ACS Chemical Biology最新文献

ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their in vitro modulation of purified ABCG2, and report four high-resolution cryo-EM structures and computational analyses to elucidate their interactions with ABCG2. We found that Ko143 derivatives that are based on a ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In contrast, closed-ring, tetracyclic analogs were highly potent inhibitors. Strikingly, the least potent of these compounds, MZ82, bound deeper into the central ABCG2 cavity than the other inhibitors and it led to partial closure of the transmembrane domains and increased flexibility of the nucleotide-binding domains. Minor structural modifications can thus convert a potent inhibitor into a compound that induces conformational changes in ABCG2 similar to those observed during binding of a substrate. Molecular dynamics simulations and free energy binding calculations further supported the correlation between reduced potency and distinct binding pose of the compounds. We introduce the highly potent inhibitor AZ99 that may exhibit improved in vivo stability.

This study examines the kinetic origins of the temperature dependence of photoelectrochemical water oxidation on nanostructured titania photoanodes. We observe that the photocurrent is enhanced at 50 °C relative to 20 °C, with this enhancement being most pronounced (by up to 70%) at low anodic potentials (<+0.6 V vs RHE). Over this low potential range, the photocurrent magnitude is largely determined by kinetic competition between water oxidation catalysis (WOC) and recombination between surface holes and bulk electrons (back electron–hole recombination, BER). We quantify the BER process by transient photocurrent analyses under pulsed irradiation. Remarkably, we find that the kinetics of BER (∼90 ms half-time) are independent of temperature. In contrast, the kinetics of WOC, determined from the analysis of the photoinduced absorption of accumulated surface holes, are found to accelerate up to 2-fold at 50 °C relative to 20 °C. We conclude that the enhanced photocurrent densities observed in the low-applied potential region result primarily from the accelerated WOC, reducing losses due to the competing BER pathway. At higher applied potentials (>+0.6 V vs RHE), a smaller (∼10%) enhancement in photocurrent density is observed at 50 °C relative to 20 °C. Photoinduced absorption studies, correlated with studies using triethanolamine as a hole scavenger, indicate that this more modest enhancement at anodic potentials primarily results from an enhanced charge separation efficiency. We conclude by discussing the implications of these results for the practical application of photoanodic WOC under solar irradiation, influenced by these temperature-independent and -dependent underlying kinetic processes.

Efficiently removing/converting methane via methane combustion imposes challenges on catalyst design: how to design local structures of a catalytic site so that it has both high intrinsic activity and atomic efficiency? By manipulating the atomic distance of isolated Pd atoms, herein we show that the intrinsic activity of Pd catalysts can be significantly improved for methane combustion via a stable Pd₂ structure on a ceria nanorod support. Guided by theory and confirmed by experiment, we find that the turnover frequency (TOF) of the Pd₂ structure with the Pd–Pd distance of 2.99 Å is higher than that of the Pd₂ structure with the Pd–Pd distance of 2.75 Å; at least 26 times that of ceria supported Pd single atoms and 4 times that of ceria supported PdO nanoparticles. The high intrinsic activity of the 2.99 Å Pd–Pd structure is attributed to the conductive local redox environment from the two O atoms bridging the two Pd²⁺ ions, which facilitates both methane adsorption and activation as well as the production of water and carbon dioxide during the methane oxidation process. This work highlights the sensitivity of catalytic behavior on the local structure of active sites and the fine-tuning of the metal–metal distance enabled by a support local environment for guiding the design of efficient catalysts for reactions that highly rely on Pt-group metals.

In this article, we describe a detailed experimental and computational study of the activation mechanism for a highly active pincer ruthenium(0) precatalyst for the hydrogenation of polar organic compounds. The precatalyst activates by reaction with 2 equiv of hydrogen, resulting in a net oxidative addition to ruthenium and hydrogenation of an imine functional group on the supporting ligand. The kinetics of precatalyst hydrogenation were measured by UV–visible spectroscopy under catalytically relevant conditions (10–39 bar hydrogen, 298 K). The kinetic data, in combination with density functional theory calculations, support an intriguing autocatalytic mechanism, where the product ruthenium(II) complex catalyzes the hydrogenation of the ruthenium(0) precatalyst.

