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1. Substrate-Dependent Sensitivity of SIRT1 to Nicotinamide Inhibition

   https://doi.org/10.3390/biom11020312  

   Rymarchyk, Stacia; Kang, Wenjia; Cen, Yana (February 2021, Biomolecules)

   null (Ed.)

   SIRT1 is the most extensively studied human sirtuin with a broad spectrum of endogenous targets. It has been implicated in the regulation of a myriad of cellular events, such as gene transcription, mitochondria biogenesis, insulin secretion as well as glucose and lipid metabolism. From a mechanistic perspective, nicotinamide (NAM), a byproduct of a sirtuin-catalyzed reaction, reverses a reaction intermediate to regenerate NAD+ through “base exchange”, leading to the inhibition of the forward deacetylation. NAM has been suggested as a universal sirtuin negative regulator. Sirtuins have evolved different strategies in response to NAM regulation. Here, we report the detailed kinetic analysis of SIRT1-catalyzed reactions using endogenous substrate-based synthetic peptides. A novel substrate-dependent sensitivity of SIRT1 to NAM inhibition was observed. Additionally, SIRT1 demonstrated pH-dependent deacetylation with normal solvent isotope effects (SIEs), consistent with proton transfer in the rate-limiting step. Base exchange, in contrast, was insensitive to pH changes with no apparent SIEs, indicative of lack of proton transfer in the rate-limiting step. Consequently, NAM inhibition was attenuated at a high pH in proteated buffers. Our study provides new evidence for “activation by de-repression” as an effective sirtuin activation strategy. 

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2. Discovery of Molecular Intermediates and Nonclassical Nanoparticle Formation Mechanisms by Liquid Phase Electron Microscopy and Reaction Throughput Analysis

   https://doi.org/10.1002/sstr.202400146  

   Sun, Jiayue; Fritsch, Birk; Körner, Andreas; Taherkhani, Mehran; Park, Chiwoo; Wang, Mei; Hutzler, Andreas; Woehl, Taylor J (August 2024, Small Structures)

   Formation kinetics of metal nanoparticles are generally describedviamass transport and thermodynamics‐based models, such as diffusion‐limited growth and classical nucleation theory (CNT). However, metal monomers are commonly assumed as precursors, leaving the identity of molecular intermediates and their contribution to nanoparticle formation unclear. Herein, liquid phase transmission electron microscopy (LPTEM) and reaction kinetic modeling are utilized to establish the nucleation and growth mechanisms and discover molecular intermediates during silver nanoparticle formation. Quantitative LPTEM measurements show that their nucleation rate decreases while growth rate is nearly invariant with electron dose rate. Reaction kinetic simulations show that Ag₄and Ag⁻follow a statistically similar dose rate dependence as the experimentally determined growth rate. We show that experimental growth rates are consistent with diffusion‐limited growthviathe attachment of these species to nanoparticles. The dose rate dependence of nucleation rate is inconsistent with CNT. A reaction‐limited nucleation mechanism is proposed and it is demonstrated that experimental nucleation kinetics are consistent with Ag₄²⁺aggregation rates at millisecond time scales. Reaction throughput analysis of the kinetic simulations uncovered formation and decay pathways mediating intermediate concentrations. We demonstrate the power of quantitative LPTEM combined with kinetic modeling for establishing nanoparticle formation mechanisms and principal intermediates. 

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3. Explaining Kinetic Trends of Inner-Sphere Transition-Metal-Ion Redox Reactions on Metal Electrodes

   https://doi.org/10.1021/acscatal.2c05694  

   Agarwal, Harsh; Florian, Jacob; Pert, Daniel; Goldsmith, Bryan R.; Singh, Nirala (January 2023, ACS Catalysis)

   Transition-metal ions regularly undergo charge transfer (CT) by directly interacting with electrodes, and this CT governs the performance of devices for numerous applications like energy storage and catalysis. These CT reactions are deemed inner sphere because they involve direct formation of a chemical bond between the electrode and the metal ion. Predicting inner-sphere CT kinetics on electrodes using simple physicochemical descriptors would aid the design of electrochemical systems with improved kinetics. Herein, we report that the average energy of the d electrons (i.e., d-band center) of a transition-metal electrode rationalizes the kinetic trends of inner-sphere CT of transition-metal ions. We demonstrate that V2+/V3+, an important redox reaction for flow batteries, is an inner-sphere reaction and that the kinetic parameters correlate with the adsorption strength of the vanadium intermediate on Au, Ag, Cu, Bi, and W electrodes, with W being the most active electrode reported to date. We show that the adsorption strength of the vanadium intermediate linearly correlates with the d-band center such that the d-band center serves as a simple descriptor for the V2+/V3+ kinetics. We extract kinetic data from the literature for four other inner-sphere CT reactions of metal ions involving Cr-, Fe-, and Co-based complexes to show that the d-band center also linearly correlates with kinetic trends for these systems. The d-band center of the electrode is a general descriptor for heterogeneous inner-sphere CT because it correlates with the adsorption strength of the metal-ion intermediate. The d-band center descriptor is analogous to the d-electron configuration of metal ions serving as a descriptor for homogeneous inner-sphere CT because the d-electron configuration controls bond strengths of intermediate metal-ion complexes. 

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4. Analysis of multi-electron, multi-step homogeneous catalysis by rotating disc electrode voltammetry: theory, application, and obstacles

   https://doi.org/10.1039/C9AN02192B  

   Lee, Katherine J.; Gruninger, Cole T.; Lodaya, Kunal M.; Qadeer, Saad; Griffith, Boyce E.; Dempsey, Jillian L. (February 2020, The Analyst)

   Rotating disc electrode (RDE) voltammetry has been widely adopted for the study of heterogenized molecular electrocatalysts for multi-step fuel-forming reactions but this tool has never been comprehensively applied to their homogeneous analogues. Here, the utility and limitations of RDE techniques for mechanistic and kinetic analysis of homogeneous molecular catalysts that mediate multi-electron, multi-substrate redox transformations are explored. Using the ECEC′ reaction mechanism as a case study, two theoretical models are derived based on the Nernst diffusion layer model and the Hale transformation. Current–potential curves generated by these computational strategies are compared under a variety of limiting conditions to identify conditions under which the more minimalist Nernst Diffusion Layer approach can be applied. Based on this theoretical treatment, strategies for extracting kinetic information from the plateau current and the foot of the catalytic wave are derived. RDEV is applied to a cobaloxime hydrogen evolution reaction (HER) catalyst under non-aqueous conditions in order to experimentally validate this theoretical framework and explore the feasibility of RDE as a tool for studying homogeneous catalysts. Crucially, analysis of the foot-of-the-wave via this theoretical framework provides rate constants for elementary reaction steps that agree with those extracted from stationary voltammetric methods, supporting the application of RDE to study homogeneous fuel-forming catalysts. Finally, obstacles encountered during the kinetic analysis of cobaloxime, along with the voltammetric signatures used to diagnose this reactivity, are discussed with the goal of guiding groups working to improve RDE set-ups and help researchers avoid misinterpretation of RDE data. 

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5. Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C–H amination of alkynes

   https://doi.org/10.1039/D1SC07067C  

   Maloney, T. Parker; Dohoda, Alexander F.; Zhu, Alec C.; Michael, Forrest E. (February 2022, Chemical Science)

   Herein we report an intermolecular propargylic C–H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C–N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities. 

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