Substrate Molecules Research Articles

Expanding limits of artificial enzymes: unprecedented catalysis by an oxidase nanozyme in activating a structural protein for covalent crosslinking and conferring remarkable proteolytic resistance.

Nature has endowed us with some complex enzymes capable of utilizing proteins as their substrates to generate functional proteins through post-translational modification. However, nanozymes' interplay with proteins as substrates is scarce, with their chemistry predominantly established using only small molecule substrates, featuring a significant gap in this area. Due to the huge prospects of nanozymes in biotechnological and therapeutic interventions, studies establishing the unexplored roles of nanozymes in the biological environments and their interplay beyond small molecule substrates warrant immediate attention. In this study, we unveil the unprecedented role of a Mn-based oxidase nanozyme (MnN) in activating a structural protein, collagen, and covalently crosslinking its tyrosine residues with only a trace amount of tannic acid (TA) without compromising its triple-helical structural integrity. While therapeutic applications demand materials prepared from collagen, the current chemical and physical crosslinking of collagen often presents significant challenges such as toxicity, denaturation, or high costs. MnN lucidly accomplishes crosslinking interplay at its 101 facets using oxygen as a co-substrate under mild conditions. This process takes advantage of MnN being active at mild acidic pH where collagen preferentially exists as a soluble triple helix (monomeric form), exposing functionalities and enhancing the crosslinking degree. Importantly, this reaction also confers 100% resistance to collagenase attack on the collagen tendon-derived biological material. The catalyzed TA-tyrosine linkage in the telopeptide region of collagen probably impedes the initial recognition step of collagenase, providing robust protection against its degradative action. Our study not only expands the repertoire of nanozymes' substrates beyond the existing library of small molecules but also establishes a significant step toward designing a gold standard for collagen crosslinking. With biomedical applications demanding biomaterials derived from protein scaffolds with preserved structural integrity, our investigation bridges the gap between nanozymes' chemistry and crosslinking proteins, opening exciting prospects for biomaterial development.

Molecular dipole-modulated visible light photoredox reaction over conjugated polymers

The molecular dipoles of conjugated polymers (CPs) have a great influence on their intrinsic photophysical properties and are one of the key factors affecting the photocatalytic activity. Therefore, we developed a molecular dipole modulation strategy to regulate the configuration of conjugated polymers by changing the symmetry of the monomer molecules and the electronegativity of the bridging atoms to modulate the magnitude of the in-built electric field (IBEF). The optimized SHOP sample has a significant molecular dipole and thus the highest IBEF, which accelerates the dissociation of excitons into electron-hole pairs and facilitates the photocatalytic redox reaction. In addition, CH4 was the principal output of photocatalytic CO2 reduction by SHOP, producing a maximum yield of 743.4 μmol g−1 and a selectivity of 86.2%. On the other hand, SHOP also efficiently converts isochromane to isochroman-1-one in 96.2% yield, realizing a high economic value conversion of a representative substrate molecule. This proposed strategy offers guidance for designing novel CPs photocatalysts for photoredox reactions.

Engineering Atomically Dispersed Cu-N1S2 Sites via Chemical Vapor Deposition to Boost Enzyme-Like Activity for Efficient Tumor Therapy.

Single-atom nanozymes (SAzymes), with well-defined and uniform atomic structures, are an emerging type of natural enzyme mimics. Currently, it is important but challenging to rationally design high-performance SAzymes and deeply reveal the interaction mechanism between SAzymes and substrate molecules. Herein, this work reports the controllable fabrication of a unique Cu-N1S2-centred SAzyme (Cu-N/S-C) via a chemical vapor deposition-based sulfur-engineering strategy. Benefiting from the optimized geometric and electronic structures of single-atom sites, Cu-N/S-C SAzyme shows boosted enzyme-like activity, especially in catalase-like activity, with a 13.8-fold increase in the affinity to hydrogen peroxide (H2O2) substrate and a 65.2-fold increase in the catalytic efficiency when compared to Cu-N-C SAzyme with Cu-N3 sites. Further theoretical studies reveal that the increased electron density around single-atom Cu is achieved through electron redistribution, and the efficient charge transfer between Cu-N/S-C and H2O2 is demonstrated to be more beneficial for the adsorption and activation of H2O2. The as-designed Cu-N/S-C SAzyme possesses an excellent antitumor effect through the synergy of catalytic therapy and oxygen-dependent phototherapy. This study provides a strategy for the rational design of SAzymes, and the proposed electron redistribution and charge transfer mechanism will help to understand the coordination environment effect of single-atom metal sites on H2O2-mediated enzyme-like catalytic processes.

