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World Journal of Microbiology &... Jul 2019Microorganisms have evolved permeases to incorporate various essential nutrients and exclude harmful products, which assists in adaptation to different environmental... (Review)
Review
Microorganisms have evolved permeases to incorporate various essential nutrients and exclude harmful products, which assists in adaptation to different environmental conditions for survival. As permeases are directly involved in the utilization of and regulatory response to nutrient sources, metabolic engineering of microbial permeases can predictably influence nutrient metabolism and regulation. In this mini-review, we have summarized the mechanisms underlying the general regulation of permeases, and the current advancements and future prospects of metabolic engineering strategies targeting the permeases in Saccharomyces cerevisiae. The different types of permeases and their regulatory mechanisms have been discussed. Furthermore, methods for metabolic engineering of permeases have been highlighted. Understanding the mechanisms via which permeases are meticulously regulated and engineered will not only facilitate research on regulation of global nutrition and yeast metabolic engineering, but can also provide important insights for future studies on the synthesis of valuable products and elimination of harmful substances in S. cerevisiae.
Topics: Biological Transport; Carbon; Glucose; Membrane Transport Proteins; Metabolic Engineering; Nitrogen; Saccharomyces cerevisiae
PubMed: 31286266
DOI: 10.1007/s11274-019-2684-z -
Annual Review of Biochemistry Jun 2016The determination of the crystal structures of small-molecule transporters has shed light on the conformational changes that take place during structural isomerization... (Review)
Review
The determination of the crystal structures of small-molecule transporters has shed light on the conformational changes that take place during structural isomerization from outward- to inward-facing states. Rather than using a simple rocking movement of two bundles around a central substrate-binding site, it has become clear that even the most simplistic transporters utilize rearrangements of nonrigid bodies. In the most dramatic cases, one bundle is fixed while the other, structurally divergent, bundle carries the substrate some 18 Å across the membrane, which in this review is termed an elevator alternating-access mechanism. Here, we compare and contrast rocker-switch, rocking-bundle, and elevator alternating-access mechanisms to highlight shared features and novel refinements to the basic alternating-access model.
Topics: Biological Transport; Crystallography, X-Ray; Escherichia coli; Escherichia coli Proteins; Evolution, Molecular; Gene Expression; Kinetics; Membrane Transport Proteins; Molecular Dynamics Simulation; Protein Domains; Protein Structure, Secondary; Thermodynamics
PubMed: 27023848
DOI: 10.1146/annurev-biochem-060815-014520 -
Annual Review of Biophysics 2015The ancient and ubiquitous major facilitator superfamily (MFS) represents the largest secondary transporter family and plays a crucial role in a multitude of... (Review)
Review
The ancient and ubiquitous major facilitator superfamily (MFS) represents the largest secondary transporter family and plays a crucial role in a multitude of physiological processes. MFS proteins transport a broad spectrum of ions and solutes across membranes via facilitated diffusion, symport, or antiport. In recent years, remarkable advances in understanding the structural biology of the MFS transporters have been made. This article reviews the history, classification, and general features of the MFS proteins; summarizes recent structural progress with a focus on the sugar porter family transporters exemplified by GLUT1; and discusses the molecular mechanisms of substrate binding, alternating access, and cotransport coupling.
Topics: Animals; Bacteria; Crystallography, X-Ray; History, 20th Century; History, 21st Century; Humans; Membrane Transport Proteins
PubMed: 26098515
DOI: 10.1146/annurev-biophys-060414-033901 -
Journal of Molecular Biology Aug 2021Infectious diseases present a major threat to public health globally. Pathogens can acquire resistance to anti-infectious agents via several means including... (Review)
Review
Infectious diseases present a major threat to public health globally. Pathogens can acquire resistance to anti-infectious agents via several means including transporter-mediated efflux. Typically, multidrug transporters feature spacious, dynamic, and chemically malleable binding sites to aid in the recognition and transport of chemically diverse substrates across cell membranes. Here, we discuss recent structural investigations of multidrug transporters involved in resistance to infectious diseases that belong to the ATP-binding cassette (ABC) superfamily, the major facilitator superfamily (MFS), the drug/metabolite transporter (DMT) superfamily, the multidrug and toxic compound extrusion (MATE) family, the small multidrug resistance (SMR) family, and the resistance-nodulation-division (RND) superfamily. These structural insights provide invaluable information for understanding and combatting multidrug resistance.
