A cytochrome P450 serves as an unexpected terpene cyclase during fungal meroterpenoid biosynthesis

Heng Chooi, Y.J. Hong, R.A. Cacho, D.J. Tantillo, Y. Tang

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Viridicatumtoxin (1) is a tetracycline-like fungal meroterpenoid with a unique, fused spirobicyclic ring system. Puzzlingly, no dedicated terpene cyclase is found in the gene cluster identified in Penicillium aethiopicum. Cytochrome P450 enzymes VrtE and VrtK in the vrt gene cluster were shown to catalyze C5-hydroxylation and spirobicyclic ring formation, respectively. Feeding acyclic previridicatumtoxin to Saccharomyces cerevisiae expressing VrtK confirmed that VrtK is the sole enzyme required for cyclizing the geranyl moiety. Thus, VrtK is the first example of a P450 that can catalyze terpene cyclization, most likely via initial oxidation of C17 to an allylic carbocation. Quantum chemical modeling revealed a possible new tertiary carbocation intermediate E that forms after allylic carbocation formation. Intermediate E can readily undergo concerted 1,2-alkyl shift/1,3-hydride shift, either spontaneously or further aided by VrtK, followed by C7 Friedel-Crafts alkylation to afford 1. The most likely stereochemical course of the reaction was proposed on the basis of the results of our computations. © 2013 American Chemical Society.
Original languageEnglish
Pages (from-to)16805-16808
JournalJournal of the American Chemical Society
Volume135
Issue number45
DOIs
Publication statusPublished - 2013

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Terpenes
Biosynthesis
Multigene Family
Cytochrome P-450 Enzyme System
Genes
Hydroxylation
Penicillium
Cyclization
Alkylation
Tetracycline
Hydrides
Yeast
Saccharomyces cerevisiae
Enzymes
Oxidation
viridicatumtoxin

Cite this

Chooi, Heng ; Hong, Y.J. ; Cacho, R.A. ; Tantillo, D.J. ; Tang, Y. / A cytochrome P450 serves as an unexpected terpene cyclase during fungal meroterpenoid biosynthesis. In: Journal of the American Chemical Society. 2013 ; Vol. 135, No. 45. pp. 16805-16808.
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abstract = "Viridicatumtoxin (1) is a tetracycline-like fungal meroterpenoid with a unique, fused spirobicyclic ring system. Puzzlingly, no dedicated terpene cyclase is found in the gene cluster identified in Penicillium aethiopicum. Cytochrome P450 enzymes VrtE and VrtK in the vrt gene cluster were shown to catalyze C5-hydroxylation and spirobicyclic ring formation, respectively. Feeding acyclic previridicatumtoxin to Saccharomyces cerevisiae expressing VrtK confirmed that VrtK is the sole enzyme required for cyclizing the geranyl moiety. Thus, VrtK is the first example of a P450 that can catalyze terpene cyclization, most likely via initial oxidation of C17 to an allylic carbocation. Quantum chemical modeling revealed a possible new tertiary carbocation intermediate E that forms after allylic carbocation formation. Intermediate E can readily undergo concerted 1,2-alkyl shift/1,3-hydride shift, either spontaneously or further aided by VrtK, followed by C7 Friedel-Crafts alkylation to afford 1. The most likely stereochemical course of the reaction was proposed on the basis of the results of our computations. {\circledC} 2013 American Chemical Society.",
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A cytochrome P450 serves as an unexpected terpene cyclase during fungal meroterpenoid biosynthesis. / Chooi, Heng; Hong, Y.J.; Cacho, R.A.; Tantillo, D.J.; Tang, Y.

In: Journal of the American Chemical Society, Vol. 135, No. 45, 2013, p. 16805-16808.

Research output: Contribution to journalArticle

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AU - Hong, Y.J.

AU - Cacho, R.A.

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AU - Tang, Y.

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AB - Viridicatumtoxin (1) is a tetracycline-like fungal meroterpenoid with a unique, fused spirobicyclic ring system. Puzzlingly, no dedicated terpene cyclase is found in the gene cluster identified in Penicillium aethiopicum. Cytochrome P450 enzymes VrtE and VrtK in the vrt gene cluster were shown to catalyze C5-hydroxylation and spirobicyclic ring formation, respectively. Feeding acyclic previridicatumtoxin to Saccharomyces cerevisiae expressing VrtK confirmed that VrtK is the sole enzyme required for cyclizing the geranyl moiety. Thus, VrtK is the first example of a P450 that can catalyze terpene cyclization, most likely via initial oxidation of C17 to an allylic carbocation. Quantum chemical modeling revealed a possible new tertiary carbocation intermediate E that forms after allylic carbocation formation. Intermediate E can readily undergo concerted 1,2-alkyl shift/1,3-hydride shift, either spontaneously or further aided by VrtK, followed by C7 Friedel-Crafts alkylation to afford 1. The most likely stereochemical course of the reaction was proposed on the basis of the results of our computations. © 2013 American Chemical Society.

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