Optimized Substrate Positioning Enables Switches in the C–H Cleavage Site and Reaction Outcome in the Hydroxylation–Epoxidation Sequence Catalyzed by Hyoscyamine 6β-Hydroxylase DOI
Eliott S. Wenger, Ryan J. Martinie, Richiro Ushimaru

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(35), P. 24271 - 24287

Published: Aug. 22, 2024

Hyoscyamine 6β-hydroxylase (H6H) is an iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase that produces the prolifically administered antinausea drug, scopolamine. After its namesake hydroxylation reaction, H6H then couples newly installed C6 oxygen to C7 produce drug's epoxide functionality. Oxoiron(IV) (ferryl) intermediates initiate both reactions by cleaving C–H bonds, but it remains unclear how enzyme switches target site promotes (C6)O–C7 coupling in preference second step. In one possible epoxidation mechanism, would─analogously mechanisms proposed for Fe/2OG halogenases and, our more recent study, N-acetylnorloline synthase (LolO)─coordinate as alkoxide C7–H-cleaving ferryl intermediate enable alkoxyl ensuing radical. Here, we provide structural kinetic evidence does not employ substrate coordination or repositioning step instead exploits distinct spatial dependencies of competitive cleavage (C6 vs C7) C–O-coupling (oxygen rebound cyclization) steps promote two-step sequence. Structural comparisons ferryl-mimicking vanadyl complexes wild-type a variant preferentially 7-hydroxylates epoxidizing 6β-hydroxyhyoscyamine suggest modest (∼10°) shift Fe–O–H(C7) approach angle sufficient change outcome. The 7-hydroxylation:epoxidation partition ratios proteins increase than 5-fold 2H2O, reflecting epoxidation-specific requirement alcohol O–H bond, which, unlike LolO oxacyclization, accomplished iron advance cleavage.

Language: Английский

Biodegradation of aromatic pollutants by metalloenzymes: A structural-functional-environmental perspective DOI
Ying‐Wu Lin

Coordination Chemistry Reviews, Journal Year: 2021, Volume and Issue: 434, P. 213774 - 213774

Published: Feb. 6, 2021

Language: Английский

Citations

47
Biotransformation of Bisphenol by Human Cytochrome P450 2C9 Enzymes: A Density Functional Theory Study DOI Creative Commons
Artur Hermano Sampaio Dias, Rolly Yadav, Thirakorn Mokkawes

et al.

Inorganic Chemistry, Journal Year: 2023, Volume and Issue: 62(5), P. 2244 - 2256

Published: Jan. 18, 2023

Bisphenol A (BPA, 2,2-bis-(4-hydroxyphenyl)propane) is used as a precursor in the synthesis of polycarbonate and epoxy plastics; however, its availability environment causing toxicity an endocrine-disrupting chemical. Metabolism BPA their analogues (substitutes) generally performed by liver cytochrome P450 enzymes often leads to mixture products, some those are toxic. To understand product distributions activation BPA, we have computational study into mechanisms reactivities using large model structures human isozyme (P450 2C9) with bound. Density functional theory (DFT) calculations on compound I were investigated, leading number possible products. The substrate-binding pocket tight, consequence, aliphatic hydroxylation not feasible methyl substituents cannot reach well due constraints pocket. Instead, find low-energy pathways that initiated phenol hydrogen atom abstraction followed OH rebound phenolic ortho- or para-position. barriers para-rebound lower energy than for ortho-rebound, consequently, our 2C9 predicts dominant hydroxycumyl alcohol reactions proceed through two-state reactivity competing doublet quartet spin state surfaces. show fast efficient substrate surface rate-determining electrophilic addition step, while has multiple high-energy can also lead various side products including C4-aromatic hydroxylation. This work shows formation more low state, physicochemical properties govern barrier heights step reaction. Finally, importance second-coordination sphere highlighted determines guides bifurcation pathways.

Language: Английский

Citations

21
From random to rational: improving enzyme design through electric fields, second coordination sphere interactions, and conformational dynamics DOI Creative Commons
Shobhit S. Chaturvedi, Daniel Bím, Christo Christov

et al.

Chemical Science, Journal Year: 2023, Volume and Issue: 14(40), P. 10997 - 11011

Published: Jan. 1, 2023

A forward-looking perspective on optimizing enzyme design through synergizing electric fields, coordination spheres, and dynamics.

Language: Английский

Citations

19
Regiodivergent sp3 C–H Functionalization via Ni-Catalyzed Chain-Walking Reactions DOI Creative Commons
Jesus Rodrigalvarez, Franz‐Lucas Haut, Rubén Martı́n

et al.

