Biocatalytic aminohydroxylation of styrenes for efficient synthesis of enantiopure β-amino alcohols

Hu, Ruiwen; Gong, Anjie; Liao, Liping; Zheng, Yao; Liu, Xin; Wu, Peng; Li, Fushuai; Yu, Hongbin; Zhao, Jing; Ye, Long‐Wu; Wang, Binju; Li, Aitao

doi:10.1016/s1872-2067(22)64174-3

Cited by 5 publications

(10 citation statements)

References 54 publications

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“…All positions of the P450 BM3 heme domain that have been mutated and show improvement toward aromatic epoxidation are shown (dark green spheres). Mutated positions in the heme domain (residues 1–471) and in the reductase domain (472–1049) are listed, with refs: 47 ( , , , , ), 51 ( , , , ), 58 (), 75 (), 78 ( , , , , , ), 82 ( , , ), 87 ( , , , , , , , , , ), 94 ( , ), 100 (), 107 (), 135 (), 138 ( , , ), 142 ( , ), 145 (), 171 ( , , ), 175 ( , , , , ), 178 ( , , ), 181 (), 184 ( , , , , ), 191 ( , , ), 205 ( , ), 226 ( , ), 235 (), 236 ( , , , , ), 239 ( , , , ), 252 ( , , , , ), 255 ( , , …”

Section: P450 Bm3 Variants Catalyzing Aromatic Epoxidationmentioning

confidence: 99%

“…It has been the topic of extensive research over the past three decades and numerous laboratories have worked on evolving this enzyme to generate novel enzymatic properties and features. As a result, P450 BM3 and its variants have been shown to catalyze a wide variety of reactions, including hydroxylation, − epoxidation, − carbene transfer, − and nitrene transfer, − with a diverse range of substrates. The advances reported by the group of Frances Arnold on the evolution of P450 BM3 toward novel biocatalytic reactions, which were prominently featured in her 2018 Nobel-winning research, are among the most transformative.…”

Section: Introductionmentioning

confidence: 99%

“…), 58(456), 75(20), 78(20,27,226,326,366,480), 82(27,226,298), 87(17,18,20,21,174,226,326,327,371,456), 94 (27, 226), 100 (456), 107 (456), 135 (456), 138 (326, 366, 480), 142 (27, 226), 145 (456), 171 (23, 25, 184), 175 (27, 226, 326, 366, 480), 178 (326, 366, 480), 181 (20), 184 (27, 226, 326, 366, 480), 191 (25, 27, 184), 205 (27, 226), 226 (27, 226), 235 (326), 236(27,226,326,366,480), 239(25,27,184,456), 252(27,226,326,366,480), 255(27,226,326,366,480), 259(25,27,184), 262 (20), 263(20,27,226), 264 (20), 268 (23), 274 (456), 276(25,…”

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confidence: 99%

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Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants

Fansher,

Besna,

Fendri

et al. 2024

ACS Catal.

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Cytochrome P450 BM3 monooxygenase is the topic of extensive research as many researchers have evolved this enzyme to generate a variety of products. However, the abundance of information on increasingly diversified variants of P450 BM3 that catalyze a broad array of chemistry is not in a format that enables easy extraction and interpretation. We present a database that categorizes variants by their catalyzed reactions and includes details about substrates to provide reaction context. This database of >1500 P450 BM3 variants is downloadable and machine-readable and includes instructions to maximize ease of gathering information. The database allows rapid identification of commonly reported substitutions, aiding researchers who are unfamiliar with the enzyme in identifying starting points for enzyme engineering. For those actively engaged in engineering P450 BM3, the database, along with this review, provides a powerful and user-friendly platform to understand, predict, and identify the attributes of P450 BM3 variants, encouraging the further engineering of this enzyme.

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Section: P450 Bm3 Variants Catalyzing Aromatic Epoxidationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants

Fansher,

Besna,

Fendri

et al. 2024

ACS Catal.

