ACS Chemical Biology最新文献

The efficiency of hydrogen production from water electrolysis is mainly restricted by the sluggish oxygen evolution reaction (OER). The mainstream adsorbate evolution mechanism and lattice oxygen-mediated mechanism face a trade-off between performance and stability, while the diatomic oxygen mechanism (DOM) based on the O–O coupling provides a solution to overcome this limitation. However, the intrinsic principles that facilitate the O–O coupling remain unclear, which complicates material design. In this work, we use spinel Co₃O₄ as a model and identify that the asymmetric sites formed by the octahedral Co with O defects and the original octahedral Co are effective sites for O–O coupling. Based on this, we propose using the degree of asymmetry of the dual site as a descriptor to quantify the reaction free energy of rate-determining step along the DOM pathway, presenting a volcano plot relationship. Experimental validation shows that plasma-prepared Co₃O₄ enables O–O coupling, requiring only 287 and 420 mV overpotentials to achieve current densities of 10 and 1000 mA cm^–2 in 0.5 M H₂SO₄, respectively. This work demonstrates efficient sites for the OER along the DOM pathway in Co₃O₄, providing valuable insights for designing high-performance OER catalysts.

Metal halide perovskite nanocrystals (PNCs) have demonstrated remarkable photocatalytic properties in diverse photochemical reactions owing to their high absorption coefficients and long photogenerated carrier lifetimes. However, their catalytic applications have been severely hindered by their structural incompatibility with polar solvents, water in particular, due to the labile ionic nature of the perovskite. Realization of the photocatalytic performance of PNCs in an aqueous medium would significantly expand their potential in photocatalysis. Herein, judiciously designed CsPbBr₃ NCs stabilized on Al₂O₃ nanoflowers (denoted as A-CsPbBr₃ NCs) are utilized as water-stable photocatalysts for aqueous photomediated reversible addition–fragmentation chain transfer (photo-RAFT) polymerization. The A-CsPbBr₃ NCs exhibited exceptional water stability and photostability owing to the stabilization effect endowed by Al₂O₃ nanoflowers without sacrificing their charge/carrier transport properties. Consequently, aqueous photo-RAFT polymerization was successfully performed by leveraging A-CsPbBr₃ NCs as photocatalysts under visible light illumination, which was inaccessible to conventional short-ligand-capped PNCs. The effects of the excitation wavelength, catalyst loading, and architectures of PNCs on the visible-light-mediated polymerization were scrutinized to reveal the polymerization via a photoinduced electron-/energy-transfer mechanism, yielding polymers/copolymers with well-defined compositions, well-controlled molecular weights, low polydispersity, and high chain-end fidelity.

Constructing compact direct Z- and S-scheme heterostructures is an efficient strategy for realizing a highly efficient charge separation and photocatalytic performance. However, the stochastic nature of interface orientation and lattice mismatch often results in a blind region for effective inner charge transfer, which hinders the logical design of compact heterojunctions. Here, experimental results and theoretical research unveiled that complicated internal charges can be directly transferred to an intermediate cocrystal plane for electron–hole recombination in compact S-scheme heterostructures, called “bone-joint” heterostructures, which facilitate the establishment of an inherent electric field to drive charge transfer. Moreover, those bone-joint structures adjust the inherent chemical and energetic interactions that manipulate the reactant adsorption mode and surface reaction energy. As a result, a synthesized catalyst displayed a remarkable hydrogen peroxide production performance and stability. This offers a paradigm for intrinsic charge transfer dynamics in heterostructures and a guiding philosophy for designing efficient heterostructures.

Estrogen receptor α (ERα)-positive breast cancer patients are typically treated with ERα inhibitors, including selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). However, the distinct pharmacological properties of various ERα inhibitors remain incompletely understood. In this study, we employed formaldehyde cross-linking followed by ERα immunoprecipitation and mass spectrometry to reveal that fulvestrant, the first FDA-approved SERD, induces the interaction between ERα and SUMO E3 ligases PIAS1 and PIAS2. Biochemical and genomic assays confirmed that fulvestrant induces SUMOylation of ERα, which inhibits ERα′s binding to chromatin DNA. In addition, raloxifene (a SERM) and elacestrant (the first FDA-approved oral SERD) were identified as compounds that similarly induce ERα SUMOylation and inhibit its chromatin interaction. Our findings reveal a mechanism by which select ERα inhibitors disrupt ERα function through SUMOylation, offering insights for the development of next-generation ERα-targeted therapies.

Different P450 isoforms may catalyze different types of reactions on the same substrate due to differences in their protein environments. To uncover how the spatial environment within the enzyme regulates substrate reactivity, we conducted quantum mechanics/molecular mechanics (QM/MM) simulations on the CYP2A6-catalyzed 7-hydroxylation of coumarin. The results revealed that water molecules can flexibly enter the active site of CYP2A6. In the absence of water molecules, the NIH shift mechanism was found to be the most favorable reaction pathway, leading to the keto intermediate that further undergoes the isomerization to form the C7-hydroxylated product. However, when water molecules are present at the active site, the N-protonation route can be facilitated by the active site waters and thus becomes the preferred one. Both the NIH mechanism and the N-protonation can rationalize the 1,2-H shift for the aromatic hydroxylation reactions. This study highlights that P450s can employ diverse and flexible mechanisms for aromatic hydroxylation, offering deeper insight into the mechanisms of P450-catalyzed aromatic hydroxylation reactions.