Selective Newman-Kwart Rearrangement Under Mild Conditions Enabled by Heterogeneous Photocatalysis and Electrochemical Catalysis

The Newman-Kwart Rearrangement (NKR), the key-step in the three-stage conversion of phenols 1 into thiophenols 4 (see figure below), holds numerous applications in various fields [1]. Usually, the NKR proceeds via thermally induced intramolecular nucleophilic ipso substitution. High temperatures up to 300 °C are required to facilitate the rearrangement, especially for electron-rich substrates, causing side reactions and high energy consumption [1].Over the past decade, several improved protocols have appeared that enable selective conversion under milder conditions. These methods are based either on homogeneous photocatalysis [2], thermochemical Pd catalysis [3], or on the use of reagents [4]. In this context, a new approach was developed in our group, in which heterogeneous electron transfer enables a radical cation pathway and thereby catalyzes the rearrangement (“hole catalysis”, see figure) [5].The radical cation mechanism is driven by catalytic amounts of charge, either induced by anodic oxidation (“electrochemical catalysis”, e-NKR) [5,6] or in a photochemical reactor using suspended titanium dioxide nanoparticles as photocatalyst (p-NKR) [7].The resulting radical cation 2∙+ then undergoes intramolecular electrophilic aromatic substitution (ArSE) to form the product radical cation 3∙+ , which reacts either in a chain process with another substrate molecule 2 (see figure, case A) or undergoes backward electron exchange with the electrode/titanium dioxide particle (case B) to form product 4 [6,7].For both the e-NKR and the p-NKR, highly selective transformation proceeds at room temperature under aerobic conditions. A variety of different substrates can be rearranged, whereby the scope is complementary to the thermal NKR with respect to electron-donating and -withdrawing aryl substituents. For the e-NKR, an electrochemical micro-flow reactor can overcome the need for supporting electrolyte due to a small distance between the electrodes [6,7].Both for the p- and the e-NKR, detailed mechanistic studies were carried out using cyclic voltammetry, operando spectroscopy, computational analysis, and control experiments. In the present contribution, both practical and mechanistic aspects will be discussed with particular focus on the photocatalytic approach [6,7], along with recent applications to biomass-derived compounds[8].

Hierarchically porous amino-functionalized nanoMOF network anchored phosphomolybdic acid for oxidative desulfurization and shaping application

The applications of hierarchically porous metal–organic frameworks (HP-MOFs) against traditional microporous counterparts for oxidative desulfurization (ODS) have triggered wide research interests due to their highly exposed accessible active sites and fast mass transfer of substrate molecules, particularly for the large-sized refractory sulfur compounds. Herein, a series of hierarchically porous amino-functionalized Zr-MOFs (HP-UiO-66-NH2-X) network with controllable mesopore sizes (3.5–9.2 nm) were firstly prepared through a template-free method, which were further utilized as anchoring support to bind the active phosphomolybdic acid (PMA) via the strong host–guest interaction to catalyze the ODS reaction. Benefitting from the hierarchically porous structure, accessible active sites and the strong host–guest interaction, the resultant PMA/HP-UiO-66-NH2-X exhibited excellent ODS performance, of which, the PMA/HP-UiO-66-NH2-9 with an appropriate mesopore size (4.0 nm) showed the highest catalytic activity, achieving a 99.9% removal of dibenzothiophene (DBT) within 60 min at 50 °C, far exceeding the microporous sample and PMA/HP-UiO-66. Furthermore, the scavenger experiments confirmed that •OH radical was the main reactive species and the density functional theory (DFT) calculations revealed that electron transfer (from amino group to PMA) made PMA react more easily with oxidant, thereby generating more •OH radical to promote the ODS reaction. Finally, from the industrial point of view, the powdered MOF nanoparticles (NPs) were in situ grown on the carboxymethyl cellulose (CMC) substrates and shaped into monolithic MOF-based catalysts, which still exhibited satisfying ODS performance in the case of model real fuel with good reusability, indicating its potential industrial application prospect.

