No abstract

The naphterpins and marinones are naphthoquinone meroterpenoids with an unusual aromatic oxidation pattern that is biosynthesized from 1,3,6,8-tetrahydroxynaphthalene (THN). We propose that cryptic halogenation of THN derivatives by vanadium-dependent chloroperoxidase (VCPO) enzymes is key to this biosynthetic pathway, despite the absence of chlorine in these natural products. This speculation inspired a total synthesis to mimic the naphterpin/marinone biosynthetic pathway. In validation of this biogenetic hypothesis, two VCPOs were discovered that interconvert several of the proposed biosynthetic intermediates.

A review of the chemical diversity, biosynthesis, synthesis and biocatalysis of naphthoquinone-based meroterpenoids is presented.

The biosynthetic route to the napyradiomycin family of bacterial meroterpenoids has been fully described 32 years following their original isolation and 11 years after their gene cluster discovery. The antimicrobial and cytotoxic natural products napyradiomycins A1 and B1 are produced using three organic substrates (1,3,6,8-tetrahydroxynaphthalene, dimethylallyl pyrophosphate, and geranyl pyrophosphate), and catalysis via five enzymes: two aromatic prenyltransferases (NapT8 and T9); and three vanadium dependent haloperoxidase (VHPO) homologues (NapH1, H3, and H4). Building upon the previous characterization of NapH1, H3, and T8, we herein describe the initial (NapT9, H1) and final (NapH4) steps required for napyradiomycin construction. This remarkably streamlined biosynthesis highlights the utility of VHPO enzymology in complex natural product generation, as NapH4 efficiently performs a unique chloronium-induced terpenoid cyclization to establish two stereocenters and a new carbon−carbon bond, and dual-acting NapH1 catalyzes chlorination and etherification reactions at two distinct stages of the pathway. Moreover, we employed recombinant napyradiomycin biosynthetic enzymes to chemoenzymatically synthesize milligram quantities in one pot in 1 day. This method represents a viable enantioselective approach to produce complex halogenated metabolites, like napyradiomycin B1, that have yet to be chemically synthesized.

The atomic coordinates and structure factors for the Aspergillus fumigatus sliding clamp can be found in the RCSB Protein Data Bank (http://www.rcsb.org) under the accession code 5TUP.