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. 2018 Dec 26;140(51):17840-17845.
doi: 10.1021/jacs.8b10134. Epub 2018 Dec 14.

Total Enzyme Syntheses of Napyradiomycins A1 and B1

Shaun M K McKinnie  1 , Zachary D Miles  1 , Peter A Jordan  1 , Takayoshi Awakawa  1 , Henry P Pepper  2 , Lauren A M Murray  2 , Jonathan H George  2 , Bradley S Moore  1   3
Affiliations

Total Enzyme Syntheses of Napyradiomycins A1 and B1

Shaun M K McKinnie et al. J Am Chem Soc. .

Abstract

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.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Total chemical syntheses of napyradiomycin A1 and comparison with chemoenzymatic approaches described herein.
Figure 2
Figure 2
NapH4-catalyzed chloronium-mediated cyclization of the geranyl moiety of 2 to form 3.
Figure 3
Figure 3
Negative mode extracted ion chromatograms showing conversion of 1 to 4 (blue trace, 327.1 m/z) and 5 (red trace, 377.1 m/z) by NapT9 and NapH1 activities, respectively.
Figure 4
Figure 4
Chemoenzymatic strategy to the one pot, three-step formation of napyradiomycin biosynthetic intermediates from metabolic precursors.
Scheme 1
Scheme 1
Biosynthetic Pathway from 1,3,6,8-Tetrahydroxynaphthalene (1) to Napyradiomycin B1 (3)
See this image and copyright information in PMC

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