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

i

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

Supporting Files

Mar 11 2014
By Lin, Hsiao-Ching ; Tsunematsu, Yuta ; Dhingra, Sourabh ; ...

Details

Alternative Title:

J Am Chem Soc
Personal Author:

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

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 ; R01 GM085128/GM/NIGMS NIH HHS/United States
Volume:

136
Issue:

11
Collection(s):

CDC Public Access
Main Document Checksum:

urn:sha256:466ab029e5d2bac0d1c9511392d24e63d1c36b23d9931442a8280e5aaf2d8078
Download URL:

https://stacks.cdc.gov/view/cdc/32204/cdc_32204_DS1.pdf
File Type:

[PDF - 2.02 MB ]

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