Single-Atom Ru Catalyst-Decorated CNF(ZnO) Nanocages for Efficient H2 Evolution and CH3OH Production.

The presence of transition-metal single-atom catalysts effectively enhances the interaction between the substrate and reactant molecules, thus exhibiting extraordinary catalytic performance. In this work, we for the first time report a facile synthetic procedure for placing highly dispersed Ru single atoms on stable CNF(ZnO) nanocages. We unravel the atomistic nature of the Ru single atoms in CNF(ZnO)/Ru systems using advanced HAADF-STEM, HRTEM, and XANES analytical methods. Density functional theory calculations further support the presence of ruthenium single-atom sites in the CNF(ZnO)/Ru system. Our work further demonstrates the excellent photocatalytic ability of the CNF(ZnO)/Ru system with respect to H2 production (5.8 mmol g-1 h-1) and reduction of CO2 to CH3OH [249 μmol (g of catalyst)-1] with apparent quantum efficiencies of 3.8% and 1.4% for H2 and CH3OH generation, respectively. Our studies unambiguously demonstrate the presence of atomically dispersed ruthenium sites in CNF(ZnO)/Ru catalysts, which greatly enhance charge transfer, thus facilitating the aforementioned photocatalytic redox reactions.

Multifunctional Micromachines Constructed by Combining Multiple Protein-Based Components with Different Functions.

Untethered mobile micromachines have considerable potential to realize more effective and minimally invasive medicine. Although diverse medical micromachines have been reported over the past few decades, these machines were developed for performing only specific tasks and the functions imparted to them were limited to a few. Hence, the methodologies for imparting a wide variety of functions to machines have not been fully explored. In this study, a novel construction strategy for the multifunctional micromachines is presented, where a specific function can be added to the machine in one step by directly combining the protein-based component, possessing the biological function of constituent proteins, to an arbitrary position of the machine by using an inkjet printing technique. As a proof-of-concept demonstration, various types of machines were constructed by combining multiple components with different functions. These constructed machines successfully performed functions as diverse as enzyme-powered self-propulsion, collection of target objects, including the bilirubin and living cells, enzyme-mediated conversion of substrate molecules to different ones, magnetic guidance, and release of anti-inflammatory drug diapocynin. The study's progressive approach as well as multifunctional and biocompatible machines composed of proteins will profoundly impact the development of intelligent machines equipped with multiplex sophisticated functionalities.

A Versatile Isocyanate-Mediated Strategy for Appending Chemical Tags onto Drug-Like Small Molecules.

Target identification studies are a major hurdle in probe and drug discovery pipelines due to the need to chemically modify small molecules of interest, which can be time intensive and have low throughput. Here, we describe a versatile and scalable method for attaching chemical moieties to a small molecule, isocyanate-mediated chemical tagging (IMCT). By preparation of a template resin with an isocyanate capture group and a cleavable linker, nucleophilic groups on small molecules can be modified with an enforced one-to-one stoichiometry. We demonstrate a small molecule substrate scope that includes primary and secondary amines, thiols, phenols, benzyl alcohols, and primary alcohols. Cheminformatic analyses predict that IMCT is reactive with more than 25% of lead-like compounds in publicly available databases. To demonstrate that the method can produce biologically active molecules, we generated FKBP12 photoaffinity labeling (PAL) compounds with a wide range of affinities and showed that purified and crude cleavage products can bind to and label FKBP12. This method could be used to rapidly modify small molecules for many applications, including the synthesis of PAL probes, fluorescence polarization probes, pull-down probes, and degraders.

