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Autophagy Apr 2023The acidic environment within lysosomes is maintained within a narrow pH range (pH 4.5-5.0) optimal for digesting autophagic cargo macromolecules so that the resulting...
The acidic environment within lysosomes is maintained within a narrow pH range (pH 4.5-5.0) optimal for digesting autophagic cargo macromolecules so that the resulting building block metabolites can be reused. This pH homeostasis is a consequence of proton influx produced by a V-type H-translocating ATPase (V-ATPase) and rapid proton efflux through an unidentified "leak" pathway. By performing a candidate expression screening, we discovered that the gene encodes a proton-activated, proton-selective channel (LyPAP) that is required for lysosomal H "leak" currents. The activity of LyPAP is most active when lysosomes are hyper-acidified, and cells lacking TMEM175 exhibit lysosomal hyper-acidification and impaired proteolytic degradation, both of which can be restored by optimizing lysosomal pH using pharmacological agents. Variants of that are associated with susceptibility to Parkinson disease (PD) cause a reduction in TMEM175-dependent LyPAP currents and lysosomal hyper-acidification. Hence, our studies not only reveal an essential H-dissipating pathway in lysosomes, but also provide a molecular target to regulate pH-dependent lysosomal functions and associated pathologies.
Topics: Vacuolar Proton-Translocating ATPases; Autophagy; Protons; Acids; Lysosomes; Hydrogen-Ion Concentration
PubMed: 36120744
DOI: 10.1080/15548627.2022.2125629 -
Chemical Reviews Aug 2021This Review describes the development of strategies for carbonyl-olefin metathesis reactions relying on stepwise, stoichiometric, or catalytic approaches. A... (Review)
Review
This Review describes the development of strategies for carbonyl-olefin metathesis reactions relying on stepwise, stoichiometric, or catalytic approaches. A comprehensive overview of currently available methods is provided starting with Paternò-Büchi cycloadditions between carbonyls and alkenes, followed by fragmentation of the resulting oxetanes, metal alkylidene-mediated strategies, [3 + 2]-cycloaddition approaches with strained hydrazines as organocatalysts, Lewis acid-mediated and Lewis acid-catalyzed strategies relying on the formation of intermediate oxetanes, and protocols based on initial carbon-carbon bond formation between carbonyls and alkenes and subsequent Grob-fragmentations. The Review concludes with an overview of applications of these currently available methods for carbonyl-olefin metathesis in complex molecule synthesis. Over the past eight years, the field of carbonyl-olefin metathesis has grown significantly and expanded from stoichiometric reaction protocols to efficient catalytic strategies for ring-closing, ring-opening, and cross carbonyl-olefin metathesis. The aim of this Review is to capture the status quo of the field and is expected to contribute to further advancements in carbonyl-olefin metathesis in the coming years.
Topics: Alkenes; Carbon; Catalysis; Cycloaddition Reaction; Lewis Acids
PubMed: 34133136
DOI: 10.1021/acs.chemrev.0c01096 -
Clinical Journal of the American... Aug 2021Acid-related injury from chronic metabolic acidosis is recognized through growing evidence of its deleterious effects, including kidney and other organ injury.... (Review)
Review
Acid-related injury from chronic metabolic acidosis is recognized through growing evidence of its deleterious effects, including kidney and other organ injury. Progressive acid accumulation precedes the signature manifestation of chronic metabolic acidosis, decreased plasma bicarbonate concentration. Acid accumulation that is not enough to manifest as metabolic acidosis, known as eubicarbonatemic acidosis, also appears to cause kidney injury, with exacerbated progression of CKD. Chronic engagement of mechanisms to mitigate the acid challenge from Western-type diets also appears to cause kidney injury. Rather than considering chronic metabolic acidosis as the only acid-related condition requiring intervention to reduce kidney injury, this review supports consideration of acid-related injury as a continuum. This "acid stress" continuum has chronic metabolic acidosis at its most extreme end, and high-acid-producing diets at its less extreme, yet detrimental, end.
