hypothesis within this marine <i>Streptomyces </i>species and we are actively pursuing rigorous <i>in vitro </i>biochemical characterization of this novel reaction. Our recent investigation into a novel VHPO from a Gram-negative myxobacterium identified that exogenous alkyl quinolone (AQ) signaling molecules serve as substrates for these halogenases. The regiospecific bromination of AQs modulate their antimicrobial activities against both AQ- and VHPO-producing microbes which raises questions into the ecological role of this enzymology in phylogenetically diverse bacterial species that possess homologous genes. Overall, we aim to improve the understanding of this unique family of halogenating enzymes within both natural product biosynthesis and microbial chemical ecology.

Expanding the biosynthetic and ecological roles of site-specific vanadium-dependent haloperoxidase enzymology

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.