Non-natural photoenzymatic catalysis exploits active site tunability for stereoselective radical reactions. In flavoproteins, light absorption promotes the excitation of an electron donor–acceptor (EDA) complex formed between the reduced flavin cofactor and a substrate (α-chloroacetamide in this case). This can trigger chloride mesolytic cleavage, leading to radical cyclization (forming a γ-lactam), or revert to the ground state. While this strategy is feasible using a broad UV/visible/near-infrared spectrum, the low quantum yield presents a significant challenge. Using a multiscale computational approach, we elucidate the mechanisms of the light-driven radical initiation step catalyzed by a Gluconobacter oxydans “ene”-reductase mutant (GluER-G6). The low experimental quantum yield stems from the limited population (<10%) of EDA complexes with a charge transfer state competent for mesolytic cleavage. Accessibility of this state requires substrate bending positioning the chlorine atom near the styrenic group. A subset of these reactive conformers exhibits enhanced cyan/red absorption due to the optimal C–Cl bond alignment with the flavin. Engineering a GluER variant to stabilize this conformation is expected to significantly enhance catalytic efficiency when using cyan/red light. The identified reactive intermediates possess the correct prochirality for enantioselective cyclization. Our findings show that ground-state conformational selection of these EDA complex conformers governs both light-activated mesolytic cleavage and enantioselectivity.

2D conductive metal–organic frameworks (2D c-MOFs) have attracted significant interest as efficient electrocatalysts for the oxygen evolution reaction (OER). However, effectively regulating their catalytic activity remains a significant challenge. Herein, density functional theory (DFT) was performed to explore the effect of π-d conjugation modulation on the electronic structure of the tetrahydroxy-1,4-benzoquinone-based 2D c-MOFs. The computational results indicate that the strong π-d conjugation caused by orbital hybridization between Co and Fe widens and enhances the hybridization between the d_xz/d_yz orbitals at the metal sites and the p orbitals of the ligands, thereby affecting the reconstruction of the MOFs during the OER process. Experimentally, CoFe-THQ with various atomic ratios was synthesized. The results indicated that the synthesized Co_0.6Fe_0.4-THQ powders only needs an overpotential of 247 mV to reach a current density of 10 mA cm^–2 for the OER in alkaline medium, which is much lower than most reported transition metal-based electrocatalysts and even better than that of the benchmark RuO₂ electrocatalyst. Furthermore, in situ Raman and in situ Fourier transform infrared spectroscopy analyses revealed that Co_0.6Fe_0.4-THQ undergoes a different reconstruction evolution during the OER process compared to Co-THQ, with the mixed (Co, Fe) bimetallic oxides ((Co, Fe)₃O₄ and α-(Co, Fe)₂O₃) formed after reconstruction identified as the true active species. This study opens up an effective avenue for the rational design of high-activity 2D c-MOF electrocatalysts.

In this study, zinc single-atom catalysts (SACs) (Zn SACs) with Zn–N₂O₂ as the coordination shell and the epoxy group (C–O–C) as the second coordination structure are synthesized. The obtained Zn SACs exhibit a high 2e^– ORR selectivity of >85% in a wide potential window of 0–0.65 V vs RHE and achieve a high generation rate of 828.9 mmol g_cat^–1 h^–1 for H₂O₂. Experimental and theoretical calculations have confirmed that the second coordination structure of adjacent C–O–C can effectively optimize the adsorption energy of Zn–N₂O₂ for *OOH and tune the 2e^– ORR selectivity. In addition, a small onset potential of 0.38 V vs RHE is achieved for sulfides oxidation reaction (SOR) by the obtained Zn SACs. Moreover, a coupled system of anodic SOR and cathodic 2e^– ORR is fabricated, which can save 45% energy consumption compared to the OER-2e^– ORR system due to a decreased cell voltage of 2.03 V at 20 mA cm^–2. This study provides new bifunctional Zn SACs modified by adjacent C–O–C, which are effective as bifunctional catalysts for electrosynthesis of H₂O₂ and electro-oxidation of sulfides. These two reactions can be performed together in a coupled system with decreased energy cost and thus should have better application potential.