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“…Despite the aforementioned mechanistic insights, the molecular mechanism of the P450-catalyzed biosynthesis of DKPs is not fully elucidated, especially regarding the protein environment effects in dictating the regio- and stereoselective C–N and C–C coupling. Extensive studies have shown that the protein environment is key to the activity and selectivity of enzyme catalysis, while the neglect of such an effect in the QM model calculations may give biased descriptions of the kinetic and thermodynamic properties of enzymatic processes. ,− In this study, we reexamined the molecular mechanism of the P450 NascB with the combined MD simulations , and quantum mechanical/molecular mechanical (QM/MM) calculations. − Particularly, we systematically explored all conceivable catalytic pathways originating from two distinct binding modes of Substrate 1. Our multiscale calculations reveal that pathway B, which involves a conformational movement of the substrate radical, is the most favorable reaction pathway.…”

Section: Introductionmentioning

confidence: 99%

Substrate Conformational Switch Enables the Stereoselective Dimerization in P450 NascB: Insights from Molecular Dynamics Simulations and Quantum Mechanical/Molecular Mechanical Calculations

Zhou,

Feng,

Wang

et al. 2024

JACS Au

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P450 NascB catalyzes the coupling of cyclo-(l-tryptophan-l-proline) (1) to generate (−)-naseseazine C (2) through intramolecular C–N bond formation and intermolecular C–C coupling. A thorough understanding of its catalytic mechanism is crucial for the engineering or design of P450-catalyzed C–N dimerization reactions. By employing MD simulations, QM/MM calculations, and enhanced sampling, we assessed various mechanisms from recent works. Our study demonstrates that the most favorable pathway entails the transfer of a hydrogen atom from N7–H to Cpd I. Subsequently, there is a conformational change in the substrate radical, shifting it from the Re-face to the Si-face of N7 in Substrate 1. The Si-face conformation of Substrate 1 is stabilized by the protein environment and the π–π stacking interaction between the indole ring and heme porphyrin. The subsequent intermolecular C3–C6′ bond formation between Substrate 1 radical and Substrate 2 occurs via a radical attack mechanism. The conformational switch of the Substrate 1 radical not only lowers the barrier of the intermolecular C3–C6′ bond formation but also yields the correct stereoselectivity observed in experiments. In addition, we evaluated the reactivity of the ferric-superoxide species, showing it is not reactive enough to initiate the hydrogen atom abstraction from the indole NH group of the substrate. Our simulation provides a comprehensive mechanistic insight into how the P450 enzyme precisely controls both the intramolecular C–N cyclization and intermolecular C–C coupling. The current findings align with the available experimental data, emphasizing the pivotal role of substrate dynamics in governing P450 catalysis.

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“…Compound 3 is a potent agonist of liver receptors, and ferroptosis inhibitor 4 is used for treating multiple sclerosis . As a result, considerable attention has been directed toward the construction of various vicinal amino alcohols. − For instance, the oxyamination or aminohydroxylation of alkenes represents one of the most powerful tools. In sharp contrast, direct and diverse construction of α-hydroxyalkyl cyclic amines still remains, to date, a challenge.…”

mentioning

confidence: 99%

Room Temperature Construction of Vicinal Amino Alcohols via Electroreductive Cross-Coupling of N-Heteroarenes and Carbonyls

Wang

Zhang

et al. 2023

J. Am. Chem. Soc.

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Despite the widespread applications of α-hydroxyalkyl cyclic amines, direct and diverse access to such a class of unique vicinal amino alcohols still remains, to date, a challenge. Here, through a strategy of electroreductive α-hydroxyalkylation of inactive N-heteroarenes with ketones or electron-rich arylaldehydes, we describe a room temperature approach for the direct construction of α-hydroxyalkyl cyclic amines, which features a broad substrate scope, operational simplicity, high chemoselectivity, and no need for pressurized H 2 gas and transition metal catalysts. The zinc ion generated from anode oxidation plays a crucial role in the activation of both reactants by decreasing their reduction potentials. The strategy of electroreduction in combination with substrate activation by Lewis acids in this work is anticipated to develop more useful transformations.

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Biocatalytic aminohydroxylation of styrenes for efficient synthesis of enantiopure β-amino alcohols

Cited by 5 publications

References 54 publications

Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants

Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants

Substrate Conformational Switch Enables the Stereoselective Dimerization in P450 NascB: Insights from Molecular Dynamics Simulations and Quantum Mechanical/Molecular Mechanical Calculations

Room Temperature Construction of Vicinal Amino Alcohols via Electroreductive Cross-Coupling of N-Heteroarenes and Carbonyls

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