With over 78 million new infections globally each year, gonorrhea remains a frustratingly common infection. Continuous development and spread of antimicrobial-resistant strains of Neisseria gonorrhoeae, the causative agent of gonorrhea, have posed a serious threat to public health. One of the mechanisms in N. gonorrhoeae involved in resistance to multiple drugs is performed by the MtrD multidrug resistance efflux pump. This study demonstrated that the MtrD pump has a broader substrate specificity than previously proposed and identified a cluster of residues important for drug binding and translocation. Additionally, a permeation pathway for the MtrD substrate progesterone actively moving through the protein was determined, revealing key interactions within the putative MtrD drug binding pockets. Identification of functionally important residues and substrate-protein interactions of the MtrD protein is crucial to develop future strategies for the treatment of multidrug-resistant gonorrhea.
Enzymes, as nature’s catalysts, speed up the very reactions that make life possible. Hydrolytic enzymes are a particularly important enzyme class responsible for the catalytic breakdown of lipids, starches, and proteins in nature, and they are displaying increasing industrial relevance. While the unrivalled catalytic effect of enzymes continues to be unmatched by synthetic systems, recent progress has been made in the design of hydrolase-inspired catalysts by imitating and incorporating specific features observed in native enzyme protein structures. The development of such enzyme-inspired materials holds promise for more robust and industrially relevant alternatives to enzymatic catalysis, as well as deeper insights into the function of native enzymes. This Review will explore recent research in the development of synthetic catalysts based on the chemistry of hydrolytic enzymes. A focus on the key aspects of hydrolytic enzyme structure and catalytic mechanism will be exploredincluding active-site chemistry, tuning transition-state interactions, and establishing reactive nanoenvironments conducive to attracting, binding, and releasing target molecules. A key focus is to highlight the progress toward an effective, versatile hydrolase-inspired catalyst by incorporating the molecular design principles laid down by nature.
Oriented electrostatic fields can exert catalytic effects upon both the kinetics and thermodynamics of chemical reactions; however, the vast majority of studies thus far have focused upon ground state chemistry and rarely consider any more than a single class of reaction. In the present study, we first use density functional theory (DFT) calculations to clarify the mechanism of CO2 storage via photochemical carboxylation of o-alkylphenyl ketones, originally proposed by Murakami et al. (J. Am. Chem. Soc. 2015, 137, 14063); we then demonstrate that oriented internal electrostatic fields arising from remote charged functional groups (CFGs) can selectively and cooperatively promote both ground-and excited-state chemical reactivity at all points along the revised mechanism, in a manner otherwise difficult to access via classical substituent effects. What is particularly striking is that electrostatic field effects upon key photochemical transitions are predictably enhanced in increasingly polar solvent, thus overcoming a central limitation of the electrostatic catalysis paradigm. We explain these observations, which should be readily extendable to the ground state.
Density functional theory calculations at the SMD/M06-2X/6-31+G(d,p)//M06-2X/6-31G(d) level of theory have been used to computationally design and test a pH-switchable electrostatic organocatalyst for Diels–Alder reactions. The successful catalyst design, bis(3-(3-phenylureido)benzyl)ammonium, was studied for the reaction of p-quinone with range of cyclic, heterocyclic, and acyclc dienes and also the reaction of cyclopentadiene with maleimide and N-phenylmaleimide. All reactions showed significant enhancements in catalysis (10–32 kJ mol–1 in barrier lowering) when the catalyst was protonated, consistent with electrostatic stabilization of the transition state. Electrostatic effects were found to diminish in polar solvents but were predicted to remain significant in nonpolar solvents.