In contemporary organic synthesis, chemists actively pursue a diverse range of substrates that can be efficiently catalyzed within an integrated system, playing a crucial role in advancing the pharmaceutical industry. However, due to the influence of substituents on reactivity and selectivity, it poses a challenging dilemma to explore different strategies for activating substrates with distinct functional groups. Herein, we have developed an important visible light-driven chiral Lewis acid catalysis platform which facilitates the unified allylations and vinylogous reactions of various allyl bromides and isatins for the highly enantio- and diastereoselective construction of valuable 3-allyl-3-hydroxy oxindoles. The success of this approach lies in utilizing a radical pathway for intermediate formation and stereocenter generation. Moreover, the activation capability of chiral Lewis acids provides an opportunity to achieve sufficient enantiocontrol and enhance regioselectivity. The robustness of this method is demonstrated by its application in precise radical-based propargylation reactions using readily accessible propargyl bromides.

Biocatalysis plays a vital role in the operations of all living organisms, which is usually thought to be mediated by protein enzymes. However, the pioneering discovery of self-splicing intron-splicing RNA ribozyme demonstrated that nucleic acids can also promote catalysis, with efficiency comparable to that of proteases. The discovery of deoxyribozyme (DNAzymes) further broadened the understanding of the catalytic function of nucleic acids. Since then, nucleic acids with various catalytic functions have been gradually discovered and significant efforts have been devoted to the applications studies of nucleic acid catalyst. Consequently, a systematically and comprehensive review is needed to summarize all the advancements in the FNAzymes field. In this review, we propose the concept of functional nucleic acid enzymes (FNAzymes). FNAzymes are nucleic acids or nucleic acid complexes with special structure and catalytic functions. Then FNAzymes are divided into four groups based on the components that make them up: ribozymes, DNAzymes, modified FNAzymes, and functional nucleic acid nanozymes (FNA nanozymes). In addition, the catalytic function, structure, and catalytic mechanism of each FNAzymes are introduced. The applications of FNAzymes in biosensing, bioimaging, and biotherapy of are summarized. Finally, future development trends and application prospects of functional nucleases are discussed.

A series of Ru/Ti_1–xMn_xO₂ catalysts with varying Mn/(Ti + Mn) molar ratios (x = 0.10–0.25) were synthesized to investigate the CO₂ methanation mechanism on anatase TiO₂-supported Ru catalysts (Ru/a-TiO₂) and develop high-performance catalysts at low temperatures. Among these catalysts, the Ru/Ti_0.8Mn_0.2O₂ exhibited the highest activity, achieving approximately 65% CO₂ conversion at 230 °C, which is markedly superior to the unmodified Ru/a-TiO₂ catalyst yielding only about 15% CO₂ conversion. The majority of Mn cations were incorporated into the lattice of a-TiO₂ as Mn³⁺ cations, forming a solid solution structure in the Ti_0.8Mn_0.2O₂ support. This modification resulted in a higher specific surface area, improved reducibility, and increased oxygen vacancy compared with pure a-TiO₂. Consequently, Ru dispersion and electronic metal–support interactions were enhanced in Ru/Ti_0.8Mn_0.2O₂ compared to those in Ru/a-TiO₂. In-situ diffuse reflectance infrared Fourier transform spectroscopy combined with temperature-programmed surface reaction experiments revealed that CO₂ methanation predominantly proceeded via the CO* route on the Ru/a-TiO₂. The CO₂ adsorption in the presence of decomposed H₂ led to dissociation to linear CO*, followed by CO methanation where CO₂ dissociation to CO* was identified as the rate-determining step (RDS). Mn cation doping induced the formation of oxygen vacancies, significantly enhancing CO₂ dissociation on Ru/Ti_0.8Mn_0.2O₂, thereby shifting the RDS to CO methanation. This mechanism explains the superior activity of Ru/Ti_0.8Mn_0.2O₂ at low temperatures for CO₂ methanation compared to the Ru/a-TiO₂.