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Chemical Reviews May 2021All living cells are surrounded by lipidic membranes that separate metabolic and macromolecular biosynthetic processes from external environments. Biological membranes...
All living cells are surrounded by lipidic membranes that separate metabolic and macromolecular biosynthetic processes from external environments. Biological membranes vary dramatically in their composition and structures and are optimized by mega-annum of evolution to effectively carry out diverse biological functions including energy production, biosynthetic reactions, signaling, uptake of nutrients and active efflux, and others. This thematic issue of , "Transporters, Porins, and Efflux Pumps", is focused on the function of biological membranes as a permeability barrier and on the proteins that create, maintain, and bypass this barrier. Effective therapeutic interventions rely on active and passive permeation of various molecules and compounds across membranes, and our successes in development of such therapeutics are strongly affected by structural and functional insights into the assembly and function of cellular permeation barriers.
Topics: Animals; Bacteria; Biological Transport; Cell Membrane; Diffusion; Eukaryotic Cells; Humans; Membrane Lipids; Porins; Solute Carrier Proteins
PubMed: 33975431
DOI: 10.1021/acs.chemrev.1c00010 -
Advances in Experimental Medicine and... 2023Aquaporins (AQP) working as membrane channels facilitated water transport, play vital roles in various physiological progress including cell migration, energy...
Aquaporins (AQP) working as membrane channels facilitated water transport, play vital roles in various physiological progress including cell migration, energy metabolism, inflammation, etc. They are quite important drug targets, but elusive for discovery due to their undruggable properties. In this chapter, we summarized most fluently used methods for screening AQP inhibitors, including cell swelling assay, cell shrinking assay, and stopped-flow assay. And three classes of AQP inhibitors have been discussed, including metal-related inhibitors, quaternary ammonium salts, and small molecule inhibitors which further divided into four parts, sulfanilamide analogies, TGN-020, antiepileptic drugs, and others. It has been suggested that although they showed inhibition effects on AQP1, AQP3, AQP4, AQP7, or AQP9 in some researches, none of them could be asserted as AQP inhibitors to some extent. Discovering AQP inhibitors is a big challenge, but if successful, it will be a great contribution for human health.
Topics: Humans; Aquaporin 1; Aquaporin 3; Aquaporin 4; Aquaporins; Biological Transport
PubMed: 36717504
DOI: 10.1007/978-981-19-7415-1_22 -
International Journal of Molecular... Jan 2023Aquaporin-5 (AQP5), belonging to the aquaporins (AQPs) family of transmembrane water channels, facilitates osmotically driven water flux across biological membranes and... (Review)
Review
Aquaporin-5 (AQP5), belonging to the aquaporins (AQPs) family of transmembrane water channels, facilitates osmotically driven water flux across biological membranes and the movement of hydrogen peroxide and CO. Various mechanisms have been shown to dynamically regulate AQP5 expression, trafficking, and function. Besides fulfilling its primary water permeability function, AQP5 has been shown to regulate downstream effectors playing roles in various cellular processes. This review provides a comprehensive overview of the current knowledge of the upstream and downstream effectors of AQP5 to gain an in-depth understanding of the physiological and pathophysiological processes involving AQP5.
Topics: Aquaporin 5; Aquaporins; Cell Membrane; Permeability; Water
PubMed: 36768212
DOI: 10.3390/ijms24031889 -
Revista Espanola de Quimioterapia :... Sep 2022Cefiderocol, a siderophore catechol cephalosporin, recently introduced in the market has been developed to enhance the in vitro activity of extended spectrum... (Review)
Review
Cefiderocol, a siderophore catechol cephalosporin, recently introduced in the market has been developed to enhance the in vitro activity of extended spectrum cephalosporins and to avoid resistance mechanisms affecting cephalosporins and carbapenems. The in vitro study of cefiderocol in the laboratory requires iron depleted media when MIC values are determined by broth microdilution. Disk diffusion presents good correlation with MIC values. In surveillance studies and in clinical trials it has been demonstrated excellent activity against Gram-negatives, including carbapenemase producers and non-fermenters such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Few cefiderocol resistant isolates have been found in surveillance studies. Resistance mechanisms are not directly associated with porin deficiency and or efflux pumps. On the contrary, they are related with gene mutations affecting iron transporters, AmpC mutations in the omega loop and with certain beta-lactamases such us KPC-variants determining also ceftazidime-avibactam resistance, certain infrequent extended-spectrum betalactamases (PER, BEL) and metallo-beta-lactamases (certain NDM variants and SPM enzyme).
