A Mechanistic Understanding of the Distinct Regio‐ and Chemoselectivity of Multifunctional P450s by Structural Comparison of IkaD and CftA Complexed with Common Substrates

Jiang, Peng; Jin, Hongbo; Zhang, Guangtao; Zhang, Wenjun; Liu, Wei; Zhu, Yiguang; Zhang, Changsheng; Zhang, Liping

doi:10.1002/anie.202310728

Cited by 6 publications

(2 citation statements)

References 34 publications

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“…Even though P450s catalyzing two-step reactions have been reported in other studies, − the second cyclization process of BTG5 is unique, which seems a formal redox-neutral reaction, rather than the common oxidation process for P450s. To better understand this unusual cyclization process catalyzed by BTG5, several control experiments were carried out in Cercospora knocking out two PKSs (Δ CTB1 /Δ BTG4 strain).…”

Section: Resultsmentioning

confidence: 86%

“…More importantly, it reveals that the second cyclization process of BTG5 should undergo an uncommon formal redox-neutral reaction. Although several P450s have the ability to catalyze two-step reactions for the biosynthesis of NPs, − this unusual two-step mechanism of BTG5 for constructing the unique bicyclo[3.2.2]nonane structure has never been reported. Therefore, this work advances the current knowledge of P450-catalyzed reactions. − …”

Section: Introductionmentioning

confidence: 99%

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Discovery of a Fungal P450 with an Unusual Two-Step Mechanism for Constructing a Bicyclo[3.2.2]nonane Skeleton

Xu,

Yuan,

Yang

et al. 2024

J. Am. Chem. Soc.

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The successful biomimetic or chemoenzymatic synthesis of target natural products (NPs) and their derivatives relies on enzyme discovery. Herein, we discover a fungal P450 BTG5 that can catalyze the formation of a bicyclo[3.2.2]nonane structure through an unusual twostep mechanism of dimerization and cyclization in the biosynthesis of beticolin 1, whose bicyclo[3.2.2]nonane skeleton connects an anthraquinone moiety and a xanthone moiety. Further investigation reveals that BTG5-T318 not only determines the substrate selectivity but also alters the catalytic reactions, which allows the separation of the reaction to two individual steps, thereby understanding its catalytic mechanism. It reveals that the first heterodimerization undergoes the common oxidation process for P450s, while the second uncommon formal redox-neutral cyclization step is proved as a redox-mediated reaction, which has never been reported. Therefore, this work advances our understanding of P450-catalyzed reactions and paves the way for expansion of the diversity of this class of NPs through synthetic biology.

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Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Discovery of a Fungal P450 with an Unusual Two-Step Mechanism for Constructing a Bicyclo[3.2.2]nonane Skeleton

Xu,

Yuan,

Yang

et al. 2024

J. Am. Chem. Soc.

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Achieving Regioselectivity for Remote C−H Activation by Substructure Conformations: an Approach of Paralogous Cytochrome P450 Enzymes

Zhang,

Jiang,

Jin

et al. 2024

Chemistry A European J

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For advanced synthetic intermediates or natural products with multiple unactivated and energetically similar C(sp3)−H bonds, controlling regioselectivity for the C‐H activation is particularly challenging. The use of cytochrome P450 enzymes (CYPs) is a promising solution to the ‘regioelectivity’ challenge in remote C–H activation. Notably, CYPs and organic catalysts share a fundamental principle: they strive to control the distance and geometry between the metal reaction center and the target C‐H site. Most structural analyses of the regioselectivity of CYPs are limited to the active pocket, particularly when explaining why regioselectivity could be altered by enzyme engineering through mutagenesis. However, the substructures responsible for forming the active pocket in CYPs are well known to display complex dynamic changes and substrate‐induced plasticity. In this context, we highlight a comparative study of the recently reported paralogous CYPs, IkaD and CftA, which achieve different regioselectivity towards the same substrate ikarugamycin by distinct substructure conformations. We propose that substructural conformation‐controlled regioselectivity might also be present in CYPs of other natural product biosynthesis pathways, which should be considered when engineering CYPs for regioselective modifications.

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Spokewise Total Syntheses of Four Erythrina Alkaloids and Telescoped Syntheses of Six Additional Alkaloids

Hu,

Gan,

et al. 2024

J. Org. Chem.

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Based on rich sulfur-involving chemical transformations, a novel spokewise synthetic strategy, a subclass of the collective strategies, has been developed to concisely synthesize four erythrina alkaloids through a single-step transformation from a common synthetic precursor. Moreover, six additional erythrina alkaloids have also been synthesized by subsequent 1−2 steps chemical transformations. The current synthetic approaches provide a valuable platform for collective total syntheses of erythrina alkaloids and pseudo-natural erythrina alkaloids.

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A Mechanistic Understanding of the Distinct Regio‐ and Chemoselectivity of Multifunctional P450s by Structural Comparison of IkaD and CftA Complexed with Common Substrates

Cited by 6 publications

References 34 publications

Discovery of a Fungal P450 with an Unusual Two-Step Mechanism for Constructing a Bicyclo[3.2.2]nonane Skeleton

Discovery of a Fungal P450 with an Unusual Two-Step Mechanism for Constructing a Bicyclo[3.2.2]nonane Skeleton

Achieving Regioselectivity for Remote C−H Activation by Substructure Conformations: an Approach of Paralogous Cytochrome P450 Enzymes

Spokewise Total Syntheses of Four Erythrina Alkaloids and Telescoped Syntheses of Six Additional Alkaloids

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