Functionalised [Ge9Ni] Clusters as Homogeneous Single‐Site Catalysts for Olefin Isomerisation Reactions

AbstractSingle‐site catalysis is an increasingly vital strategy to optimise heterogeneous catalytic reactions. In an ideal case, the nature and the population of catalytically active sites are all identical, which is impossible to realise on a solid support. The idea of single site catalysts is transferred from heterogeneous to homogeneous catalysis by the incorporation of a transition metal with oxidation state 0 in the surface of a small, soluble, molecular, homoatomic germanium atom cluster that also comprises main group atoms with oxidation state close to zero. An optimised synthetic protocol for four cluster compounds Hyp3Et[Ge9Ni]PR3 (R=Ph, ptolyl, iPr, Me) is presented, in which the transition metal is embedded in Ge atoms of a polyhedral cluster. The products were characterised by NMR spectroscopy, LIFDI/MS and elemental analysis and also structurally characterised for R=iPr and Me by single crystal X‐ray structure determination comprising a closo‐[Ge9Ni] core. The catalytic potential is investigated for various olefin isomerisation reactions. The formation of an active metal site is realized by ligand dissociation, which is observed for PPh3. DFT calculations of Hyp3Et[Ge9Ni]PR3 (R=Ph, iPr, Me), Hyp3Et[Ge9Ni](tolyl) and Hyp3Et[Ge9Ni](C6H12) show that ligand exchange with substrate molecules occurs during the catalytic reaction. Since the same principle, namely a bare metal atom site at the cluster surface, applies as in single‐site heterogeneous catalysis and since in contrast to classical homogeneous catalysis the metal atom is embedded in a cluster surface, the abbreviation SSHoC for Single Site Homogeneous Catalyst is proposed for this catalyst type. Since each metal atom is catalytically active, SSHoC enable a considerable increase in efficiency of catalysts and thus allow for sustainable use of expensive and less abundant transition metals.

The Universal Antitumor Activity of TAS0612, a Triple Inhibitor for RSK, AKT, and S6K, in B-Cell Lymphomas Regardless of Disease Subtype

B-cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. Although the prognosis of most BCL subtypes has been greatly improved by the advancements of disease subtype-oriented molecular-targeted therapeutics, there remain patients who are incurable with currently available therapeutics. Therefore, further development of new therapies that are effective regardless of disease subtypes is still awaited. 3-phosphoinositide dependent protein kinase 1 (PDPK1) is the master serine-threonine kinase of >20 AGC kinases, including RSK family proteins, AKT, S6K, and several non-AGC kinases. By regulating a series of downstream molecules and mediating the RAS/ERK/RSK2 and PI3K/AKT pathways, PDPK1 plays a pivotal role in disease development and progression in various malignancies. We have also shown that PDPK1/RSK2 axis plays pivotal roles in the pathophysiology of multiple myeloma and mantle cell lymphoma (MCL) (Chinen Y, Cancer Res 2014; Shimura Y, Mol Cancer Ther 2012; Matsumura-Kimoto Y, Cancer Med 2020). In the search for novel molecular targeted therapy for BCLs, these provoked us to investigate the role of PDPK1 and its effector molecules as the therapeutic targets in a broad range of BCLs. We first revealed that the blockade of phosphoinositide-dependent kinase-1 (PDPK1) using its specific inhibitor BX-912 induces a growth inhibition via G2/M cell cycle arrest and the induction of apoptosis in all 8 BCL-derived cell lines examined, including two from activated B-cell-like diffuse large B cell lymphoma (DLBCL), two from double expressor DLBCL, two from Burkitt lymphoma, and two from follicular lymphoma (FL). By using specific inhibitors for the downstream kinases of PDPK1, we also demonstrated that RSK2, AKT, and S6K, but not other PDPK1 substrates, such as PLK1, SGK, or PKC, plays critical roles for cell survival and proliferation as target molecules of PDPK1 in these cell lines examined. In addition, RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1. Following these results, we next investigated the anti-BCL efficacy of TAS0612 which is the triple inhibitor for total RSK, including RSK2, AKT, and S6K, by inhibiting the binding of its target RSK, AKT, and S6K with their substrate molecules (Shibata T, Mol Cancer Ther 2020). As the results, TAS0612 showed the antiproliferative effect in all 8 BCL-derived cell lines examined with IC80s ranging from 1.18 to 8.46 µM, leading to G1 or G2/M cell cycle blockade, and induced apoptosis. At the protein level, TAS0612 caused the accumulation of its direct substrates p-total RSK Ser380, p-AKT Ser473, and p-S6K Thr389 in most cell lines examined as the results of the inhibition of binding to their respective substrates, and the subsequent inactivation through dephosphorylation of their respective target substrates in all cell lines examined. The 72-hour treatment with TAS0612 at 2.5 and 5.0 µM also showed the ex vivo antiproliferative effect in 25 patients-derived lymphoma cells of various disease subtypes, including nine DLBCLs, seven FLs, three MCLs, one mucosa-associated lymphoid tissue lymphoma, one splenic marginal zone B cell lymphoma, one chronic lymphocytic leukemia, and three B-lymphoblastic lymphomas. We finally examined the global molecular effects of TAS0612 using gene expression profiling. Among several tumor suppressor genes upregulated by TAS0612, we found the increased expression of tumor protein 53 inducible nuclear protein 1 (TP53INP1) in cell lines regardless of disease subtypes. Moreover, gene set enrichment analysis identified that TAS0612 significantly downregulated the gene sets driven by the upregulation of MYC and mTORC1, reactive oxygen species, and the unfolded protein response. Thus, this study revealed that the concomitant blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel universally active therapeutic target for the various disease subtypes of BCLs, and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.

