Mechanistically informed predictions of binding modes for carbocation intermediates of a sesquiterpene synthase reaction

O’Brien, Terrence E.; Bertolani, Steve J.; Tantillo, Dean J.; Siegel, Justin B.

doi:10.1039/c6sc00635c

Cited by 49 publications

(63 citation statements)

References 49 publications

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“…This result may point to ( R )‐GLPP as intermediate, because PP will leave towards the front side of the projection plane of Scheme in the cyclisation to A and is thus perfectly located for the terminating abstraction of H1 R , similar to the observations made with spiroviolene synthase and tsukubadiene synthase, in which PP likely acts as base . On the other hand, for tobacco epi ‐aristolochene synthase, a specific amino acid residue (Tyr520) and not the PP anion was suggested to participate in the deprotonation step, which challenges the argumentation above. The conversion of the pure GLPP enantiomers (Scheme S2 and Figure S12 in the Supporting Information) by PcS yielded small amounts of 1 in both cases (Figure S13; the lower efficiency than for the conversion of GGPP is at least in part due to rapid decomposition of GLPP, as revealed by controls without enzyme).…”

Section: Methodssupporting

confidence: 61%

Mechanisms of the Diterpene Cyclases β‐Pinacene Synthase from Dictyostelium discoideum and Hydropyrene Synthase from Streptomyces clavuligerus

Rinkel

Rabe

Chen

et al. 2017

Chemistry A European J

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Two diterpene cyclases, one from the social amoeba Dictyostelium discoideum and the other from the bacterium Streptomyces clavuligerus, with products containing a Z-configured double bond between the original C2 and C3 of geranylgeranyl diphosphate, were extensively investigated for their mechanisms through isotopic labelling experiments. The participation of geranyllinalyl diphosphate, in analogy to the role of linalyl and nerolidyl diphosphate for mono- and sesquiterpene biosynthesis, as an intermediate towards diterpenes with a Z-configured C2=C3 double bond is discussed.

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Section: Methodssupporting

confidence: 61%

Mechanisms of the Diterpene Cyclases β‐Pinacene Synthase from Dictyostelium discoideum and Hydropyrene Synthase from Streptomyces clavuligerus

Rinkel

Rabe

Chen

et al. 2017

Chemistry A European J

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“…We note that O’Brien et al have suggested an alternative approach to docking the substrate and intermediates in terpene synthases. 17 …”

Section: Computational Detailsmentioning

confidence: 99%

Chemical Control in the Battle against Fidelity in Promiscuous Natural Product Biosynthesis: The Case of Trichodiene Synthase

et al. 2016

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Terpene cyclases catalyze the highly stereospecific molding of polyisoprenes into terpenes, which are precursors to most known natural compounds. The isoprenoids are formed via intricate chemical cascades employing rich, yet highly erratic, carbocation chemistry. It is currently not well understood how these biocatalysts achieve chemical control. Here, we illustrate the catalytic control exerted by trichodiene synthase, and in particular, we discover two features that could be general catalytic tools adopted by other terpenoid cyclases. First, to avoid formation of byproducts, the enzyme raises the energy of bisabolyl carbocation, which is a general mechanistic branching point in many sesquiterpene cyclases, resulting in an essentially concerted cyclization cascade. Second, we identify a sulfur–carbocation dative bonding interaction that anchors the bisabolyl cation in a reactive conformation, avoiding tumbling and premature deprotonation. Specifically, Met73 acts as a chameleon, shifting from an initial sulfur–π interaction in the Michaelis complex to a sulfur–carbocation complex during catalysis.

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“…Next to MD simulations, advanced docking of carbocations has recently been used to study terpene cyclases. This was applied in outstanding studies to predict the function of a novel terpene cyclase and additionally revealed a detailed all‐atom model of the full reaction pathway for the tobacco epi ‐aristolochene synthase . In contrast, our computational strategy addressed the feasibility of different substrates in remaining pre‐folded in a productive conformation which we used to explain differences in overall activities.…”

Section: Substrate Conversions and Relative Probabilities To Form Promentioning

confidence: 99%

Substrate Pre‐Folding and Water Molecule Organization Matters for Terpene Cyclase Catalyzed Conversion of Unnatural Substrates

Hammer

Syrén

Hauer³

2016

ChemistrySelect

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Terpene cyclase enzymes have recently been challenged with terpene substrate derivatives to generate additional chemical complexity beyond to what is currently found in nature. Herein, molecular dynamics and biocatalysis are used to shed light on the flexibility and inherent limitation of a triterpene cyclase in converting unnatural substrates. Our studies suggest that populating binding modes which allows for concerted reaction pathways is a key element towards an expanded substrate scope and new chemistries displayed by terpene cyclases. Additionally, we show that the spatial organization of water, which is influenced by both the substrate architecture as well as the active site geometry, controls the product selectivity. This highlights that activity and selectivity displayed by terpene cyclases acting on unnatural substrates is particularly difficult to predict, since they depend on various parameters.

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Mechanistically informed predictions of binding modes for carbocation intermediates of a sesquiterpene synthase reaction

Abstract: Predicting the binding mode of carbocations produced in sesquiterpene synthase enzymes is not unlike finding a piece of hay in a haystack. A new method for tackling this problem is described.

Cited by 49 publications

References 49 publications

Mechanisms of the Diterpene Cyclases β‐Pinacene Synthase from Dictyostelium discoideum and Hydropyrene Synthase from Streptomyces clavuligerus

Mechanisms of the Diterpene Cyclases β‐Pinacene Synthase from Dictyostelium discoideum and Hydropyrene Synthase from Streptomyces clavuligerus

Chemical Control in the Battle against Fidelity in Promiscuous Natural Product Biosynthesis: The Case of Trichodiene Synthase

Substrate Pre‐Folding and Water Molecule Organization Matters for Terpene Cyclase Catalyzed Conversion of Unnatural Substrates

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