Ergothioneine and its congeners: anti-ageing mechanisms and pharmacophore biosynthesis

Protein & Cell, Год журнала: 2023, Номер 15(3), С. 191 - 206

Опубликована: Авг. 10, 2023

Abstract Ergothioneine, Ovothiol, and Selenoneine are sulfur/selenium-containing histidine-derived natural products widely distributed across different organisms. They exhibit significant antioxidant properties, making them as potential lead compounds for promoting health. Increasing evidence suggests that Ergothioneine is positively correlated with healthy ageing longevity. The mechanisms underlying Ergothioneine's regulation of the process at cellular molecular levels beginning to be understood. In this review, we provide an in-depth extensive coverage anti-ageing studies on discuss its possible intracellular targeting pathways. addition, highlight recent efforts in elucidating biosynthetic details Selenoneine, a particular focus study their pharmacophore-forming enzymology.

Язык: Английский

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Evaluating the Transition State Stabilization/Destabilization Effects of the Electric Fields from Scaffold Residues by a QM/MM Approach

The Journal of Physical Chemistry B, Год журнала: 2023, Номер 127(19), С. 4245 - 4253

Опубликована: Май 8, 2023

The protein scaffolds of enzymes not only provide structural support for the catalytic center but also exert preorganized electric fields electrostatic catalysis. In recent years, uniform oriented external (OEEFs) have been widely applied to enzymatic reactions mimic effects environment. However, exerted by individual residues in proteins may be quite heterogeneous across active site, with varying directions and strengths at different positions site. Here, we propose a QM/MM-based approach evaluate scaffold. particular, heterogeneity residue effect native environment can properly accounted this QM/MM approach. A case study O–O heterolysis reaction cycle TyrH shows that (1) scaffold are relatively far from field site is very significant stabilization/destabilization due each well approximated interaction energy between QM region dipole; (2) near highly along breaking bond. such case, approximating as misrepresent overall residue. present residues' impact on reactions, which useful computational optimization boost enzyme

Язык: Английский

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Unraveling the Catalytic Mechanism of Taxadiene-5α-hydroxylase from Crystallography and Computational Analyses

ACS Catalysis, Год журнала: 2024, Номер 14(6), С. 3912 - 3925

Опубликована: Фев. 26, 2024

Paclitaxel is a famous chemotherapeutic agent, but its microbial production poses long-standing challenge due to poor product selectivity. Taxadiene-5α-hydroxylase (CYP725A4) plays crucial role in the biosynthesis of paclitaxel, catalyzing oxidation taxadiene and iso-taxadiene. This process yields several products, including byproducts 5(12)-oxa-3(11)-cyclotaxane (OCT) 5(11)-oxa-3(11)-cyclotaxane (iso-OCT), as well target compound taxadien-5α-ol (T5OH). Despite extensive studies, molecular mechanism CYP725A4-catalyzed transformations still elusive, which could impede our understanding further engineering paclitaxel biosynthetic pathway. In this study, crystal structure CYP725A4 complex with elucidated. Through comprehensive computational analyses, catalytic mechanisms natural are deciphered. Our calculations indicate that affords zwitterion intermediate, can undergo two competing transformation routes. One involves formation epoxide, undergoes water-mediated rearrangement form T5OH product. alternative pathway, protonation oxygen intermediate facilitates subsequent hydride transfer carbon–oxygen coupling, resulting side products OCT/iso-OCT. Contrary taxadiene, hydroxylation at C5 iso-taxadiene directly T5OH. These crystallographic studies analyses have yielded valuable insights into laid foundation for CYP725A4.

Язык: Английский

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Conformational Isomerization of the Fe(III)–OH Species Enables Selective Halogenation in Carrier-Protein-Independent Halogenase BesD and Hydroxylase-Evolved Halogenase

ACS Catalysis, Год журнала: 2024, Номер 14(12), С. 9342 - 9353

Опубликована: Июнь 5, 2024

Despite extensive studies, how carrier-protein-independent BesD dictates the reaction toward thermodynamically unfavored halogenation is still elusive. Here, we investigated chlorination versus hydroxylation selectivity in both halogenase and hydroxylase-evolved Chi-14, employing MD simulations QM/MM calculations. In BesD, our calculations have shown that 2OG-assisted O2 activation affords axial Fe(IV)-oxo species responsible for substrate C–H activation. To facilitate following Cl-rebound reaction, nascent Fe(III)–OH has to undergo conformational isomerization equatorial one. This can remove steric effects between radical, thereby enhancing migration of radical Cl− ligand during Cl-rebound. Notably, hydrogen-bond interactions with second-sphere residue Asn are vital maintain unsaturated five-coordination shell Fe center. maintenance essential enabling transition from an orientation. Our results concordance existing experimental findings, underscoring pivotal influence iron coordination dynamics governing catalytic processes nonheme enzymes.

