Methylation of Unactivated Alkenes with Engineered Methyltransferases To Generate Non‐natural Terpenoids DOI Creative Commons
Benjamin Aberle, Daniel Kowalczyk,

Simon Massini

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(26)

Published: March 31, 2023

Abstract Terpenoids are built from isoprene building blocks and have numerous biological functions. Selective late‐stage modification of their carbon scaffold has the potential to optimize or transform activities. However, synthesis terpenoids with a non‐natural is often challenging endeavor because complexity these molecules. Herein we report identification engineering ( S )‐adenosyl‐ l ‐methionine‐dependent sterol methyltransferases for selective C ‐methylation linear terpenoids. The engineered enzyme catalyzes methylation unactivated alkenes in mono‐, sesqui‐ diterpenoids produce 11 , 16 21 derivatives. Preparative conversion product isolation reveals that this biocatalyst performs − bond formation high chemo‐ regioselectivity. alkene most likely proceeds via carbocation intermediate regioselective deprotonation. This method opens new avenues modifying general particular.

Language: Английский

Recent trends in biocatalysis DOI Creative Commons
Dong Yi, Thomas Bayer, Christoffel P. S. Badenhorst

et al.

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(14), P. 8003 - 8049

Published: Jan. 1, 2021

Technological developments enable the discovery of novel enzymes, advancement enzyme cascade designs and pathway engineering, moving biocatalysis into an era technology integration, intelligent manufacturing enzymatic total synthesis.

Language: Английский

Citations

282
Enzymatic Late‐Stage Modifications: Better Late Than Never DOI Creative Commons
Elvira Romero, Bethan S. Jones, Bethany N. Hogg

et al.

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(31), P. 16824 - 16855

Published: Jan. 16, 2021

Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means bioinformatics and enzyme engineering opens up an immense variety selective reactions. Biocatalysis especially provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven be useful direct introduction functional groups into complex scaffolds, as well rapid diversification compound libraries. Particularly important highly topical are enzyme-catalysed oxyfunctionalisations, halogenations, methylations, reductions, amide bond formations due high prevalence these motifs pharmaceuticals. This Review gives overview strengths limitations enzymatic modifications using native engineered enzymes synthesis while focusing on examples drug development.

Language: Английский

Citations

116
Methyltransferases: Functions and Applications DOI Creative Commons
Eman M. M. Abdelraheem,

Benjamin Thair,

Romina Fernández Varela

et al.

ChemBioChem, Journal Year: 2022, Volume and Issue: 23(18)

Published: June 13, 2022

In this review the current state-of-the-art of S-adenosylmethionine (SAM)-dependent methyltransferases and SAM are evaluated. Their structural classification diversity is introduced key mechanistic aspects presented which then detailed further. Then, catalytic as a target for drugs, approaches to utilise cofactor in synthesis with different supply regeneration The use analogues also described. Finally O-, N-, C- S-MTs, their synthetic applications potential compound diversification given.

Language: Английский

Citations

96
Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions DOI Creative Commons

Wenhan Ju,

Yuewen Zhao, Yi Yu

et al.

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: April 17, 2024

Mitochondria plays an essential role in regulating cellular metabolic homeostasis, proliferation/differentiation, and cell death. Mitochondrial dysfunction is implicated many age-related pathologies. Evidence supports that the of mitochondria decline mitochondrial DNA copy number negatively affect ovarian aging. However, mechanism aging still unclear. Treatment methods, including antioxidant applications, transplantation, emerging biomaterials, advanced technologies, are being used to improve function restore oocyte quality. This article reviews key evidence research updates on damage pathogenesis aging, emphasizing may accelerate lead senescence as well exploring potential methods for using mechanisms slow down

Language: Английский

Citations

16
Directed Evolution of a Halide Methyltransferase Enables Biocatalytic Synthesis of Diverse SAM Analogs DOI Creative Commons
Qingyun Tang, Christoph W. Grathwol, Aşkın S. Aslan‐Üzel

et al.

Angewandte Chemie International Edition, Journal Year: 2020, Volume and Issue: 60(3), P. 1524 - 1527

Published: Oct. 27, 2020

Abstract Biocatalytic alkylations are important reactions to obtain chemo‐, regio‐ and stereoselectively alkylated compounds. This can be achieved using S‐adenosyl‐ l ‐methionine (SAM)‐dependent methyltransferases SAM analogs. It was recently shown that a halide methyltransferase (HMT) from Chloracidobacterium thermophilum synthesize SAH methyl iodide. We developed an iodide‐based assay for the directed evolution of HMT Arabidopsis thaliana used it identify V140T variant also accept ethyl‐, propyl‐, allyl iodide produce corresponding analogs (90, 50, 70 % conversion 15 mg SAH). The AtHMT in one‐pot cascades with O ‐methyltransferases (IeOMT or COMT) achieve regioselective ethylation luteolin allylation 3,4‐dihydroxybenzaldehyde. While cascade propylation 3,4‐dihydroxybenzaldehyde gave low conversion, propyl‐SAH intermediate could confirmed by NMR spectroscopy.

