Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 136, Issue 11, Pages 4426-4436Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja500881e
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Funding
- National Science Council of Taiwan [102-2917-I-564-008]
- US National Institutes of Health [1R01GM085128, 1DP1GM106413, 5R01GM030301]
- JSPS through the Funding Program for NEXT [LS103]
- Nagase Science and Technology Foundation Japan
- Northern Illinois University
- NSF [CHE-1048804]
- Direct For Mathematical & Physical Scien [1048804] Funding Source: National Science Foundation
- Division Of Chemistry [1048804] Funding Source: National Science Foundation
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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 beta-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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