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

Lin, Hsiao-Ching; Tsunematsu, Yuta; Dhingra, Sourabh; Xu, Wei; Fukutomi, Manami; Chooi, Yit-Heng; Cane, David
E.; Calvo, Ana M.; Watanabe, Kenji; Tang, Yi

doi:10.1021/ja500881e

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

Published Date:

Mar 11 2014

Publisher's site:

http://dx.doi.org/10.1021/ja500881e New Site Icon

Source:

J Am Chem Soc. 2014; 136(11):4426-4436.

[PDF-2.02 MB]

Details:

Personal Authors:

Lin, Hsiao-Ching ; Tsunematsu, Yuta ; Dhingra, Sourabh ; Xu, Wei ; Fukutomi, Manami ; ... More ▼

Keywords:

[+]

Pubmed ID:

24568283

Pubmed Central ID:

PMC3985917

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.

Document Type:

Journal Article

Collection(s):

CDC Public Access

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
R01 GM085128/GM/NIGMS NIH HHS/United States

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