6jjs

Structural highlights

Function

PHNH_PENHR Hydroalkoxylation enzyme; part of the gene cluster that mediates the biosynthesis of phenalenones such as herqueinone, compounds that have been reported to treat tumors, bacterial infections and/or mycoses, and rheumatic diseases (PubMed:26978228). The non-reducing polyketide synthase phnA synthesizes the heptaketide backbone and cyclizes it into the angular, hemiketal-containing naphtho-gamma-pyrone prephenalenone. The product template (PT) domain of phnA catalyzes only the C4-C9 aldol condensation, which is unprecedented among known PT domains (PubMed:28240554, PubMed:26978228). The transformation of prephenalenone to phenalenones requires an FAD-dependent monooxygenase phnB, which catalyzes the C2 aromatic hydroxylation of prephenalenone and ring opening of the gamma-pyrone ring simultaneously (PubMed:28240554, PubMed:26978228). Subsequent intramolecular deprotonation of C3 phenolic oxygen accelerates phenalenone ring closure to yield the tricyclic phenalenone core with a C2 hydroxylation (PubMed:28240554, PubMed:26978228). The prenyltransferase phnF further catalyzes reverse C-prenylation of phenalenone by direct electrophilic substitution at C6, or possibly via first a forward O-prenylation of a neighboring phenol in phenalenone, followed by a Claisen rearrangement (PubMed:28240554). The hydroalkoxylation enzyme phnH catalyzes the 5-exo-trigcyclization via acid catalysis after the spontaneous deprotonation of 7-OH, which leads to the formation of the dihydrobenzofuran atrovenetin (PubMed:28240554). Atrovenetin is further converted to deoxyherqueinone by the O-methyltransferase phnC which can methylate C2-OH to stabilize the northern portion of the phenalenone core (PubMed:28240554). Finally, the oxidoreductase phnG converts deoxyherqueinone to herqueinone via C6 hydroxylation (PubMed:28240554).^{[1] [2]}

References

1. ↑ Gao SS, Duan A, Xu W, Yu P, Hang L, Houk KN, Tang Y. Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase. J Am Chem Soc. 2016 Mar 30;138(12):4249-59. PMID:26978228 doi:10.1021/jacs.6b01528
2. ↑ Gao SS, Garcia-Borràs M, Barber JS, Hai Y, Duan A, Garg NK, Houk KN, Tang Y. Enzyme-Catalyzed Intramolecular Enantioselective Hydroalkoxylation. J Am Chem Soc. 2017 Mar 15;139(10):3639-3642. PMID:28240554 doi:10.1021/jacs.7b01089
3. ↑ Feng Y, Yu X, Huang JW, Liu W, Li Q, Hu Y, Yang Y, Chen Y, Jin J, Li H, Chen CC, Guo RT. Crystal structure and proposed mechanism of an enantioselective hydroalkoxylation enzyme from Penicillium herquei. Biochem Biophys Res Commun. 2019 Aug 27;516(3):801-805. doi:, 10.1016/j.bbrc.2019.06.100. Epub 2019 Jun 27. PMID:31256936 doi:http://dx.doi.org/10.1016/j.bbrc.2019.06.100