TAS0612, a Triple Inhibitor for RSK, AKT, and S6K, Is a Promising Anti-Myeloma Agent Regardless of Types of Cytogenetic/Genetic Abnormality

Introduction: Despite advancements in therapeutic approaches, treatment outcome for multiple myeloma (MM) remains unsatisfactory. One critical factor of the poor outcomes is the complex inter-patient and intra-clonal heterogeneity of cytogenetic, genetic, and molecular abnormalities. To overcome this, the exploration of therapeutic target molecules that play a universal and essential role in MM regardless of the types of molecular profile is crucial even in the post-genomic era. We have previously demonstrated that RSK2 Ser227 at the N-terminal kinase domain (NTKD), as the downstream signaling hub of the RAS/ERK pathway, plays essential roles in the proliferation and survival of myeloma cells (Shimura Y, Mol Cancer Ther 2012). We also identified that RSK2-NTKD is constitutively activated by constitutive active PDPK1, the master serine-threonine kinase of >20 AGC kinases, in myeloma cells of approximately 90% of MM patients regardless of cytogenetic abnormalities (Chinen Y, Cancer Res 2014, Tatekawa S, Br J Haematol 2017). Moreover, the combinatory blockade of RSK2 and AKT, one of the other important molecules regulated by PDPK1, exhibited synergistic anti-myeloma efficacy through the modulation of various critical gene sets involved in myeloma pathophysiology, such as MYC (Isa R, Int J Mol Sci 2022). Based upon these, this study investigates the anti-myeloma potency of TAS0612 (Taiho Oncology Inc., Princeton, NJ) that targets RSK, including RSK2, AKT, and S6K, and inhibits the bindings to their respective substrate molecules (Shibata T, Mol Cancer Ther 2020). Methods and Results: Firstly, we examined the activation status of RSK, AKT, and S6K in eight human myeloma-derived cell lines (HMCLs) with diverse genetic and molecular profiles at the protein level. RSK2 Ser227 was found to be commonly activated through phosphorylation in all HMCLs examined. In contrast, the activation patterns of p-AKT Ser473 and p-S6K Thr389 were inconsistent among eight HMCLs, and depending on cell types. Despite these cell type-dependent effects, the exposure to TAS0612 resulted in the accumulation of p-total RSK Ser380, p-AKT Ser473, and p-S6K Thr389 in the majority of HMCLs examined, and this led to the subsequent inactivation of their respective target substrates, such as p-YB1 Ser102, p-PRAS Thr246, and p-S6 Ser235/236, through dephosphorylation. In accompany with these molecular effects, the modified MTT assay showed the dose-dependent growth inhibitory effects of TAS0612 in all cell lines with various types of cytogenetic/genetic abnormalities with IC50 values mostly below 0.5 μM (48 hours). In addition, flow cytometry analyses for the cell cycle analysis and the apoptosis assay by the counterstaining of propidium iodide and Annexin-V showed that TAS0612 induced G1/S cell cycle arrest and apoptotic cell death. Furthermore, patient-derived primary myeloma cells were labeled with anti-CD138 MicroBeads, and were positively isolated from bone marrow mononuclear cells from patients with newly diagnosed MM (n=7) and relapsed/refractory MM (n=11), and, then, were treated by TAS0612. As the results, the ex vivo treatment of 2.5-5.0 μM TAS0612 for 72 hours showed robust cell reductive effects on primary-myeloma cells from all 18 patients examined irrespective of cytogenetic profile. To clarify the precise molecular effects of TAS0612 treatment in myeloma cells, we conducted a comprehensive molecular analysis with TAS0612 treatment by gene expression profiling. The results showed that TAS0612 treatment significantly modulated the gene sets involved in Myc signaling, mTOR signaling, and the core serum response (CSR). Additionally, TAS0612 caused the concomitant upregulation of several bona-fide tumor suppressor genes, including TP53INP, HBP1, FBOX32, and YPEL3, while the downregulation of oncogenes LYAR and HSPA1. Intriguingly, according to MMRF CoMMpass Study, 8 of 18 upregulated genes by TAS0612 in HMCLs were reported to be associated with favorable survival outcomes when highly expressed in myeloma cells. Conclusion: Our findings strongly support the potential of TAS0612 as an effective anti-myeloma agent. Further preclinical investigations are necessary to substantiate these results and facilitate its future clinical development.

