Generation of complexity in fungal terpene biosynthesis: Discovery of a multifunctional cytochrome P450 in the fumagillin pathway

H.C. Lin, Y. Tsunematsu, S. Dhingra, W. Xu, M. Fukutomi, Heng Chooi, D.E. Cane, A.M. Calvo, K. Watanabe, Y. Tang

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Abstract

Fumagillin (1), a meroterpenoid from Aspergillus fumigatus, is known for its antiangiogenic activity due to binding to human methionine aminopeptidase 2. 1 has a highly oxygenated structure containing a penta-substituted cyclohexane that is generated by oxidative cleavage of the bicyclic sesquiterpene β-trans-bergamotene. The chemical nature, order, and biochemical mechanism of all the oxygenative tailoring reactions has remained enigmatic despite the identification of the biosynthetic gene cluster and the use of targeted-gene deletion experiments. Here, we report the identification and characterization of three oxygenases from the fumagillin biosynthetic pathway, including a multifunctional cytochrome P450 monooxygenase, a hydroxylating nonheme-iron-dependent dioxygenase, and an ABM family monooxygenase for oxidative cleavage of the polyketide moiety. Most significantly, the P450 monooxygenase is shown to catalyze successive hydroxylation, bicyclic ring-opening, and two epoxidations that generate the sesquiterpenoid core skeleton of 1. We also characterized a truncated polyketide synthase with a ketoreductase function that controls the configuration at C-5 of hydroxylated intermediates. © 2014 American Chemical Society.
Original languageEnglish
Pages (from-to)4426-4436
JournalJournal of the American Chemical Society
Volume136
Issue number11
DOIs
Publication statusPublished - 2014

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    Lin, H. C., Tsunematsu, Y., Dhingra, S., Xu, W., Fukutomi, M., Chooi, H., Cane, D. E., Calvo, A. M., Watanabe, K., & Tang, Y. (2014). Generation of complexity in fungal terpene biosynthesis: Discovery of a multifunctional cytochrome P450 in the fumagillin pathway. Journal of the American Chemical Society, 136(11), 4426-4436. https://doi.org/10.1021/ja500881e