Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

Tantillo, Dean J.

doi:10.1002/wcms.1453

Cited by 11 publications

(6 citation statements)

References 62 publications

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“…Likewise, gas phase calculations of the carbocation rearrangements required for miltiradiene formation suggest that ∼50% of trajectories should lead to a rearranged product not observed in miltiradiene synthase. These examples and others suggest that TSs intervene to achieve a specificity far greater than intrinsic reactivity alone. − …”

Section: Catalytic Motifs In Terpene Synthasesmentioning

confidence: 96%

Decoding Catalysis by Terpene Synthases

Whitehead,

Leferink,

Johannissen

et al. 2023

ACS Catal.

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The review by Christianson, published in 2017 on the twentieth anniversary of the emergence of the field, summarizes the foundational discoveries and key advances in terpene synthase/cyclase (TS) biocatalysis (Christianson, D. W. Chem Rev 2017, 117 (17), 11570–11648. DOI: 10.1021/acs.chemrev.7b00287). Here, we review the TS literature published since then, bringing the field up to date and looking forward to what could be the near future of TS rational design. Many revealing discoveries have been made in recent years, building on the knowledge and fundamental principles uncovered during those initial two decades of study. We use these to explore TS reaction chemistry and see how a combined experimental and computational approach helps to decipher the complexities of TS catalysis. Revealed are a suite of catalytic motifs which control product outcome in TSs, some obvious, some more subtle. We examine each in detail, using the most recent papers and insights to illustrate how exactly this fascinating class of enzymes takes a single acyclic substrate and turns it into the many thousands of complex terpenoids found in Nature. We then explore some of the recent strategies for TS engineering, including machine learning and other data-driven approaches. From this, rational and predictive engineering of TSs, “designer terpene synthases”, will begin to emerge as a realistic goal.

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Section: Catalytic Motifs In Terpene Synthasesmentioning

confidence: 96%

Decoding Catalysis by Terpene Synthases

Whitehead,

Leferink,

Johannissen

et al. 2023

ACS Catal.

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“…This provided the free energy of distinct carbocation intermediates and transition states along the proposed reaction path leading to products in the gas phase. The gas phase is a natural choice as a reference environment for terpene synthases [10][11][12]15,16,[21][22][23][24][25]. The proposed reaction mechanisms yielding HP and IE and are presented in Scheme 1, while the reaction free energy profile is presented in Figure 2.…”

Section: Reaction Mechanismmentioning

confidence: 99%

“…In the current work, we focus on the mechanistic details of the HP and IE pathways using computational methods in the gas phase. Gas-phase studies have been crucial in understanding terpene chemistry [10][11][12][13][14][15][16][17][18][19][20][21][22]. This work sheds light on the thermodynamic and kinetic parameters of the inherent chemistry in these reactions and also points to some understanding of the possible thermodynamic and kinetic control in the enzyme.…”

Section: Introductionmentioning

confidence: 95%

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

Zev¹,

Ringel²,

Driller³

et al. 2022

Beilstein J. Org. Chem.

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Terpene synthases are responsible for the biosynthesis of terpenes, the largest family of natural products. Hydropyrene synthase generates hydropyrene and hydropyrenol as its main products along with two byproducts, isoelisabethatrienes A and B. Fascinatingly, a single active site mutation (M75L) diverts the product distribution towards isoelisabethatrienes A and B. In the current work, we study the competing pathways leading to these products using quantum chemical calculations in the gas phase. We show that there is a great thermodynamic preference for hydropyrene and hydropyrenol formation, and hence most likely in the synthesis of the isoelisabethatriene products kinetic control is at play.

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“…Quantum chemical methods based on the calculation of accurate and reliable electronic energies are routinely used to predict and explain the outcome of chemical reactions . In particular, the N–Y reaction has been studied previously using DFT methods by Tang and Paton .…”

Section: Introductionmentioning

confidence: 99%

“…28 Quantum chemical methods based on the calculation of accurate and reliable electronic energies are routinely used to predict and explain the outcome of chemical reactions. 33 In particular, the N−Y reaction has been studied previously using DFT methods by Tang and Paton. 34 Their conclusion is that the reaction stereochemistry is determined by a very rapid diradical recombination instead of emerging from following the minimum energy path.…”

Section: ■ Introductionmentioning

confidence: 99%

Unusually Chemoselective Photocyclization of 2-(Hydroxyimino)aldehydes to Cyclobutanol Oximes: Synthetic, Stereochemical, and Mechanistic Aspects

et al. 2022

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Photocyclization of carbonyl compounds (known as the Norrish−Yang reaction) to yield cyclobutanols is, in general, accompanied by fragmentation reactions. The latter are predominant in the case of aldehydes so that secondary cyclobutanols are not considered accessible via the straightforward Norrish−Yang reaction. A noteworthy exception has been reported in our laboratory, where cyclobutanols bearing a secondary alcohol function were observed upon UV light irradiation of 2-(hydroxyimino)aldehydes (HIAs). This reaction is here investigated in detail by combining synthesis, spectroscopic data, molecular dynamics, and DFT calculations. The synthetic methodology is generally applicable to a series of HIAs, affording the corresponding cyclobutanol oximes (CBOs) chemoselectively (i.e., without sizable fragmentation side-reactions), diastereoselectively (up to >99:1), and in good to excellent yields (up to 95%). CBO oxime ether derivatives can be purified and diastereomers isolated by standard column chromatography. The mechanistic and stereochemical picture of this photocyclization reaction, as well as of the postcyclization E/Z isomerization of the oxime double bond is completed.

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Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

Cited by 11 publications

References 62 publications

Decoding Catalysis by Terpene Synthases

Decoding Catalysis by Terpene Synthases

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

Unusually Chemoselective Photocyclization of 2-(Hydroxyimino)aldehydes to Cyclobutanol Oximes: Synthetic, Stereochemical, and Mechanistic Aspects

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