(R)-PFI-2 Analogues as Substrates and Inhibitors of Histone Lysine Methyltransferase SETD7.

(R)-PFI-2 is a histone substrate-competitive inhibitor of the human histone lysine monomethyltransferase SETD7. Aimed at developing potent inhibitors of SETD7 that can also act as small molecule substrates, we replaced the pyrrolidine ring of (R)-PFI-2 with several side chains bearing nucleophilic functional groups. We explored the inhibitory activity of 20 novel (R)-PFI-2 analogues, and found that the most potent analogue has a hydroxyethyl side chain (7). SETD7's ability to catalyse methylation of (R)-PFI-2-based small molecules was evaluated by mass spectrometric assays, and we observed efficient methylation of analogues bearing lysine mimicking nucleophilic amines. The optimal side chain was found to be an aminoethyl group (1), which was surprisingly also dimethylated by SETD7. The work demonstrates that small molecules can act as both substrates and inhibitors of biomedically important SETD7.

Ultra‐stable cycling of organic carboxylate molecule hydrogen bonded with inorganic Ti3C2Tx MXene with improved redox kinetics for sodium‐ion batteries

AbstractThe application of small organic molecules for sodium‐ion batteries is generally plagued by their high solubility, poor conductivity, and sluggish redox dynamics in organic electrolyte, thus developing efficient strategies to restrain solubilization while obtaining fast charge transfer becomes a challenge. Herein, a rational hybridization strategy through hydrogen bond between organic molecule and inorganic substrate has been proposed, employing the terminal –C═O of trisodium 1, 2, 4‐benzenetricarboxylate (TBC) molecule and –OH groups of inorganic Ti3C2Tx MXene, respectively. In general, such a design evidently mitigates the aggregation of both TBC molecules and Ti3C2Tx MXene. Furthermore, the robust hydrogen bonding significantly mitigates the dissolution of TBC and guarantees the robust coupling between them, thus contributing to the integrity of electrode and modifying the electrochemical sodium storage in both half and full cells. Moreover, the systematic kinetic analysis and mechanism detection reveal improved charge transportation and robust two‐electron electrochemical reversibility of the hybrid TBC/Ti3C2Tx. Taken together, this work demonstrates a potential novel strategy toward stable and practical organic battery chemistries through hydrogen bonding with inorganic compounds.

Stretching-Induced 2D-to-3D Shape Transformation of an Elastic Composite for Sensitivity-Tailorable Soft Electronics.