Язык: Английский

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An S=1 Iron(IV) Intermediate Revealed in a Non‐Heme Iron Enzyme‐Catalyzed Oxidative C−S Bond Formation

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(43)

Опубликована: Авг. 29, 2023

Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol-histidine derivatives. ESH has been implicated as a longevity vitamin OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step in aerobic pathways is O

Язык: Английский

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OvoA _Th2 : A Mononuclear Nonheme Iron Enzyme from Hydrogenimonas thermophila for Ovothiol Biosynthesis

Encyclopedia of Inorganic and Bioinorganic Chemistry, Год журнала: 2025, Номер unknown, С. 1 - 9

Опубликована: Март 26, 2025

Abstract Ergothioneine and ovothiol are thiol‐histidine derivatives. Besides investigating their biological activities, biosynthetic pathways have been characterized in recent years. In ergothioneine aerobic pathways, one of the key steps is mononuclear nonheme iron enzyme‐catalyzed oxidative CS coupling reactions (sulfoxide synthase: EgtB, Egt1, OvoA). this work, we summarized features recently reported OvoA crystal structures. conjunction with pre‐steady‐state kinetics, spectroscopic, computational study results, mechanistic models also summarized.

Язык: Английский

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Peroxo-Diiron(III/III) as the Reactive Intermediate for N-Hydroxylation Reactions in the Multidomain Metalloenzyme SznF: Evidence from Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations

ACS Catalysis, Год журнала: 2023, Номер 13(9), С. 5808 - 5818

Опубликована: Апрель 13, 2023

Upon oxygen activation, the non-heme diiron enzymes can generate various active species for oxidative transformations. In this work, catalytic mechanism of site (heme-oxygenase-like oxidase (HDO) domain) in SznF has been comprehensively studied by molecular docking, classical dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) MD simulations, hybrid QM/MM calculations. The HDO domain catalyzes selective hydroxylation Nω-methyl-l-arginine (l-NMA) to Nδ-hydroxy-Nω-methyl-l-Arg (l-HMA) Nδ,Nω-dihydroxy-Nω,-methyl-l-Arg (l-DHMA), which is a key step synthesis nitrosourea pharmacophore pancreatic cancer drug streptozotocin (SZN). Our study shows that peroxo-diiron(III/III) intermediate Sznf maintains butterfly-like conformation, while further protonation diiron(III/III) found be inaccessible unfavorable thermodynamically. Among mechanisms, we most favorable involves nucleophilic attack guanidium group onto peroxo P1, drives heterolytic cleavage O–O bond. Moreover, selectivity N-hydroxylation fully supported suggesting reactive SznF. present expands our understanding on O2 activation enzymes.

Язык: Английский

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Coordination Dynamics of Iron is a Key Player in the Catalysis of Non‐heme Enzymes

ChemBioChem, Год журнала: 2023, Номер 24(14)

Опубликована: Апрель 3, 2023

Abstract Mononuclear nonheme iron enzymes catalyze a large variety of oxidative transformations responsible for various biosynthesis and metabolism processes. Unlike their P450 counterparts, non‐heme generally possess flexible variable coordination architecture, which can endow rich reactivity enzymes. This Concept highlights that the dynamics be key player in controlling activity selectivity In ergothioneine synthase EgtB, switch sulfoxide radical species enables efficient selective C−S coupling reaction. iron(II)‐ 2‐oxoglutarate‐dependent (Fe/2OG) oxygenases, conformational flip ferryl‐oxo intermediate extensively involved oxidation reactions. Especially, five‐coordinate may allow substrate via O or N atom, facilitate C−O C−N reactions stabilizing transition states inhibiting unwanted hydroxylation

Язык: Английский

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Unravelling the C-C and C-N coupling mechanism for the CYP96T1-catalyzed biosynthesis of Amaryllidaceae alkaloids

Molecular Catalysis, Год журнала: 2023, Номер 550, С. 113609 - 113609

Опубликована: Окт. 7, 2023

Язык: Английский

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Effects of Clinical Mutations in the Second Coordination Sphere and Remote Regions on the Catalytic Mechanism of Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Aspartyl Hydroxylase AspH

ChemPhysChem, Год журнала: 2024, Номер 25(18)

Опубликована: Июнь 6, 2024

Abstract Aspartyl/asparaginyl hydroxylase (AspH) catalyzes the post‐translational hydroxylations of vital human proteins, playing an essential role in maintaining their biological functions. Single‐point mutations Second Coordination Sphere (SCS) and long‐range (LR) residues AspH have been linked to pathological conditions such as ophthalmologic condition Traboulsi syndrome chronic kidney disease (CKD). Although clinical impacts these are established, there is a critical knowledge gap regarding specific atomistic effects on catalytic mechanism AspH. In this study, we report integrated computational investigations potential mechanistic implications four mutant forms with importance: R735W, R735Q, R688Q, G434V. All exhibited altered binding interactions co‐substrate 2‐oxoglutarate (2OG) main substrate ferric‐superoxo ferryl complexes, which for catalysis, compared wild‐type (WT). Importantly, strongly influence energetics frontier molecular orbitals (FMOs) and, thereby, activation energies hydrogen atom transfer (HAT) step WT Insights from our study can contribute enzyme engineering development selective modulators mutants AspH, ultimately aiding treating cancers, CKD.

Язык: Английский

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