Topics: Anti-Bacterial Agents; Carbapenems; Catechols; Cephalosporins; Drug Resistance, Multiple, Bacterial; Humans; Iron; Microbial Sensitivity Tests; Porins; Pseudomonas aeruginosa; Siderophores; beta-Lactamases; Cefiderocol
PubMed: 36193981
DOI: 10.37201/req/s02.03.2022 -
International Journal of Molecular... Feb 2021The evolution of the eukaryotic cell from the primal endosymbiotic event involved a complex series of adaptations driven primarily by energy optimization. Transfer of... (Review)
Review
The evolution of the eukaryotic cell from the primal endosymbiotic event involved a complex series of adaptations driven primarily by energy optimization. Transfer of genes from endosymbiont to host and concomitant expansion (by infolding) of the endosymbiont's chemiosmotic membrane greatly increased output of adenosine triphosphate (ATP) and placed selective pressure on the membrane at the host-endosymbiont interface to sustain the energy advantage. It is hypothesized that critical functions at this interface (metabolite exchange, polypeptide import, barrier integrity to proteins and DNA) were managed by a precursor β-barrel protein ("pβB") from which the voltage-dependent anion-selective channel (VDAC) descended. VDAC's role as hub for disparate and increasingly complex processes suggests an adaptability that likely springs from a feature inherited from pβB, retained because of important advantages conferred. It is proposed that this property is the remarkable structural flexibility evidenced in VDAC's gating mechanism, a possible origin of which is discussed.
Topics: Animals; Humans; Ion Channel Gating; Lipid Bilayers; Membrane Potentials; Mitochondria; Voltage-Dependent Anion Channels
PubMed: 33567508
DOI: 10.3390/ijms22041685 -
Advances in Experimental Medicine and... 2023The skin is the largest organ of our body and plays a protective role against the external environment. The skin functions as a mechanical and water permeability...
The skin is the largest organ of our body and plays a protective role against the external environment. The skin functions as a mechanical and water permeability barrier, assisting with thermoregulation and defending our body against a variety of stresses such as ultraviolet radiation, microbial infection, physical injuries, and chemical hazards. The structure of the skin consists of three main layers: the hypodermis, the dermis, and the epidermis. Aquaporins (AQPs) are a family of integral membrane proteins whose function is to regulate intracellular fluid hemostasis by facilitating the transportation of water, and in some cases small molecules, across the cell membranes. Up to six different AQPs (AQP1, 3, 5, 7, 9, and 10) are expressed in a variety of cell types in the skin. The AQP family plays an important role in these various locations, contributing to many key functions of the skin including hydration, wound healing, and immune responses. The involvement of different aquaporin family members in skin is discussed.
Topics: Ultraviolet Rays; Skin; Aquaporins; Epidermis; Water
PubMed: 36717497
DOI: 10.1007/978-981-19-7415-1_15 -
MBio Jan 2020The evolution of phage resistance poses an inevitable threat to the efficacy of phage therapy. The strategic selection of phage combinations that impose high genetic...
