Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, USA.
Department of Chemistry, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Nat Chem. 2017 Dec;9(12):1235-1242. doi: 10.1038/nchem.2829. Epub 2017 Jul 31.
Bacterial meroterpenoids constitute an important class of natural products with diverse biological properties and therapeutic potential. The biosynthetic logic for their production is unknown and defies explanation via classical biochemical paradigms. A large subgroup of naphthoquinone-based meroterpenoids exhibits a substitution pattern of the polyketide-derived aromatic core that seemingly contradicts the established reactivity pattern of polyketide phenol nucleophiles and terpene diphosphate electrophiles. We report the discovery of a hitherto unprecedented enzyme-promoted α-hydroxyketone rearrangement catalysed by vanadium-dependent haloperoxidases to account for these discrepancies in the merochlorin and napyradiomycin class of meroterpenoid antibiotics, and we demonstrate that the α-hydroxyketone rearrangement is potentially a conserved biosynthetic reaction in this molecular class. The biosynthetic α-hydroxyketone rearrangement was applied in a concise total synthesis of naphthomevalin, a prominent member of the napyradiomycin meroterpenes, and sheds further light on the mechanism of this unifying enzymatic transformation.
细菌混合萜类化合物是一类具有多种生物特性和治疗潜力的重要天然产物。它们的生物合成逻辑尚不清楚，也无法用经典的生化范例来解释。一类大型的萘醌类混合萜类化合物表现出聚酮衍生芳香核的取代模式，这似乎与聚酮酚亲核试剂和萜二磷酸亲电试剂的既定反应模式相矛盾。我们报告了一种迄今为止尚未被发现的酶促α-羟基酮重排反应的发现，这种反应由钒依赖性卤过氧化物酶催化，用于解释梅罗氯林和萘拉霉素类混合萜类抗生素中的这些差异，并且我们证明了α-羟基酮重排反应在这个分子类别中是一种潜在的保守生物合成反应。该生物合成的α-羟基酮重排反应被应用于萘甲羟戊酸的简洁全合成中，萘甲羟戊酸是萘拉霉素混合萜类化合物中的一个重要成员，这进一步阐明了这种统一酶促转化的机制。
