Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway

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• 作者：Hsiao-Ching Lin ; Yuta Tsunematsu ; Sourabh Dhingra ; Wei Xu ; Manami Fukutomi ; Yit-Heng Chooi ; David E. Cane ; Ana M. Calvo ; Kenji Watanabe ; Yi Tang
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：March 19, 2014
• 年：2014
• 卷：136
• 期：11
• 页码：4426-4436
• 全文大小：656K
• 年卷期：v.136,no.11(March 19, 2014)
• ISSN：1520-5126

文摘

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 尾-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.