The evolution of phage resistance poses an inevitable threat to the efficacy of phage therapy. The strategic selection of phage combinations that impose high genetic barriers to resistance and/or high compensatory fitness costs may mitigate this threat. However, for such a strategy to be effective, the evolution of phage resistance must be sufficiently constrained to be consistent. In this study, we isolated lytic phages capable of infecting a modified clinical isolate and characterized a total of 57 phage-resistant mutants that evolved from their prolonged coculture Single- and double-phage-resistant mutants were isolated from independently evolved replicate cocultures grown in broth or on plates. Among resistant isolates evolved against the same phage under the same conditions, mutations conferring resistance occurred in different genes, yet in each case, the putative functions of these genes clustered around the synthesis or assembly of specific cell surface structures. All resistant mutants demonstrated impaired phage adsorption, providing a strong indication that these cell surface structures functioned as phage receptors. Combinations of phages targeting different host receptors reduced the incidence of resistance, while, conversely, one three-phage cocktail containing two phages targeting the same receptor increased the incidence of resistance (relative to its two-phage, nonredundant receptor-targeting counterpart). Together, these data suggest that laboratory characterization of phage-resistant mutants is a useful tool to help optimize therapeutic phage selection and cocktail design. The therapeutic use of bacteriophage (phage) is garnering renewed interest in the setting of difficult-to-treat infections. Phage resistance is one major limitation of phage therapy; therefore, developing effective strategies to avert or lessen its impact is critical. Characterization of phage resistance may be an important first step in evaluating the relative likelihood with which phage-resistant populations emerge, the most likely phenotypes of resistant mutants, and the effect of certain phage cocktail combinations in increasing or decreasing the genetic barrier to resistance. If this information confers predictive power , then routine studies of phage-resistant mutants and their evolution should be a valuable means for improving the safety and efficacy of phage therapy in humans.
Topics: Anti-Bacterial Agents; Bacteriophages; Drug Resistance, Multiple, Bacterial; Evolution, Molecular; Genetic Complementation Test; Host-Pathogen Interactions; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Mutation; Porins; Virus Attachment
PubMed: 31992617
DOI: 10.1128/mBio.02530-19 -
Current Opinion in Structural Biology Aug 2021Pore-forming proteins (PFPs) are of special interest because of the association of their activity with the disruption of the membrane impermeability barrier and cell... (Review)
Review
Pore-forming proteins (PFPs) are of special interest because of the association of their activity with the disruption of the membrane impermeability barrier and cell death. They generally convert from a monomeric, soluble form into transmembrane oligomers that induce the opening of membrane pores. The study of pore formation in membranes with molecular detail remains a challenging endeavor because of its highly dynamic and complex nature, usually involving diverse oligomeric structures with different functionalities. Here we discuss current methods applied for the structural and functional characterization of PFPs at the individual vesicle and cell level. We highlight how the development of high-resolution and single-molecule imaging techniques allows the analysis of the structural organization of protein oligomers and pore entities in lipid membranes.
Topics: Cell Membrane; Macromolecular Substances; Porins
PubMed: 33945958
DOI: 10.1016/j.sbi.2021.03.012 -
Biochimica Et Biophysica Acta.... Sep 2021Aquaporin water channels facilitate the bi-directional flow of water and small, neutral solutes down an osmotic gradient in all kingdoms of life. Over the last two... (Review)
Review
Aquaporin water channels facilitate the bi-directional flow of water and small, neutral solutes down an osmotic gradient in all kingdoms of life. Over the last two decades, the availability of high-quality protein has underpinned progress in the structural and functional characterization of these water channels. In particular, recombinant protein technology has guaranteed the supply of aquaporin samples that were of sufficient quality and quantity for further study. Here we review the features of successful expression, purification and characterization strategies that have underpinned these successes and that will drive further breakthroughs in the field. Overall, Escherichia coli is a suitable host for prokaryotic isoforms, while Pichia pastoris is the most commonly-used recombinant host for eukaryotic variants. Generally, a two-step purification procedure is suitable after solubilization in glucopyranosides and most structures are determined by X-ray following crystallization.
Topics: Aquaporins; Crystallography, X-Ray; Escherichia coli; Models, Molecular; Saccharomycetales
PubMed: 34019902
DOI: 10.1016/j.bbamem.2021.183650 -
The Journal of Physiology Jul 2024
Topics: Aquaporins; Humans; Animals
PubMed: 38896793
DOI: 10.1113/JP286369