Ligand engineering is one of the most important, but labor-intensive processes in the development of transition metal catalysis. Historically, this process has been guided by ligand descriptors such as Tolman’s electronic parameter and the cone angle. Analyzing reaction outcomes in terms of these parameters has enabled chemists to identify the most important properties for controlling catalytic pathways and thus designing better ligands. However, typical strategies for these analyses rely on regression approaches, which often require extensive experimental studies to identify trends across chemical space and understand outliers. Here, we introduce the virtual ligand-assisted optimization (VLAO) method, a computational approach for reactivity-directed ligand engineering. In this method, important features of ligands are identified by simple mathematical operations on equilibrium structures and/or transition states of interest, and derivative values of arbitrary objective functions with respect to ligand parameters are obtained. These derivative values are then used as a guiding principle to optimize ligands within the parameter space. The VLAO method was demonstrated in the optimization of monodentate and bidentate phosphine ligands including asymmetric quinoxaline-based ligands. In addition, we successfully found an optimal ligand for the α-selective hydrogermylation of a terminal ynamide, applying the design principle suggested by the VLAO method. These results highlight the practical utility of the VLAO method, with the potential for directed optimization of a wide variety of ligands for transition metal catalysis.

Heme peroxidases represent an important category of heme-containing metalloenzymes that harness peroxide to oxidize a diverse array of substrates. Capitalizing on a well-established catalytic mechanism, diverse peroxidase mimics have been widely investigated and optimized. Herein, we report on the design, assembly, characterization, and genetic engineering of an artificial heme-based peroxidase relying on the biotin–streptavidin technology. The crystal structures of the wild-type and the best-performing double mutant of artificial peroxidases provide valuable insight regarding the nearby residues strategically mutated to optimize the peroxidase activity (i.e., Sav S112E K121H). We hypothesize that these two residues mimic the polar residues in the second coordination sphere, involved in activating the bound peroxide in two very widely studied peroxidases: chloroperoxidase (CPO) (i.e., Glu 183 and His 105) and horseradish peroxidase (i.e., Arg 38 and His 42). Despite the absence of a tightly bound axial ligand, which can exert a “push effect”, the evolved artificial peroxidase exhibits best-in-class activity for oxidizing two standard substrates (TMB and ABTS) in the presence of hydrogen peroxide.

The limitations imposed by the high carrier recombination rate in the current photocatalytic H₂O₂ production system substantially restrict the rate of H₂O₂ generation. Herein, we successfully prepared an In₂S₃/HTCC dense heterojunction bridged by In–S–C bonds through in situ polymerization of glucose on In₂S₃. This interfacial In–S–C bond provides a fast transfer channel for electrons at the interface to achieve a highly efficient interfacial charge transfer efficiency, leading to the formation of an enhanced built-in electric field between In₂S₃ and HTCC, thus dramatically accelerating the rate of charge separation and effectively prolonging the lifetime of the photogenerated carriers. Moreover, the coverage of HTCC enhances the absorption of visible light and sorption of O₂ by In₂S₃, while lowering its two-electron oxygen reduction reaction (ORR) energy barrier. Notably, our research demonstrates that In₂S₃/HTCC can generate H₂O₂ not only through the well-known two-step one-electron ORR but also via an alternative pathway utilizing ¹O₂ as an intermediate, thereby enhancing H₂O₂ production. Benefiting from these advantages, In₂S₃/HTCC-2 can produce H₂O₂ at a rate of up to 1392 μmol g^–1 h^–1 in a pure aqueous system, which is 18.2 and 5.2 times higher than that of pure In₂S₃ and HTCC, respectively. Our work not only provides a novel synthesis method of new organic/inorganic heterojunction photocatalysts based on HTCC but also offers new insights into the potential mechanism of interfacial bonding of heterostructures to regulate the photocatalytic H₂O₂ production activity.

Helical systems have attracted considerable interest across multiple scientific fields due to not only their essential roles in biological processes but also their potential to unveil chirality-associated phenomena, properties, and functionalities. Today, the distinctive topologies of helicenes have found extensive applications in materials science, molecular recognition, and asymmetric catalysis owing to their structural diversity and unique optical and electronic characteristics. Nonetheless, in contrast to the advancements in the synthesis of optically pure point-chiral and axially chiral compounds, the catalytic enantioselective assembly of helically chiral molecules remains in its nascent stages. This Perspective delves into the latest developments in the organocatalytic asymmetric synthesis of helically chiral compounds, emphasizing both the strengths and limitations of the existing literature, with perspectives on the remaining challenges within the field. It is expected that this Perspective will serve as a catalyst for innovation, inspiring the creation of more efficient strategies to synthesize helically chiral molecules.

Didemnins are a class of cyclic depsipeptides derived from sea tunicates that exhibit potent anticancer, antiviral, and immunosuppressive properties. Although certain Tistrella species can produce didemnins, their complete biosynthetic potential remains largely unexplored. In this study, we utilize feature-based molecular networking to analyze the metabolomics of Tistrella mobilis and Tistrella bauzanensis, focusing on the production of didemnin natural products. In addition to didemnin B, we identify nordidemnin B and [hysp²]didemnin B, as well as several minor didemnin analogs. Heterologous expression of the didemnin biosynthetic gene cluster in a Streptomyces host results in the production of only didemnin B and nordidemnin B in limited quantities. Isotope-labeling studies reveal that the substrate promiscuity of the adenylation domains during biosynthesis leads to the accumulation of nordidemnin B and [hysp²]didemnin B. Additionally, precursor-directed biosynthesis is applied to generate eight novel didemnin derivatives by supplementing the culture with structurally related amino acids. Furthermore, we increased the titers of nordidemnin B and [hysp²]didemnin B by supplementing the fermentation medium with l-valine and l-isoleucine, respectively. Finally, both compounds undergo side-chain oxidation to enhance their biological activity, with their anticancer properties found to be as potent as plitidepsin.