Quantitative exploration of the catalytic landscape separating divergent plant sesquiterpene synthases

Paul E. O'Maille; Arthur Malone; Nikki Dellas; B. Andes Hess; Lidia Smentek; Iseult Sheehan; Bryan T. Greenhagen; Joe Chappell; Gerard Manning; Joseph P. Noel

doi:10.1038/nchembio.113

Quantitative exploration of the catalytic landscape separating divergent plant sesquiterpene synthases

Paul E. O'Maille, Arthur Malone, Nikki Dellas, B. Andes Hess, Lidia Smentek, Iseult Sheehan, Bryan T. Greenhagen, Joe Chappell, Gerard Manning, Joseph P. Noel

Research output: Contribution to journal › Article › peer-review

165 Scopus citations

Abstract

Throughout molecular evolution, organisms create assorted chemicals in response to varying ecological niches. Catalytic landscapes underlie metabolic evolution, wherein mutational steps alter the biosynthetic properties of enzymes. Here we report the first systematic quantitative characterization of the catalytic landscape underlying the evolution of sesquiterpene chemical diversity. On the basis of our previous discovery of a set of nine naturally occurring amino acid substitutions that functionally interconverted orthologous sesquiterpene synthases from Nicotiana tabacum and Hyoscyamus muticus, we created a library of all possible residue combinations (2⁹ = 512) in the N. tabacum enzyme. The product spectra of 418 active enzymes revealed a rugged landscape where several minimal combinations of the nine mutations encode convergent solutions to the interconversions of parental activities. Quantitative comparisons indicated context dependence for mutational effects - epistasis - in product specificity and promiscuity. These results provide a measure of the mutational accessibility of phenotypic variability in a diverging lineage of terpene synthases.

Original language	English
Pages (from-to)	617-623
Number of pages	7
Journal	Nature Chemical Biology
Volume	4
Issue number	10
DOIs	https://doi.org/10.1038/nchembio.113
State	Published - Oct 2008

Bibliographical note

Funding Information:
We thank M. Austin and J. Melnick for critical review of the manuscript, Y. Zhai for computational support and J. Gullberg and A. Nordstom for insightful discussions. This work was supported by National Institutes of Health grant GM54029 to J.C. and J.P.N. J.P.N. is supported by the Howard Hughes Medical Institute.

Funding

We thank M. Austin and J. Melnick for critical review of the manuscript, Y. Zhai for computational support and J. Gullberg and A. Nordstom for insightful discussions. This work was supported by National Institutes of Health grant GM54029 to J.C. and J.P.N. J.P.N. is supported by the Howard Hughes Medical Institute.

Funders	Funder number
National Institutes of Health (NIH)
Howard Hughes Medical Institute
National Institute of General Medical Sciences	R01GM054029

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1038/nchembio.113

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abstract = "Throughout molecular evolution, organisms create assorted chemicals in response to varying ecological niches. Catalytic landscapes underlie metabolic evolution, wherein mutational steps alter the biosynthetic properties of enzymes. Here we report the first systematic quantitative characterization of the catalytic landscape underlying the evolution of sesquiterpene chemical diversity. On the basis of our previous discovery of a set of nine naturally occurring amino acid substitutions that functionally interconverted orthologous sesquiterpene synthases from Nicotiana tabacum and Hyoscyamus muticus, we created a library of all possible residue combinations (29 = 512) in the N. tabacum enzyme. The product spectra of 418 active enzymes revealed a rugged landscape where several minimal combinations of the nine mutations encode convergent solutions to the interconversions of parental activities. Quantitative comparisons indicated context dependence for mutational effects - epistasis - in product specificity and promiscuity. These results provide a measure of the mutational accessibility of phenotypic variability in a diverging lineage of terpene synthases.",

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AU - Sheehan, Iseult

AU - Greenhagen, Bryan T.

AU - Chappell, Joe

AU - Manning, Gerard

AU - Noel, Joseph P.

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Quantitative exploration of the catalytic landscape separating divergent plant sesquiterpene synthases

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