Topics: ATP-Binding Cassette Transporters; Anti-Infective Agents; Drug Resistance, Microbial; Drug Resistance, Multiple; Humans; Membrane Transport Proteins; Structure-Activity Relationship
PubMed: 33891902
DOI: 10.1016/j.jmb.2021.167005 -
Nutrition (Burbank, Los Angeles County,... Feb 2017Tissues with high-energy output, such as the brain and skeletal muscle, suffer the most from impaired or depleted energy levels, with innovative nutritional approaches... (Review)
Review
Tissues with high-energy output, such as the brain and skeletal muscle, suffer the most from impaired or depleted energy levels, with innovative nutritional approaches needed to effectively tackle metabolic deficits in bioenergetics. Here, we highlight the role of guanidinoacetic acid in the control and provision of cellular energy by its interaction with cellular transporters for taurine (SLC6 A6) and γ-aminobutyric acid (SLC6 A13), previously dismissed as "untargetable" carriers by other bioenergetics therapeutics.
Topics: Creatine; Energy Metabolism; GABA Plasma Membrane Transport Proteins; Glycine; Humans; Membrane Glycoproteins; Membrane Transport Proteins
PubMed: 28063512
DOI: 10.1016/j.nut.2016.09.010 -
Nano Letters Jul 2017How complex cytoplasmic membrane proteins insert and fold into cellular membranes is not fully understood. One problem is the lack of suitable approaches that allow...
How complex cytoplasmic membrane proteins insert and fold into cellular membranes is not fully understood. One problem is the lack of suitable approaches that allow investigating the process by which polypeptides insert and fold into membranes. Here, we introduce a method to mechanically unfold and extract a single polytopic α-helical membrane protein, the lactose permease (LacY), from a phospholipid membrane, transport the fully unfolded polypeptide to another membrane and insert and refold the polypeptide into the native structure. Insertion and refolding of LacY is facilitated by the transmembrane chaperone/insertase YidC in the absence of the SecYEG translocon. Insertion into the membrane occurs in a stepwise, stochastic manner employing multiple coexisting pathways to complete the folding process. We anticipate that our approach will provide new means of studying the insertion and folding of membrane proteins and to mechanically reconstitute membrane proteins at high spatial precision and stoichiometric control, thus allowing the functional programming of synthetic and biological membranes.
Topics: Cell Membrane; Escherichia coli Proteins; Membrane Transport Proteins; Membranes, Artificial; Models, Molecular; Monosaccharide Transport Proteins; Phospholipids; Protein Binding; Protein Conformation; Protein Folding; Protein Transport; Stress, Mechanical; Symporters
PubMed: 28627175
DOI: 10.1021/acs.nanolett.7b01844 -
Current Opinion in Cell Biology Apr 2015Pyruvate metabolism plays a pivotal role in cell homeostasis and energy production. Pyruvate, the end product of glycolysis, is either catabolized in the cytosol, or... (Review)
Review
Pyruvate metabolism plays a pivotal role in cell homeostasis and energy production. Pyruvate, the end product of glycolysis, is either catabolized in the cytosol, or enters into mitochondria to promote oxidative phosphorylation. The import of pyruvate into mitochondria requires a specific carrier in the inner mitochondrial membrane, the mitochondrial pyruvate carrier (MPC), whose identity was only recently discovered. Here we report our current knowledge of the structure and function of the MPC and we describe how dysfunction of the MPC could participate in various pathologies, including type 2 diabetes and cancer.
Topics: Animals; Glucose; Homeostasis; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Monocarboxylic Acid Transporters; Mutation; Neoplasms; Pyruvic Acid
PubMed: 25463844
DOI: 10.1016/j.ceb.2014.10.008 -
Metallomics : Integrated Biometal... Jul 2018Virtually all organisms require iron and have evolved to obtain this element in free or chelated forms. Under anaerobic or low pH conditions commonly encountered by... (Review)
Review
Virtually all organisms require iron and have evolved to obtain this element in free or chelated forms. Under anaerobic or low pH conditions commonly encountered by numerous pathogens, iron predominantly exists in the ferrous (Fe2+) form. The ferrous iron transport (Feo) system is the only widespread mechanism dedicated solely to bacterial ferrous iron import, and this system has been linked to pathogenic virulence, bacterial colonization, and microbial survival. The canonical feo operon encodes for three proteins that comprise the Feo system: FeoA, a small cytoplasmic β-barrel protein; FeoB, a large, polytopic membrane protein with a soluble G-protein domain capable of hydrolyzing GTP; and FeoC, a small, cytoplasmic protein containing a winged-helix motif. While previous studies have revealed insight into soluble and fragmentary domains of the Feo system, the chief membrane-bound component FeoB remains poorly studied. However, recent advances have demonstrated that large quantities of intact FeoB can be overexpressed, purified, and biophysically characterized, revealing glimpses into FeoB function. Two models of full-length FeoB have been published, providing starting points for hypothesis-driven investigations into the mechanism of FeoB-mediated ferrous iron transport. Finally, in vivo studies have begun to shed light on how this system functions as a unique multicomponent complex. In light of these new data, this review will summarize what is known about the Feo system, including recent advancements in FeoB structure and function.
