Generation of complexity in fungal terpene biosynthesis: Discovery of a multifunctional cytochrome P450 in the fumagillin pathway
Date
2014
Authors
Lin, Hsiao-Ching
Tsunematsu, Yuta
Dhingra, Sourabh
Xu, Wei
Fukutomi, Manami
Chooi, Yit-Heng
Cane, David E
Calvo, Ana M
Watanabe, Kenji
Tang, Yi
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American Chemical Society
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.
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Journal of the American Chemical Society
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Journal article
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2037-12-31
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