S-Adenosylmethionine: more than just a methyl donor

Natural Product Reports, Journal Year: 2023, Volume and Issue: 40(9), P. 1521 - 1549

Published: Jan. 1, 2023

This review summarizes the chemistry of S -adenosylmethionine dependent enzymes that goes beyond methylation.

Language: Английский

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Sulfenylnitrene-mediated nitrogen-atom insertion for late-stage skeletal editing of N -heterocycles

Science, Journal Year: 2025, Volume and Issue: 387(6729), P. 102 - 107

Published: Jan. 2, 2025

Given the prevalence of nitrogen-containing heterocycles in commercial drugs, selectively incorporating a single nitrogen atom is promising scaffold hopping approach to enhance chemical diversity drug discovery libraries. We harness distinct reactivity sulfenylnitrenes, which insert transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, triazines, respectively. Our additive-free method for skeletal editing employs easily accessible, benchtop-stable sulfenylnitrene precursors over broad temperature range (−30 150°C). This compatible with diverse functional groups, including oxidation-sensitive functionalities such as phenols thioethers, has been applied various natural products, amino acids, pharmaceuticals. Furthermore, we have conducted mechanistic studies explored regioselectivity outcomes through density theory calculations.

Language: Английский

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

JACS Au, Journal Year: 2024, Volume and Issue: 4(4), P. 1591 - 1604

Published: April 9, 2024

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

Language: Английский

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Recent Advances on Direct Functionalization of Indoles in Aqueous Media

The Chemical Record, Journal Year: 2023, Volume and Issue: 23(3)

Published: Feb. 1, 2023

Abstract Indoles and their derivatives have dominated a significant proportion of nitrogen‐containing heterocyclic compounds play an essential role in synthetic medicinal chemistry, pesticides, advanced materials. Compared with conventional strategies, direct functionalization indoles provides straightforward access to construct diverse indole scaffolds. As we enter era emphasizing green sustainable utilizing environment‐friendly solvents represented by water demonstrates great potential synthesizing valuable derivatives. This review aims depict the critical aspects aqueous‐mediated over past decade discusses future challenges prospects this fast‐growing field. For convenience readers, is classified into three parts according bonding modes (C−C, C−N, C−S bonds), which focus on diversity derivatives, prominent chemical process, types catalyst systems mechanisms. We hope can promote development discovery novel practical organic methods aqueous phase.

Language: Английский

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A Ferric-Superoxide Intermediate Initiates P450-Catalyzed Cyclic Dipeptide Dimerization

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(35), P. 19256 - 19264

Published: Aug. 23, 2023

The cytochrome P450 (CYP) AspB is involved in the biosynthesis of diketopiperazine (DKP) aspergilazine A. Tryptophan-linked dimeric DKP alkaloids are a large family natural products that found numerous species and exhibit broad often potent bioactivity. proposed mechanisms for C-N bond formation by AspB, similar C-C formations related CYPs, have invoked use ferryl-intermediate as an oxidant to promote substrate dimerization. Here, parallel application steady-state transient kinetic approaches reveals very different mechanism involves ferric-superoxide primary initiate DKP-assembly. Single turnover isotope effects analog suggest probable nature site abstraction. direct observation CYP-superoxide reactivity rationalizes atypical outcome new reaction manifold heme enzymes.

Language: Английский

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Efficient construction of functionalized pyrroloindolines through cascade radical cyclization/intermolecular coupling

Chemical Science, Journal Year: 2024, Volume and Issue: 15(6), P. 2205 - 2210

Published: Jan. 1, 2024

A novel tandem radical cyclization/intermolecular coupling between 2-azaallyl anions and indole N -aryloxy acetamides is developed, which enables the synthesis of C3a-substituted pyrroloindolines under mild conditions.

Language: Английский

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Selective Synthesis of Cyclopeptides with a 2-Oxindole or 3a-Hydroxy-hexahydropyrrolo-[2,3-b]indole Structure by Cytochrome P450 Enzymes

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

The structural groups of 2-oxindole and tricyclic 3a-hydroxy-hexahydropyrrolo-[2,3-b]indole (HO-HPI) are important pharmacophores. Chemical synthesis complex alkaloids containing a or HO-HPI moiety, especially the latter one, has been long-standing challenge. Herein, we characterized P450 enzyme AfnD, its homologue proteins, HmtT, ClpD, KtzM, LtzR, as cyclopeptide monooxygenases (cpOPMOs) that could introduce moiety into tryptophan-containing cyclopeptides in pH-dependent manner. A universal catalytic mechanism was proposed for five cpOPMOs, which two conserved residues, Asp Ser (Thr LtzR), were to divergently open epoxide intermediates, thereby forming moiety. Based on this, constructed ten Ser/Thr mutants synthesize with an structure, selectively, under appropriate reaction conditions. All cpOPMO exhibited high substrate promiscuities usually performed well structurally similar their native substrates. Overall, our work discovers group intriguing enzymes, provides powerful enzymatic toolkit selective HO-HPI- 2-oxindole-containing cyclopeptides.

Language: Английский

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N-Halosuccinimide enables cascade oxidative trifluorination and halogenative cyclization of tryptamine-derived isocyanides

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 16, 2024

Both the pyrroloindoline core and N-CF

Language: Английский

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Engineering the Substrate Specificity of a P450 Dimerase Enables the Collective Biosynthesis of Heterodimeric Tryptophan‐Containing Diketopiperazines

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(25)

Published: April 21, 2023

Heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are an important class of bioactive secondary metabolites. Biosynthesis offers a practical opportunity to access their structural diversity, however, it is restricted by the limited substrate scopes HTDKPs-forming P450 dimerases. Herein, genome mining and investigation sequence-product relationships, we unveiled three residues (F387, F388 E73) in these P450s that pivotal for selecting different diketopiperazine (DKP) substrates upper binding pocket. Engineering NasF5053 significantly expanded its specificity enabled collective biosynthesis, including 12 self-dimerized at least 81 cross-dimerized HTDKPs. Structural molecular dynamics analysis F387G E73S revealed they control via reducing steric hindrance regulating tunnels, respectively.

Language: Английский

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Unveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 3, 2023

Abstract The 2,5-diketopiperazines are a prominent class of bioactive molecules. nocardioazines actinomycete natural products that feature pyrroloindoline diketopiperazine scaffold composed two D-tryptophan residues functionalized by N - and C -methylation, prenylation, diannulation. Here we identify characterize the nocardioazine B biosynthetic pathway from marine Nocardiopsis sp. CMB-M0232 using heterologous biotransformations, in vitro biochemical assays, macromolecular modeling. Assembly cyclo -L-Trp-L-Trp precursor is catalyzed cyclodipeptide synthase. A separate genomic locus encodes tailoring this includes an aspartate/glutamate racemase homolog as unusual D/L isomerase acting upon substrates, phytoene synthase-like prenyltransferase catalyst indole alkaloid rare dual function methyltransferase both -methylation final steps biosynthesis. paradigms revealed herein showcase Nature’s molecular ingenuity lay foundation for diversification via biocatalytic approaches.

Language: Английский

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