Details:

Alternative Title:
J Am Chem Soc
Publisher's site:
http://dx.doi.org/10.1021/ja500881e
Personal Author:
Lin, Hsiao-Ching; Tsunematsu, Yuta; Dhingra, Sourabh; Xu, Wei; Fukutomi, Manami; ... More +
Lin, Hsiao-Ching; Tsunematsu, Yuta; Dhingra, Sourabh; Xu, Wei; Fukutomi, Manami; Chooi, Yit-Heng; Cane, David E.; Calvo, Ana M.; Watanabe, Kenji; Tang, Yi; Less -
Description:
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.
Subject:
[+]
Article
Aspergillus Fumigatus
Cyclohexanes
Cytochrome P-450 Enzyme System
Fatty Acids, Unsaturated
Molecular Structure
Sesquiterpenes
Terpenes

Source:
J Am Chem Soc. 2014; 136(11):4426-4436.;
Pubmed ID:
24568283
Pubmed Central ID:
PMC3985917
Document Type:
Journal Article;
Funding:
1DP1GM106413/DP/NCCDPHP CDC HHS/United States; 1R01GM085128/GM/NIGMS NIH HHS/United States; 5R01GM030301/GM/NIGMS NIH HHS/United States; DP1 GM106413/GM/NIGMS NIH HHS/United States; R01 GM030301/GM/NIGMS NIH HHS/United States; ... More +
1DP1GM106413/DP/NCCDPHP CDC HHS/United States; 1R01GM085128/GM/NIGMS NIH HHS/United States; 5R01GM030301/GM/NIGMS NIH HHS/United States; DP1 GM106413/GM/NIGMS NIH HHS/United States; R01 GM030301/GM/NIGMS NIH HHS/United States; R01 GM085128/GM/NIGMS NIH HHS/United States; Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:466ab029e5d2bac0d1c9511392d24e63d1c36b23d9931442a8280e5aaf2d8078
File Type:

Supporting Files

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