5wqf

Structural highlights

Function

TRT14_ASPTN Isomerase; part of the gene cluster that mediates the biosynthesis of terretonin, a fungal meroterpenoid that acts as a mycotoxin (PubMed:22549923, PubMed:23116177, PubMed:25671343). The first step of the pathway is the synthesis of 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase trt4 (PubMed:22549923, PubMed:23116177). DMOA is then prenylated into farnesyl-DMOA by the polyprenyl transferase trt2 (PubMed:22549923, PubMed:22782788, PubMed:23116177). Methylation by the methyltransferase trt5 then leads to farnesyl-DMOA methyl ester which is further subject to epoxidation by the FAD-dependent monooxygenase trt8 to yield epoxyfarnesyl-DMOA methyl ester (PubMed:22549923, PubMed:22782788, PubMed:23116177). Cyclization of epoxyfarnesyl-DMOA methyl ester by the terpene cyclase trt1 leads to a tetracycle intermediate which is in turn converted to preterretonin (PubMed:22549923, PubMed:22782788, PubMed:23116177). Dehydrogenase trt9 comes next to transform preterretonin to preterrenoid (PubMed:22549923, PubMed:23116177). The FAD-dependent monooxygenase trt3 is then required for the C-hydroxylation at C16 of preterrenoid to yield terrenoid (PubMed:22549923, PubMed:23116177). The cytochrome P450 trt6 catalyzes three successive oxidations to transform terrenoid into an unstable intermediate, which then undergoes the D-ring expansion and unusual rearrangement of the methoxy group to afford the core skeleton of terretonin (PubMed:25671343). This unprecedented rearrangement is catalyzed by the isomerase trt14 (PubMed:25671343). Finally, the nonheme iron-dependent dioxygenase trt7 accomplishes the last two oxidation reactions steps to complete the biosynthesis of terretonin (PubMed:25671343). Terretonin C is produced via spontaneous decarboxylation of the terretonin precursor (PubMed:23116177). Another shunt product of the terretonin biosynthesis is dihydrofarnesyl-DMOA, derived from epoxyfarnesyl-DMOA through hydrolysis of the epoxide (PubMed:22549923, PubMed:22782788, PubMed:23116177).^{[1] [2] [3] [4]}

References

1. ↑ Itoh T, Tokunaga K, Radhakrishnan EK, Fujii I, Abe I, Ebizuka Y, Kushiro T. Identification of a key prenyltransferase involved in biosynthesis of the most abundant fungal meroterpenoids derived from 3,5-dimethylorsellinic acid. Chembiochem. 2012 May 29;13(8):1132-5. doi: 10.1002/cbic.201200124. Epub 2012 Apr, 30. PMID:22549923 doi:http://dx.doi.org/10.1002/cbic.201200124
2. ↑ Matsuda Y, Awakawa T, Itoh T, Wakimoto T, Kushiro T, Fujii I, Ebizuka Y, Abe I. Terretonin biosynthesis requires methylation as essential step for cyclization. Chembiochem. 2012 Aug 13;13(12):1738-41. doi: 10.1002/cbic.201200369. Epub 2012, Jul 10. PMID:22782788 doi:http://dx.doi.org/10.1002/cbic.201200369
3. ↑ Guo CJ, Knox BP, Chiang YM, Lo HC, Sanchez JF, Lee KH, Oakley BR, Bruno KS, Wang CC. Molecular genetic characterization of a cluster in A. terreus for biosynthesis of the meroterpenoid terretonin. Org Lett. 2012 Nov 16;14(22):5684-7. doi: 10.1021/ol302682z. Epub 2012 Nov 1. PMID:23116177 doi:http://dx.doi.org/10.1021/ol302682z
4. ↑ Matsuda Y, Iwabuchi T, Wakimoto T, Awakawa T, Abe I. Uncovering the unusual D-ring construction in terretonin biosynthesis by collaboration of a multifunctional cytochrome P450 and a unique isomerase. J Am Chem Soc. 2015 Mar 11;137(9):3393-401. doi: 10.1021/jacs.5b00570. Epub 2015 , Feb 25. PMID:25671343 doi:http://dx.doi.org/10.1021/jacs.5b00570