7f11

Structural highlights

Function

NSRQ_ASPN1 Monooxygenase; part of the gene cluster that mediates the biosynthesis of the tetrahydroxanthone dimer neosartorin, which exhibits antibacterial activity (PubMed:30394754, PubMed:32105084, PubMed:33891392). The two different monomeric units appear to be synthesized by the same set of enzymes, among which the Baeyer-Villiger monooxygenase nsrF is the key enzyme for the divergence of the biosynthetic routes (PubMed:32105084). The pathway begins with the synthesis of atrochrysone thioester by the polyketide synthase nsrB (PubMed:32105084). The atrochrysone carboxyl ACP thioesterase nsrC then breaks the thioester bond and releases the atrochrysone carboxylic acid from AacuL (PubMed:32105084). Atrochrysone carboxylic acid is decarboxylated by the decarboxylase nsrE, and oxidized by the anthrone oxygenase nsrD to yield emodin (PubMed:32105084). Emodin is then reduced to emodin hydroquinone by the oxidoreductase nsrR (PubMed:32105084). A-ring reduction by the short chain dehydrogenase nsrJ, dehydration by the scytalone dehydratase-like protein nsrI and probable spontaneous re-oxidation, results in overall deoxygenation to chrysophanol (PubMed:32105084). The Baeyer-Villiger monooxygenase nsrF accepts chrysophanol as a substrate to insert one oxygen atom at two different positions to yield the precursors of both monomric units (PubMed:30394754, PubMed:32105084, PubMed:33891392). NsrF is promiscuous/flexible in interacting with the 2 (non methylated and methylated) aromatic rings of chrysophanol, thus diverging the biosynthetic pathway at this point (PubMed:30394754, PubMed:32105084, PubMed:33891392). After the hydrolysis of the lactones, methylesterification by the methyltransferase nsrG yields respectively moniliphenone and 2,2',6'-trihydroxy-4-methyl-6-methoxya-cyldiphenylmethanone (PubMed:30394754, PubMed:32105084). The next steps are the hydroxylation by the FAD-dependent monooxygenase nsrK, followed by isomerization by the monooxygenase nsrQ (PubMed:32105084). The short chain dehydrogenase/reductase nsrO then catalyzes the C-5 ketoreduction to give the xanthone skeleton of blennolide C and 5-acetylblennolide A (PubMed:32105084). The acetyltransferase nsrL has a strict substrate specificity and uses only blennolide A but not blennolide C to yield 5-acetylblennolide A as the single-acetylated product (PubMed:30394754). In the final step of the biosynthesis, the heterodimerization of the 2 xanthones, blennolide C and 5-acetylblennolide A, is catalyzed by the cytochrome P450 monooxygenase nsrP (PubMed:30394754). NsrP can utilize at least three different xanthones as its substrates to perform the dimerization reaction (PubMed:30394754).^{[1] [2] [3]}

References

1. ↑ Matsuda Y, Gotfredsen CH, Larsen TO. Genetic Characterization of Neosartorin Biosynthesis Provides Insight into Heterodimeric Natural Product Generation. Org Lett. 2018 Nov 16;20(22):7197-7200. PMID:30394754 doi:10.1021/acs.orglett.8b03123
2. ↑ Wei X, Matsuda Y. Unraveling the Fungal Strategy for Tetrahydroxanthone Biosynthesis and Diversification. Org Lett. 2020 Mar 6;22(5):1919-1923. PMID:32105084 doi:10.1021/acs.orglett.0c00285
3. ↑ Wei X, Chen X, Chen L, Yan D, Wang WG, Matsuda Y. Heterologous Biosynthesis of Tetrahydroxanthone Dimers: Determination of Key Factors for Selective or Divergent Synthesis. J Nat Prod. 2021 May 28;84(5):1544-1549. PMID:33891392 doi:10.1021/acs.jnatprod.1c00022
4. ↑ Yang J, Mori T, Wei X, Matsuda Y, Abe I. Structural Basis for Isomerization Reactions in Fungal Tetrahydroxanthone Biosynthesis and Diversification. Angew Chem Int Ed Engl. 2021 Aug 23;60(35):19458-19465. doi:, 10.1002/anie.202107884. Epub 2021 Jul 20. PMID:34180120 doi:http://dx.doi.org/10.1002/anie.202107884