The remarkable power of enzymes to undertake catalysis frequently stems from their grouping of multiple, complementary chemical units within close proximity around the enzyme active site. Motivated by this, we report here a bioinspired surfactant catalyst that incorporates a variety of chemical functionalities common to hydrolytic enzymes. The textbook hydrolase active site, the catalytic triad, is modeled by positioning the three groups of the triad (-OH, -imidazole, and -CO2H) on a single, trifunctional surfactant molecule. To support this, we recreate the hydrogen bond donating arrangement of the oxyanion hole by imparting surfactant functionality to a guanidinium headgroup. Self-assembly of these amphiphiles in solution drives the collection of functional headgroups into close proximity around a hydrophobic nano-environment, affording hydrolysis of a model ester at rates that challenge α-chymotrypsin. Structural assessment via NMR and XRD, paired with MD simulation and QM calculation, reveals marked similarities of the co-micelle catalyst to native enzymes.
The αIIbβ3 integrin receptor coordinates platelet adhesion, activation and mechanosensing in thrombosis and haemostasis. Using differential cysteine alkylation and mass spectrometry, we have identified a disulfide bond in the αIIb subunit linking cysteines 490 and 545 that is missing in about one in three integrin molecules on the resting and activated human platelet surface. This alternate covalent form of αIIbβ3 is pre-determined as it is also produced by human megakaryoblasts and baby hamster kidney fibroblasts (BHK) transfected with recombinant integrin. From co-immunoprecipitation experiments, the alternate form selectively partitions into focal adhesions on the activated platelet surface. Its function was evaluated in BHK cells expressing a mutant integrin with an ablated C490-C545 disulfide bond. The disulfide mutant integrin has functional outside-in signalling but extended residency time in focal adhesions due to reduced rate of clathrin-mediated integrin internalisation and recycling, which is associated with enhanced affinity of the αIIb subunit for clathrin adaptor protein-2. Molecular dynamics simulations indicate that the alternate covalent form of αIIb requires higher forces to transition from bent to open conformational states that is in accordance with reduced affinity for fibrinogen and activation by manganese ions. These findings indicate that the αIIbβ3 integrin receptor is produced in different covalent forms that have different cell surface distribution and function. The C490, C545 cysteine pair is conserved across all 18 integrin α subunits and the disulfide bond in the αV and α2 subunits in cultured cells is similarly missing, suggesting that this alternate integrin form and function is also conserved.
Instantaneous and spontaneous room temperature C–ON bond mesolysis of alkoxyamines triggered by chemical oxidation.
The first broad spectrum investigation into the photoenolization/Diels-Alder (PEDA) sequence was carried out using M06-2X/6-31+G(d,p) in conjunction with SMD solvation and supported by experimental UV−vis spectroscopy. A test set of 20 prodienes was chosen to examine the role of the H atom acceptor group (substituted and unsubstituted carbonyl, thiocarbonyl, and imine), the H atom donor group, and bystander ring substituents. As reaction partners for the photogenerated dienes, a diverse test set of 20 dienophiles was examined, comprising electron rich, electron poor, neutral, strain activated, hydrocarbon, and heteroatom-containing molecules including CO 2 and CO. A key finding of this work is the demonstration that the PEDA sequence of carbonyl based prodienes is tolerant of most substitution patterns. Another is that thiocarbonyl derivatives should behave analogously to the carbonyls but are likely to do so much more slowly, due to an inefficient intersystem crossing, an endothermic 1,5-hydrogen atom transfer (HAT) step, and a [1,5] sigmatropic H shift to regenerate the starting material that outcompetes the [4 + 2]cycloaddition. In contrast, the T 1 state of the ortho-alkyl imines displays the incorrect orbital symmetry for 1,5-HAT and is correspondingly accompanied by higher barriers, even in the excited state. However, provided these barriers can be overcome, the remaining steps in the PEDA sequence are predicted to be facile. The Diels−Alder reaction is predicted to be of much broader scope than reported synthetic literature: while electron poor dienophiles are expected to be the most reactive partners, ethylene and electron rich alkenes should react at a synthetically useful rate. CO is predicted to undergo a facile (4 + 1)cheletropic addition instead of the normal [4 + 2]cycloaddition pathway. This unique photoenolization/cheletropic addition (PECA) sequence could provide metal-free access to benzannelated cyclopentanones.
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