Synthesis of Diverse 11- and 12-Membered Macrolactones from a Common Linear Substrate Using a Single Biocatalyst

Gilbert, Michael M.; DeMars, Matthew D.; Yang, Song; Grandner, Jessica M.; Wang, Shoulei; Wang, Hengbin; Narayan, Alison R. H.; Sherman, David H.; Houk, K. N.; Montgomery, John

doi:10.1021/acscentsci.7b00450

Cited by 20 publications

(15 citation statements)

References 33 publications

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“…CYPs offer several advantages as biocatalysts. They can, for example, oxidise inert C-H bonds and they have a broad substrate scope, regio- and stereo-selectivities 3 , 4 . Some CYPs were reported to be capable of oxygenating a few monoterpene scaffolds 2 , 5 , 6 .…”

Section: Introductionmentioning

confidence: 99%

A Toolbox for Diverse Oxyfunctionalisation of Monoterpenes

Hernández-Ortega

Vinaixa

Zebec

et al. 2018

Sci Rep

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The successful implementation of synthetic biology for chemicals biosynthesis relies on the availability of large libraries of well-characterized enzymatic building blocks. Here we present a scalable pipeline that applies the methodology of synthetic biology itself to bootstrap the creation of such a library. By designing and building a cytochrome P450 enzyme collection and testing it in a custom-made untargeted GC/MS-metabolomics-based approach, we were able to rapidly create and characterize a comprehensive enzyme library for the controlled oxyfunctionalisation of terpene scaffolds with a wide range of activities and selectivities towards several monoterpenes. This novel resource can now be used to access the extensive chemical diversity of terpenoids by pathway engineering and the assembly of biocatalytic cascades to subsequently produce libraries of oxygenated terpenoids and their derivatives for diverse applications, including drug discovery.

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Section: Introductionmentioning

confidence: 99%

A Toolbox for Diverse Oxyfunctionalisation of Monoterpenes

Hernández-Ortega

Vinaixa

Zebec

et al. 2018

Sci Rep

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“…A nice demonstration was thus given at the end of last year with the diversification of macrocycles 4 – 6 . From the common intermediate 3 , 12‐ and 11‐membered products 4 and S , S ‐ 5 , as well as the latter's diastereomeric equivalent R , R ‐ 6 , were formed by endo‐ and exocyclisation, respectively.…”

Section: Examplesmentioning

confidence: 97%

“…The recent example of Gilbert et al . therefore represents an appealing template for macrocycle functionalisation using P450s . The P450 enzyme of choice was the bacterial PikC from the pikromycin pathway, which had been characterised by the Sherman group, then engineered to make it self‐sufficient by fusion to the known RhFRED reductase domain .…”

Section: Examplesmentioning

confidence: 99%

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P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation

Fessner

2019

ChemCatChem

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The biological potency of natural products has been exploited for decades. Their inherent structural complexity and natural diversity might hold the key to efficiently address the urgent need for the development of novel pharmaceuticals. At the same time, it is that very complexity, which impedes necessary chemical modifications such as structural diversification, to improve the effectiveness of the drug. For this purpose, Cytochrome P450 enzymes, which possess unique abilities to activate inert sp3‐hybridised C−H bonds in a late‐stage fashion, offer an attractive synthetic tool. In this review the potential of cytochrome P450 enzymes in chemoenzymatic lead diversification is illustrated discussing studies reporting late‐stage functionalisations of natural products and other high‐value compounds. These enzymes were proven to extend the synthetic toolbox significantly by adding to the flexibility and efficacy of synthetic strategies of natural product chemists, and scientists of other related disciplines.

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“…The x-axis captures the O heme −H distances and y-axis of O heme −H–C angles compared to that of DFT optimized transition state (in black). Adapted with permission from references Narayan et al (2015) and Gilbert et al (2017).…”

Section: Combination Of Theozymes and Molecular Dynamics Simulations mentioning

confidence: 99%

Computational Protocol to Understand P450 Mechanisms and Design of Efficient and Selective Biocatalysts

2019

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Cytochrome P450 enzymes have gained significant interest as selective oxidants in late-stage chemical synthesis. Their broad substrate scope enables them to be good candidates for their use in non-natural reactivity. Directed evolution evolves new enzyme biocatalysts that promote alternative reactivity for chemical synthesis. While directed evolution has proven useful in developing biocatalysts for specific purposes, this process is very time and labor intensive, and therefore not easily repurposed. Computational analysis of these P450 enzymes provides great insights into the broad substrate scope, the variety of reactions catalyzed, the binding specificity and the study of novel biosynthetic reaction mechanisms. By discovering new P450s and studying their reactivities, we uncover new insights into how this reactivity can be harnessed. We discuss a standard protocol using both DFT calculations and MD simulations to study a variety of cytochrome P450 enzymes. The approach entails theozyme models to study the mechanism and transition states via DFT calculations and subsequent MD simulations to understand the conformational poses and binding mechanisms within the enzyme. We discuss a few examples done in collaboration with the Tang and Sherman/Montgomery groups toward elucidating enzyme mechanisms and rationally designing new enzyme mutants as tools for selective C–H functionalization methods.

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Synthesis of Diverse 11- and 12-Membered Macrolactones from a Common Linear Substrate Using a Single Biocatalyst

Cited by 20 publications

References 33 publications

A Toolbox for Diverse Oxyfunctionalisation of Monoterpenes

A Toolbox for Diverse Oxyfunctionalisation of Monoterpenes

P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation

Computational Protocol to Understand P450 Mechanisms and Design of Efficient and Selective Biocatalysts

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