7enb

Structural highlights

Function

NVFI_ASPN1 Fe(II)/2-oxoglutarate-dependent dioxygenase; part of the gene cluster that mediates the biosynthesis of novofumigatonin, a heavily oxygenated meroterpenoid containing a unique orthoester moiety (PubMed:29968715). The first step of the pathway is the synthesis of 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase nvfA via condensation of one acetyl-CoA starter unit with 3 malonyl-CoA units and 2 methylations (PubMed:29968715). DMOA is then converted to farnesyl-DMOA by the farnesyltransferase nvfB (PubMed:29968715). Epoxydation by FAD-dependent monooxygenase nvfK, followed by a protonation-initiated cyclization catalyzed by the terpene cyclase nvfL leads to the production of asnavolin H (PubMed:29968715). The short chain dehydrogenase nvfC then as a 3-OH dehydrogenase of asnovolin H to yield chemesin D (PubMed:29968715). There are two branches to synthesize asnovolin A from chemesin D (PubMed:29968715). In one branch, chemesin D undergoes Baeyer-Villiger oxidation by nvfH, methylation by nvfJ, and enoyl reduction by the nvfM D enoylreductase that reduces the double bond between C-5'and C-6', to form respectively asnovolin I, asnovolin K, and asnovolin A (PubMed:29968715). In the other branch, the methylation precedes the Baeyer-Villiger oxidation and the enoyl reduction to yield asnovolin A via the asnovolin J intermediate (PubMed:29968715). Asnovolin A is further converted to fumigatonoid A by the Fe(II)/2-oxoglutarate-dependent dioxygenase nvfI that catalyzes an endoperoxidation reaction (PubMed:29968715). The alpha/beta hydrolase nvfD then acts as an epimerase that converts fumigatonoid A to its C-5' epimer, which then undergoes spontaneous or nvfD-catalyzed lactonization (PubMed:29968715). The following step utilizes the ketoreductase nvfG to produce fumigatonoid B (PubMed:29968715). The dioxygenase nvfE further converts fumigatonoid B into fumigatonoid C (PubMed:29968715). Finally the Fe(II)/2-oxoglutarate-dependent dioxygenase nvfF catalyzes two rounds of oxidation to transform fumigatonoid C into the end product, novofumigatonin A (PubMed:29968715).^[1]

References

1. ↑ Matsuda Y, Bai T, Phippen CBW, Nødvig CS, Kjærbølling I, Vesth TC, Andersen MR, Mortensen UH, Gotfredsen CH, Abe I, Larsen TO. Novofumigatonin biosynthesis involves a non-heme iron-dependent endoperoxide isomerase for orthoester formation. Nat Commun. 2018 Jul 3;9(1):2587. PMID:29968715 doi:10.1038/s41467-018-04983-2
2. ↑ Mori T, Zhai R, Ushimaru R, Matsuda Y, Abe I. Molecular insights into the endoperoxide formation by Fe(II)/alpha-KG-dependent oxygenase NvfI. Nat Commun. 2021 Jul 20;12(1):4417. doi: 10.1038/s41467-021-24685-6. PMID:34285212 doi:http://dx.doi.org/10.1038/s41467-021-24685-6