Topics: Acid-Base Equilibrium; Acidosis; Acids; Bicarbonates; Chronic Disease; Diet; Glomerular Filtration Rate; Humans; Kidney Diseases; Stress, Physiological
PubMed: 33741720
DOI: 10.2215/CJN.17541120 -
Molecules (Basel, Switzerland) Feb 20202-Formylphenylboronic acids display many interesting features, not only from synthetic but also from an application as well as structural points of view....
2-Formylphenylboronic acids display many interesting features, not only from synthetic but also from an application as well as structural points of view. 5-Trifluoromethyl-2-formyl phenylboronic acid has been synthesized and characterized in terms of its structure and properties. The presence of an electron-withdrawing substituent results in a considerable rise in the acidity in comparison with its analogues. In some solutions, the title compound isomerizes with formation of the corresponding 3hydroxybenzoxaborole. Taking into account the probable mechanism of antifungal action of benzoxaboroles, which blocks the cytoplasmic leucyl-tRNA synthetase (LeuRS) of the microorganism, docking studies with the active site of the enzymes have been carried out. It showed possible binding of the cyclic isomer into the binding pocket of LeuRS, similar to that of the recently approved benzoxaborole antifungal drug (, Tavaborole, Kerydin). In case of LeuRS, the opened isomer displays a much higher inhibition constant in comparison with the cyclic one. The antimicrobial activity of the title compound was also investigated , showing moderate action against . The compound reveals higher activity against as well as bacteria such as and . In case of , the determined Minimum Inhibitory Concentration (MIC) value is lower than that of (Tavaborole). The results confirm potential of 2-formylphenylboronic acids as antibacterial agents and give a hint of their possible mechanism of action.
Topics: Anti-Bacterial Agents; Antifungal Agents; Benzaldehydes; Boronic Acids; Candida albicans; Escherichia coli; Leucine-tRNA Ligase; Microbial Sensitivity Tests
PubMed: 32059517
DOI: 10.3390/molecules25040799 -
ACS Sensors Apr 2021Boronic acids can reversibly bind diols, a molecular feature that is ubiquitous within saccharides, leading to their use in the design and implementation of sensors for... (Review)
Review
Boronic acids can reversibly bind diols, a molecular feature that is ubiquitous within saccharides, leading to their use in the design and implementation of sensors for numerous saccharide species. There is a growing understanding of the importance of saccharides in many biological processes and systems; while saccharide or carbohydrate sensing in medicine is most often associated with detection of glucose in diabetes patients, saccharides have proven to be relevant in a range of disease states. Herein the relevance of carbohydrate sensing for biomedical applications is explored, and this review seeks to outline how the complexity of saccharides presents a challenge for the development of selective sensors and describes efforts that have been made to understand the underpinning fluorescence and binding mechanisms of these systems, before outlining examples of how researchers have used this knowledge to develop ever more selective receptors.
Topics: Boronic Acids; Carbohydrates; Glucose; Humans
PubMed: 33844515
DOI: 10.1021/acssensors.1c00462 -
Journal of Industrial Microbiology &... Apr 2022Organic acids are an important class of compounds that can be produced by microbial conversion of renewable feedstocks and have huge demands and broad applications in... (Review)
Review
Organic acids are an important class of compounds that can be produced by microbial conversion of renewable feedstocks and have huge demands and broad applications in food, chemical, and pharmaceutical industries. An economically viable fermentation process for production of organic acids requires robust microbial cell factories with excellent tolerance to low pH conditions, high concentrations of organic acids, and lignocellulosic inhibitors. In this review, we summarize various strategies to engineer robust microorganisms for organic acid production and highlight their applications in a few recent examples.
Topics: Acids; Fermentation; Metabolic Engineering; Organic Chemicals
PubMed: 34549297
DOI: 10.1093/jimb/kuab067 -
Applied Microbiology and Biotechnology Jan 2020Microorganisms encounter acid stress during multiple bioprocesses. Microbial species have therefore developed a variety of resistance mechanisms. The damage caused by... (Review)
Review
Microorganisms encounter acid stress during multiple bioprocesses. Microbial species have therefore developed a variety of resistance mechanisms. The damage caused by acidic environments is mitigated through the maintenance of pH homeostasis, cell membrane integrity and fluidity, metabolic regulation, and macromolecule repair. The acid tolerance mechanisms can be used to protect probiotics against gastric acids during the process of food intake, and can enhance the biosynthesis of organic acids. The combination of systems and synthetic biology technologies offers new and wide prospects for the industrial applications of microbial acid tolerance mechanisms. In this review, we summarize acid stress response mechanisms of microbial cells, illustrate the application of microbial acid tolerance in industry, and prospect the introduction of systems and synthetic biology to further explore the acid tolerance mechanisms and construct a microbial cell factory for valuable chemicals.