Language: Английский

Citations

87
Non-Native Site-Selective Enzyme Catalysis DOI
Dibyendu Mondal, Harrison M. Snodgrass,

Christian A. Gomez

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(16), P. 10381 - 10431

Published: July 31, 2023

The ability to site-selectively modify equivalent functional groups in a molecule has the potential streamline syntheses and increase product yields by lowering step counts. Enzymes catalyze site-selective transformations throughout primary secondary metabolism, but leveraging this capability for non-native substrates reactions requires detailed understanding of limitations enzyme catalysis how these bounds can be extended protein engineering. In review, we discuss representative examples involving group manipulation C-H bond functionalization. We include illustrative native catalysis, our focus is on cases often using engineered enzymes. then use enzymes chemoenzymatic target-oriented synthesis conclude with survey tools techniques that could expand scope catalysis.

Language: Английский

Citations

24
SubTuner leverages physics-based modeling to complement AI in enzyme engineering toward non-native substrates DOI
Qianzhen Shao,

Asher C. Hollenbeak,

Yaoyukun Jiang

et al.

Chem Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 101334 - 101334

Published: March 1, 2025

Language: Английский

Citations

1
FluorinatedS‐Adenosylmethionine as a Reagent for Enzyme‐Catalyzed Fluoromethylation DOI
Jiaming Peng, Cangsong Liao, Carsten Bauer

et al.

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(52), P. 27178 - 27183

Published: Oct. 1, 2021

Strategic replacement of protons with fluorine atoms or functional groups fluorine-containing fragments has proven a powerful strategy to optimize the activity therapeutic compounds. For this reason, synthetic chemistry organofluorides been subject intense development and innovation for many years. By comparison, literature on biocatalysis still makes slim chapter. Herein we introduce S-adenosylmethionine (SAM) dependent methyltransferases as new tool production fluorinated We demonstrate ability halide form SAM (S-adenosyl-S-(fluoromethyl)-L-homocysteine) from S-adenosylhomocysteine fluoromethyliodide. Fluorinated (F-SAM) is too unstable isolation, but accepted substrate by C-, N- O-specific enzyme-catalyzed fluoromethylation small molecules.

Language: Английский

Citations

48
Synthetic Reagents for Enzyme‐Catalyzed Methylation DOI Open Access

Xiaojin Wen,

Florian Leisinger,

Viviane Leopold

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(41)

Published: Aug. 22, 2022

Late-stage methylation is a key technology in the development of pharmaceutical compounds. Methyltransferase biocatalysis may provide powerful options to insert methyl groups into complex molecules with high regio- and chemoselectivity. The challenge large-scale application methyltransferases their dependence on S-adenosylmethionine (SAM) as stoichiometric, thus exceedingly expensive co-substrate. As solution this problem, we others have explored use halides reagents for situ regeneration SAM. However, need handle volatile electrophiles, such iodide (MeI), also hamper applications at scale. more practical solution, now developed an enzyme-catalyzed process SAM toluene sulfonate. Herein, describe enzymes from thiopurine methyltransferase family that accept sulfate- sulfonate-based donors convert S-adenosylhomocysteine efficiencies rival MeI-based reactions.

Language: Английский

Citations

36
Engineering an O‐methyltransferase for the Regioselective Biosynthesis of Hesperetin Dihydrochalcone DOI Creative Commons
Andreas Kunzendorf, Bastian Zirpel, Lars Milke

et al.

ChemCatChem, Journal Year: 2023, Volume and Issue: 15(22)

Published: Aug. 21, 2023

Abstract Directed evolution of the O ‐methyltransferase ZgOMT from Zooshikella ganghwensis focusing on active site residues resulted in highly regioselective biocatalysts (regioisomeric ratios up to 99 : 1) for preparation taste hesperetin dihydrochalcone and related compounds. These newly constructed enzyme variants provide an attractive synthesis route para ‐methylation catechol scaffolds, which is challenging perform with high regioselectivity utilizing wild‐type ‐methyltransferases.

Language: Английский

Citations

17