Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 4426-4436 |
| Journal | Journal of the American Chemical Society |
| Volume | 136 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2014 |
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Generation of complexity in fungal terpene biosynthesis: Discovery of a multifunctional cytochrome P450 in the fumagillin pathway. / Lin, H.C.; Tsunematsu, Y.; Dhingra, S.; Xu, W.; Fukutomi, M.; Chooi, Heng; Cane, D.E.; Calvo, A.M.; Watanabe, K.; Tang, Y.
In: Journal of the American Chemical Society, Vol. 136, No. 11, 2014, p. 4426-4436.Research output: Contribution to journal › Article
TY - JOUR
T1 - Generation of complexity in fungal terpene biosynthesis: Discovery of a multifunctional cytochrome P450 in the fumagillin pathway
AU - Lin, H.C.
AU - Tsunematsu, Y.
AU - Dhingra, S.
AU - Xu, W.
AU - Fukutomi, M.
AU - Chooi, Heng
AU - Cane, D.E.
AU - Calvo, A.M.
AU - Watanabe, K.
AU - Tang, Y.
PY - 2014
Y1 - 2014
N2 - 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. © 2014 American Chemical Society.
AB - 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. © 2014 American Chemical Society.
U2 - 10.1021/ja500881e
DO - 10.1021/ja500881e
M3 - Article
VL - 136
SP - 4426
EP - 4436
JO - Journal of the Amercian Chemical Society
JF - Journal of the Amercian Chemical Society
SN - 0002-7863
IS - 11
ER -