Topics: Cation Transport Proteins; Cell Membrane; Escherichia coli Proteins; Ferrous Compounds; Gene Expression Regulation, Bacterial; Ion Transport; Iron; Membrane Transport Proteins; Operon; Protein Conformation; Virulence
PubMed: 29953152
DOI: 10.1039/c8mt00097b -
Wiley Interdisciplinary Reviews.... May 2016Despite all the major breakthroughs in antibiotic development and treatment procedures, there is still no long-term solution to the bacterial antibiotic resistance... (Review)
Review
Despite all the major breakthroughs in antibiotic development and treatment procedures, there is still no long-term solution to the bacterial antibiotic resistance problem. Among all the known types of resistance, adaptive resistance (AdR) is particularly inconvenient. This phenotype is known to emerge as a consequence of concentration gradients, as well as contact with subinhibitory concentrations of antibiotics, both known to occur in human patients and livestock. Moreover, AdR has been repeatedly correlated with the appearance of multidrug resistance, although the biological processes behind its emergence and evolution are not well understood. Epigenetic inheritance, population structure and heterogeneity, high mutation rates, gene amplification, efflux pumps, and biofilm formation have all been reported as possible explanations for its development. Nonetheless, these concepts taken independently have not been sufficient to prevent AdR's fast emergence or to predict its low stability. New strains of resistant pathogens continue to appear, and none of the new approaches used to kill them (mixed antibiotics, sequential treatments, and efflux inhibitors) are completely efficient. With the advent of systems biology and its toolsets, integrative models that combine experimentally known features with computational simulations have significantly improved our understanding of the emergence and evolution of the adaptive-resistant phenotype. Apart from outlining these findings, we propose that one of the main cornerstones of AdR in bacteria, is the conjunction of two types of mechanisms: one rapidly responding to transient environmental challenges but not very efficient, and another much more effective and specific, but developing on longer time scales. WIREs Syst Biol Med 2016, 8:253-267. doi: 10.1002/wsbm.1335 For further resources related to this article, please visit the WIREs website.
Topics: Anti-Bacterial Agents; Bacteria; DNA Damage; DNA Methylation; DNA Repair; Drug Resistance, Bacterial; Membrane Transport Proteins; Systems Biology
PubMed: 27103502
DOI: 10.1002/wsbm.1335 -
The Journal of Biological Chemistry Jan 2023Understanding L-fucose metabolism is important because it is used as a therapy for several congenital disorders of glycosylation. Exogenous L-fucose can be activated and...
Understanding L-fucose metabolism is important because it is used as a therapy for several congenital disorders of glycosylation. Exogenous L-fucose can be activated and incorporated directly into multiple N- and O-glycans via the fucose salvage/recycling pathway. However, unlike for other monosaccharides, no mammalian L-fucose transporter has been identified. Here, we functionally screened nearly 140 annotated transporters and identified GLUT1 (SLC2A1) as an L-fucose transporter. We confirmed this assignment using multiple approaches to alter GLUT1 function, including chemical inhibition, siRNA knockdown, and gene KO. Collectively, all methods demonstrate that GLUT1 contributes significantly to L-fucose uptake and its utilization at low micromolar levels. Surprisingly, millimolar levels of D-glucose do not compete with L-fucose uptake. We also show macropinocytosis, but not other endocytic pathways, can contribute to L-fucose uptake and utilization. In conclusion, we determined that GLUT1 functions as the previously missing transporter component in mammalian L-fucose metabolism.
Topics: Biological Transport; Fucose; Glucose; Glucose Transporter Type 1; Membrane Transport Proteins
PubMed: 36423686
DOI: 10.1016/j.jbc.2022.102738