Vanadium Bromoperoxidase-Catalyzed Biosynthesis of Halogenated Marine Natural Products

Abstract

Marine red algae (Rhodophyta) are a rich source of bioactive halogenated natural products. The biogenesis of the cyclic halogenated terpene marine natural products, in particular, has attracted sustained interest in part because terpenes are the biogenic precursors of many bioactive metabolites. The first enzymatic asymmetric bromination and cyclization of a terpene, producing marine natural products isolated from red algae, is reported. Vanadium bromoperoxidase (V-BrPO) isolated from marine red algae (species of Laurencia, Plocamium, Corallina) catalyzes the bromination of the sesquiterpene (E)-(+)-nerolidol producing alpha-, beta-, and gamma-snyderol and (+)-3beta-bromo-8-epicaparrapi oxide. alpha-Snyderol, beta-snyderol, and (+)-3beta-bromo-8-epicaparrapi oxide have been isolated from Laurencia obtusa, and each have also been isolated from other species of marine red algae. gamma-Snyderol is a proposed intermediate in other bicyclo natural products. Single diastereomers of beta-snyderol, gamma-snyderol, and mixed diastereomers of (+)-3beta-bromo-8-epicaparrapi oxide (de = 20-25%) are produced in the enzyme reaction, whereas two diastereomers of these compounds are formed in the synthesis with 2,4,4,6-tetrabromocyclohexa-2,5-dienone (TBCO). V-BrPO likely functions by catalyzing the two-electron oxidation of bromide ion by hydrogen peroxide producing a bromonium ion or equivalent in the active site that brominates one face of the terminal olefin of nerolidol. These results establish V-BrPO's role in the biosynthesis of brominated cyclic sesquiterpene structures from marine red algae for the first time.

Vanadium haloperoxidases: From the discovery 30 years ago to X-ray crystallographic and V K-edge absorption spectroscopic studies

“…Corallina [82]. The VBPO from Delisea pulchra produces bromofuranones, which are involved in the disruption of quorum sensing of epiphytic bacterial biofilms [80].…”

Halogenated Organic Molecules of Rhodomelaceae Origin: Chemistry and Biology

“…This report established for the first time the likely biosynthetic role of V-BrPOs in the production of brominated cyclic sesquiterpenes from marine red algae. 493 …”

Exploring the Chemistry and Biology of Vanadium-dependent Haloperoxidases

“…However, unlike the heme enzyme, there is no change in the oxidation state of the V-HPO metal center during the synthesis of the halogenating agent. Hence, V-HPOs do not suffer from oxidative inactivation during turnover and have received increasing attention as biocatalysts for pharmaceutical applications given their tolerance for organic solvents and high temperatures (12, 13), their ability to halogenate a range of organic compounds in a regio-and stereospecific manner (9,14,15), and their ability to oxidize organic sulfides in the absence of halides (16,17).The majority of naturally occurring organohalogens are of marine origin, and nearly all brominated natural products are produced by marine organisms (10). Some of the most frequently reported halometabolites are produced by marine red algae (Rhodophyceae) and include halogenated indoles, terpenes, acetylenes, phenols, and volatile hydrocarbons (9,10,15,18,19).…”