i
Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway
-
Mar 11 2014
-
-
Source: J Am Chem Soc. 2014; 136(11):4426-4436.
[PDF-2.02 MB]
Details:
-
Alternative Title:J Am Chem Soc
-
Personal Author:
-
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:
-
Source:
-
Pubmed ID:24568283
-
Pubmed Central ID:PMC3985917
-
Document Type:
-
Funding:
-
Collection(s):
-
Main Document Checksum:
-
Download URL:
-
File Type:
Supporting Files
-
gif
jpeg
gif
jpeg
gif
jpeg
gif
jpeg
gif
jpeg
gif
gif
jpeg
gif
jpeg 
txt
pdf
txt
jpeg
gif
jpeg
gif
jpeg
gif
jpeg
