9les

Structural highlights

Function

FTMF_ASPFM Verruculogen synthase; part of the gene cluster that mediates the biosynthesis of fumitremorgins, indole alkaloids that carry not only intriguing chemical structures, but also interesting biological and pharmacological activities (PubMed:19763315, PubMed:23649274). The biosynthesis of fumitremorgin-type alkaloids begins by condensation of the two amino acids L-tryptophan and L-proline to brevianamide F, catalyzed by the non-ribosomal peptide synthetase ftmA (PubMed:16755625). Brevianamide F is then prenylated by the prenyltransferase ftmPT1/ftmB in the presence of dimethylallyl diphosphate, resulting in the formation of tryprostatin B (PubMed:16000710, PubMed:21105662, PubMed:23090579). The three cytochrome P450 monooxygenases, ftmP450-1/ftmC, ftmP450-2/ftmE and ftmP450-3/FtmG, are responsible for the conversion of tryprostatin B to 6-hydroxytryprostatin B, tryprostatin A to fumitremorgin C and fumitremorgin C to 12,13-dihydroxyfumitremorgin C, respectively (PubMed:19226505). The putative methyltransferase ftmMT/ftmD is expected for the conversion of 6-hydroxytryprostatin B to tryprostatin A (Probable). FtmPT2/FtmH catalyzes the prenylation of 12,13-dihydroxyfumitre-morgin C in the presence of dimethylallyl diphosphate, resulting in the formation of fumitremorgin B (PubMed:18683158). Fumitremorgin B is further converted to verruculogen by ftmOx1/ftmF via the insertion of an endoperoxide bond between the two prenyl moieties (PubMed:19763315). In some fungal species, verruculogen is further converted to fumitremorgin A, but the enzymes involved in this step have not been identified yet (Probable).^{[1] [2] [3] [4] [5] [6] [7] [8] [9]}

References

1. ↑ Grundmann A, Li SM. Overproduction, purification and characterization of FtmPT1, a brevianamide F prenyltransferase from Aspergillus fumigatus. Microbiology. 2005 Jul;151(Pt 7):2199-207. PMID:16000710 doi:http://dx.doi.org/10.1099/mic.0.27962-0
2. ↑ Maiya S, Grundmann A, Li SM, Turner G. The fumitremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. Chembiochem. 2006 Jul;7(7):1062-9. PMID:16755625 doi:10.1002/cbic.200600003
3. ↑ Grundmann A, Kuznetsova T, Afiyatullov SSh, Li SM. FtmPT2, an N-prenyltransferase from Aspergillus fumigatus, catalyses the last step in the biosynthesis of fumitremorgin B. Chembiochem. 2008 Sep 1;9(13):2059-63. PMID:18683158 doi:10.1002/cbic.200800240
4. ↑ Kato N, Suzuki H, Takagi H, Asami Y, Kakeya H, Uramoto M, Usui T, Takahashi S, Sugimoto Y, Osada H. Identification of cytochrome P450s required for fumitremorgin biosynthesis in Aspergillus fumigatus. Chembiochem. 2009 Mar 23;10(5):920-8. PMID:19226505 doi:10.1002/cbic.200800787
5. ↑ Steffan N, Grundmann A, Afiyatullov S, Ruan H, Li SM. FtmOx1, a non-heme Fe(II) and alpha-ketoglutarate-dependent dioxygenase, catalyses the endoperoxide formation of verruculogen in Aspergillus fumigatus. Org Biomol Chem. 2009 Oct 7;7(19):4082-7. doi: 10.1039/b908392h. Epub 2009 Aug 6. PMID:19763315 doi:http://dx.doi.org/10.1039/b908392h
6. ↑ Jost M, Zocher G, Tarcz S, Matuschek M, Xie X, Li SM, Stehle T. Structure-Function Analysis of an Enzymatic Prenyl Transfer Reaction Identifies a Reaction Chamber with Modifiable Specificity. J Am Chem Soc. 2010 Nov 24. PMID:21105662 doi:10.1021/ja106817c
7. ↑ Wollinsky B, Ludwig L, Xie X, Li SM. Breaking the regioselectivity of indole prenyltransferases: identification of regular C3-prenylated hexahydropyrrolo[2,3-b]indoles as side products of the regular C2-prenyltransferase FtmPT1. Org Biomol Chem. 2012 Dec 14;10(46):9262-70. doi: 10.1039/c2ob26149a. Epub 2012, Oct 23. PMID:23090579 doi:http://dx.doi.org/10.1039/c2ob26149a
8. ↑ Kato N, Suzuki H, Okumura H, Takahashi S, Osada H. A point mutation in ftmD blocks the fumitremorgin biosynthetic pathway in Aspergillus fumigatus strain Af293. Biosci Biotechnol Biochem. 2013;77(5):1061-7. PMID:23649274 doi:10.1271/bbb.130026
9. ↑ Grundmann A, Li SM. Overproduction, purification and characterization of FtmPT1, a brevianamide F prenyltransferase from Aspergillus fumigatus. Microbiology. 2005 Jul;151(Pt 7):2199-207. PMID:16000710 doi:http://dx.doi.org/10.1099/mic.0.27962-0