JACS Au, Journal Year: 2023, Volume and Issue: 3(12), P. 3270 - 3282

Published: Nov. 28, 2023

The catalytic translocation of a metal catalyst along saturated hydrocarbon side chain constitutes powerful strategy for enabling bond-forming reactions at remote, yet previously unfunctionalized, sp3 C–H sites. In recent years, Ni-catalyzed chain-walking have offered counterintuitive strategies forging architectures that would be difficult to accomplish otherwise. Although these evolved into mature tools advanced organic synthesis, it was only recently chemists showed the ability control motion which "walks" throughout alkyl chain. Specialized ligand backbones, additives and judicious choice noninnocent functional groups on allowed design "a la carte" protocols enable regiodivergent scenarios different sites with distinct topological surface areas. Given inherent interest in increasing fraction hybridized carbons medicinal chemistry, might expedite access target leads drug discovery campaigns.

Language: Английский

Citations

17
A New Age of Biocatalysis Enabled by Generic Activation Modes DOI Creative Commons
Shubhanshu Jain, Felipe Ospina, Stephan C. Hammer

et al.

JACS Au, Journal Year: 2024, Volume and Issue: 4(6), P. 2068 - 2080

Published: May 31, 2024

Biocatalysis is currently undergoing a profound transformation. The field moves from relying on nature's chemical logic to discipline that exploits generic activation modes, allowing for novel biocatalytic reactions and, in many instances, entirely new chemistry. Generic modes enable wide range of reaction types and played pivotal role advancing the fields organo- photocatalysis. This perspective aims summarize principal harnessed enzymes develop biocatalysts. Although extensively researched past, highlighted when applied within enzyme active sites, facilitate transformations have largely eluded efficient selective catalysis. advance attributed multiple tunable interactions substrate binding pocket precisely control competing pathways transition states. We will highlight cases synthetic methodologies achieved by engineered provide insights into potential future developments this rapidly evolving field.

Language: Английский

Citations

8
Quantum Mechanical Cluster Models for Calculations on Enzymatic Reaction Mechanisms: Set‐Up and Accuracy DOI Creative Commons
Sam P. de Visser, Henrik P. H. Wong, Yi Zhang

et al.

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(60)

Published: Aug. 7, 2024

Enzymes turnover substrates into products with amazing efficiency and selectivity as such have great potential for use in biotechnology pharmaceutical applications. However, details of their catalytic cycles the origins surrounding regio- chemoselectivity enzymatic reaction processes remain unknown, which makes engineering enzymes challenging. Computational modelling can assist experimental work field establish factors that influence rates product distributions. A popular approach is quantum mechanical cluster models take first- second coordination sphere enzyme active site consideration. These QM are widely applied but often results obtained dependent on model choice selection. Herein, we show give highly accurate reproduce distributions free energies activation within several kcal mol

Language: Английский

Citations

7
Unusual catalytic strategy by non-heme Fe(ii)/2-oxoglutarate-dependent aspartyl hydroxylase AspH DOI Creative Commons
Anandhu Krishnan, Sodiq O. Waheed, Ann Varghese

et al.

Chemical Science, Journal Year: 2024, Volume and Issue: 15(10), P. 3466 - 3484

Published: Jan. 1, 2024

The second coordination sphere, Asp721, participates in a hydrogen bond with an iron-coordinated water molecule, thus compensating for the missing facial triad carboxylate AspH and enabling stereoselective C–H oxidation.

Language: Английский

Citations

6
Machine learning-aided engineering of a cytochrome P450 for optimal bioconversion of lignin fragments DOI Creative Commons

Artur Hermano Sampaio Dias,

Yuanxin Cao, Munir S. Skaf

et al.

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(25), P. 17577 - 17587

Published: Jan. 1, 2024

Using molecular dynamics, machine learning, and density functional theory calculations we make predictions on engineered cytochrome P450 structures their product distributions.

Language: Английский

Citations

6
A Molecular Iron-Based System for Divergent Bond Activation: Controlling the Reactivity of Aldehydes DOI Creative Commons
Basujit Chatterjee, Soumyashree Jena, Vishal Chugh

et al.

ACS Catalysis, Journal Year: 2021, Volume and Issue: 11(12), P. 7176 - 7185

Published: June 4, 2021

The direct synthesis of amides and nitriles from readily available aldehyde precursors provides access to functional groups major synthetic utility. To date, most reliable catalytic methods have typically been optimized supply one product exclusively. Herein, we describe an approach centered on operationally simple iron-based system that, depending the reaction conditions, selectively addresses either C═O or C–H bond aldehydes. This way, two divergent pathways can be opened furnish both products in high yields selectivities under mild conditions. catalyst takes advantage iron's dual reactivity capable acting as (1) a Lewis acid (2) nitrene transfer platform govern building block. present transformation offers rare control over selectivity basis iron system's ionic nature. expands repertoire protocols for amide nitrile shows that fine adjustments molecular environment activation processes, thus providing easy various primary blocks.

Language: Английский

Citations

34
Harnessing heme chemistry: Recent advances in the biocatalytic applications of cytochrome P450 monooxgenases DOI
Gabriela C. Schröder, Martha S. Smit, Diederik J. Opperman

et al.

Current Opinion in Green and Sustainable Chemistry, Journal Year: 2022, Volume and Issue: 39, P. 100734 - 100734

Published: Nov. 28, 2022

Language: Английский

Citations

26