The shapes of rubbers and elastomers are challenging to alter, and current methods relying on permanent plasticity and dynamic cross-linking strategies are usually laborious and can inevitably compromise the network elasticity. Here, we report a photoresponsive elastic composite that can be programmed into 3D shapes by first UV light irradiation and then stretching. The composite comprises ethylene propylene rubber as the elastic substrate and photoliquefiable azobenzene small molecules as the responsive filler. Upon UV light irradiation, the liquefication of the filler induces the destruction of the crystalline aggregates near the irradiated surface, and after stretching and subsequent stress release, the irradiated part bends to the irradiated side based on a gradient network orientation mechanism. The position and amplitude of bending deformation can be controlled to realize a 2D-to-3D shape transformation. We further show that the resulting 3D-shaped elastomer can integrate with silver conductive paste to develop soft conductive lines with tailorable strain-sensitive conductivities. This study may open a new door for the development of shape-tailorable elastomers and soft electronics with designable strain-sensitive conductivities.

A Novel Biosensing Approach: Improving SnS2 FET Sensitivity with a Tailored Supporter Molecule and Custom Substrate.

The exclusive features of two-dimensional (2D) semiconductors, such as high surface-to-volume ratios, tunable electronic properties, and biocompatibility, provide promising opportunities for developing highly sensitive biosensors. However, developing practical biosensors that can promptly detect low concentrations of target analytes remains a challenging task. Here, a field-effect-transistor comprising n-type transition metal dichalcogenide tin disulfide (SnS2 ) is developed over the hexagonal boron nitride (h-BN) for the detection of streptavidin protein (Strep.) as a target analyte. A self-designed receptor based on the pyrene-lysine conjugated with biotin (PLCB) is utilized to maintain the sensitivity of the SnS2 /h-BN FET because of the π-π stacking. The detection capabilities of SnS2 /h-BN FET are investigated using both Raman spectroscopy and electrical characterizations. The real-time electrical measurements exhibit that the SnS2 /h-BN FET is capable of detecting streptavidin at a remarkably low concentration of 0.5 pm, within 13.2s. Additionally, the selectivity of the device is investigated by measuring its response against a Cow-like serum egg white protein (BSA), having a comparative molecular weight to that of the streptavidin. These results indicate a high sensitivity and rapid response of SnS2 /h-BN biosensor against the selective proteins, which can have significant implications in several fields including point-of-care diagnostics, drug discovery, and environmental monitoring.

An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function

Autophosphorylation controls the transition between discrete functional and conformational states in protein kinases, yet the structural and molecular determinants underlying this fundamental process remain unclear. Here we show that c-terminal Tyr 530 is a de facto c-Src autophosphorylation site with slow time-resolution kinetics and a strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes faster kinetics and a cis-to-trans phosphorylation switch that controls c-terminal Tyr 530 autophosphorylation, enzyme specificity, and strikingly, c-Src non-catalytic function as a substrate. In line with this, we visualize by X-ray crystallography a snapshot of Tyr 530 intermolecular autophosphorylation. In an asymmetric arrangement of both catalytic domains, a c-terminal palindromic phospho-motif flanking Tyr 530 on the substrate molecule engages the G-loop of the active kinase adopting a position ready for entry into the catalytic cleft. Perturbation of the phospho-motif accounts for c-Src dysfunction as indicated by viral and colorectal cancer (CRC)-associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 autophosphorylation, and such a detrimental effect is caused by the substrate molecule inhibiting allosterically the active kinase. Our work reveals a crosstalk between the activation and c-terminal segments that control the allosteric interplay between substrate- and enzyme-acting kinases during autophosphorylation.

Improving the Selectivity of the C-C Coupled Product Electrosynthesis by Using Molecularly Imprinted Polymer─An Enhanced Route from Phenol to Biphenol.