Topics: Acids; Bacteria; Gastric Acid; Hydrogen-Ion Concentration; Industrial Microbiology; Metabolic Engineering; Probiotics; Stress, Physiological; Synthetic Biology; Systems Biology
PubMed: 31773206
DOI: 10.1007/s00253-019-10226-1 -
Molecules (Basel, Switzerland) Sep 2019Indole derivatives are associated with a variety of both biological activities and applications in the field of material chemistry. A number of different strategies for... (Review)
Review
Indole derivatives are associated with a variety of both biological activities and applications in the field of material chemistry. A number of different strategies for synthesizing substituted indoles by means of the reactions of indolylboronic acids with electrophilic compounds are considered the methods of choice for modifying indoles because indolylboronic acids are easily available, stable, non-toxic and new reactions using indolylboronic acids have been described in the literature. Thus, the aim of this review is to summarize the methods available for the preparation of indolylboronic acids as well as their chemical transformations. The review covers the period 2010-2019.
Topics: Boronic Acids; Cyclization; Indoles; Metabolic Networks and Pathways; Metals; Models, Chemical; Molecular Structure
PubMed: 31569441
DOI: 10.3390/molecules24193523 -
Journal of Computational Chemistry Feb 2023The determination of gas phase thermochemical properties of per- and polyfluoroalkyl substances (PFAS) is central to understanding the long-range transport behavior of...
The determination of gas phase thermochemical properties of per- and polyfluoroalkyl substances (PFAS) is central to understanding the long-range transport behavior of PFAS in the atmosphere. Prior gas-phase studies have reported the properties of perfluorinated sulfonic acid (PFOS) and perfluorinated octanoic acid (PFOA). Here, this study reports the gas phase enthalpies of formation of short- and long-chain PFAS and their precursor molecules determined using density functional theory (DFT) and ab initio approaches. Two density functionals, two ab initio methods and an empirical method were used to compute enthalpies of formation with the total atomization approach and an isogyric reaction. The performance of the computational methods employed in this work were validated against the experimental enthalpies of linear alkanoic acids and perfluoroalkanes. The gas-phase determinations will be useful for future studies of PFAS in the atmosphere, and the methodological choices will be helpful in the study of other PFAS.
Topics: Alkanesulfonic Acids; Sulfonic Acids; Fluorocarbons; Thermodynamics; Environmental Pollutants
PubMed: 36334029
DOI: 10.1002/jcc.27023 -
International Journal of Molecular... Nov 2021Peptides inherently feature the favorable properties of being easily synthesized, water-soluble, biocompatible, and typically non-toxic. Thus, boronic acid has been... (Review)
Review
Peptides inherently feature the favorable properties of being easily synthesized, water-soluble, biocompatible, and typically non-toxic. Thus, boronic acid has been widely integrated with peptides with the goal of discovering peptide ligands with novel biological activities, and this effort has led to broad applications. Taking the integration between boronic acid and peptide as a starting point, we provide an overview of the latest research advances and highlight the versatile and robust functionalities of boronic acid. In this review, we summarize the diverse applications of peptide boronic acids in medicinal chemistry and chemical biology, including the identification of covalent reversible enzyme inhibitors, recognition, and detection of glycans on proteins or cancer cell surface, delivery of siRNAs, development of pH responsive devices, and recognition of RNA or bacterial surfaces. Additionally, we discuss boronic acid-mediated peptide cyclization and peptide modifications, as well as the facile chemical synthesis of peptide boronic acids, which paved the way for developing a growing number of peptide boronic acids.
Topics: Antineoplastic Agents; Boron Compounds; Boronic Acids; Bortezomib; Drug Design; Enzyme Inhibitors; Glycine; Humans; Peptides; Protease Inhibitors
PubMed: 34884766
DOI: 10.3390/ijms222312958