We developed a procedure for selective 2,4-dimethylphenol, DMPh, direct electro-oxidation to 3,3',5,5'-tetramethyl-2,2'-biphenol, TMBh, a C-C coupled product. For that, we used an electrode coated with a product-selective molecularly imprinted polymer (MIP). The procedure is reasonably selective toward TMBh without requiring harmful additives or elevated temperatures. The TMBh product itself was used as a template for imprinting. We followed the template interaction with various functional monomers (FMs) using density functional theory (DFT) simulations to select optimal FM. On this basis, we used a prepolymerization complex of TMBh with carboxyl-containing FM at a 1:2 TMBh-to-FM molar ratio for MIP fabrication. The template-FM interaction was also followed by using different spectroscopic techniques. Then, we prepared the MIP on the electrode surface in the form of a thin film by the potentiodynamic electropolymerization of the chosen complex and extracted the template. Afterward, we characterized the fabricated films by using electrochemistry, FTIR spectroscopy, and AFM, elucidating their composition and morphology. Ultimately, the DMPh electro-oxidation was performed on the MIP film-coated electrode to obtain the desired TMBh product. The electrosynthesis selectivity was much higher at the electrode coated with MIP film in comparison with the reference nonimprinted polymer (NIP) film-coated or bare electrodes, reaching 39% under optimized conditions. MIP film thickness and electrosynthesis parameters significantly affected the electrosynthesis yield and selectivity. At thicker films, the yield was higher at the expense of selectivity, while the electrosynthesis potential increase enhanced the TMBh product yield. Computer simulations of the imprinted cavity interaction with the substrate molecule demonstrated that the MIP cavity promoted direct coupling of the substrate to form the desired TMBh product.

Insights into mechanisms on electrochemical oxygen evolution substitution reactions

The high total energy consumption of water electrolysis systems is often attributed to the slow kinetics of oxygen evolution reaction (OER). To address this issue, substituting small molecule oxidation reaction that is thermodynamically more advantageous for OER at the anode can significantly increase its energy conversion efficiency. Diversified oxidation substrates can ensure efficient conversion of the cathodic reaction while generating high value-added products or pollutant degradation at the anode. However, the complexity of the elemental composition of the substrate requires an in-depth study of the reaction mechanism. This review focuses on the mechanism of electrooxidation of different substrate molecules, such as ethanol, urea, and hydrazine. Additionally, it introduces some design ideas and strategies for high-performance electrocatalysts in conjunction with reaction path selectivity. The work also foresees the challenges in achieving industrial transformation in this field.

3D Oxide-Derived Ru Catalyst for Ultra-Efficient Hydrogenation of Levulinic Acid to γ-Valerolactone.

γ-valerolactone (GVL) is a key value-added chemical catalytically produced from levulinic acid (LA), an important biomass derivative platform chemical. Here an ultra-efficient 3D Ru catalyst generated by in situ reduction of RuZnOx nanoboxes is reported; the catalyst features a well-defined structure of highly dispersed in situ oxide-derived Ru (IOD-Ru) clusters (≈1nm in size) spatially confined within the 3D nanocages with rich mesopores, which guarantees a maximized atom utilization with a high exposure of Ru active sites as well as a 3D accessibility for substrate molecules. The IOD-Ru exhibits ultrahigh performance for the hydrogenation of LA into GVL with a record-breaking turnover frequency (TOF) up to 59400 h-1 , 14 times higher than that of the ex situ reduction of RuZnOx nanoboxes catalyst. Structural characterizations and theoretical calculations collectively indicate that the defect-rich and coordination-unsaturated IOD-Ru sites can boost the activation of the carbonyl group in LA with a significantly lowered energy barrier of hydrogenation.

Computational analyses of RPIA gene mutation causing Ribose-5-phosphate isomerase deficiency: a rarest known metabolic disorder in humans

The main aim of current study was to perform in silico functional analysis of all reported RPIA mutations. In silico analysis was done using different tools i.e. trRosetta tool, Autodock Vina, PatchDock and iMODS. Among all the reported mutations, lowest percentage identity of 4.69% with wild-type protein was shown by splice site mutation, while highest percentage identity of 78.78%, was shown by p.Ser61Val mutation. In protein-substrate docking, wild-type protein was docking with substrate with 11 different bonds. However in case of mutant protein highest interaction with substrate molecule was shown by mutant p.Ile257Thr proteins via 13 different bonds, while lowest interaction was noted in mutant p.Asn255Ilefs17Term protein via 5 bonds. From the results, it was concluded that the binding of RPIA with ribose 5-phosphate is altered by the type of amino acid substitution, as well as the nature and number of bonds, which are capable to influence its biological activity.