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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 -
The Journal of Biological Chemistry Apr 2023Tapasin (Tsn) plays a critical role in antigen processing and presentation by major histocompatibility complex class I (MHC-I) molecules. The mechanism of Tsn-mediated... (Review)
Review
Tapasin (Tsn) plays a critical role in antigen processing and presentation by major histocompatibility complex class I (MHC-I) molecules. The mechanism of Tsn-mediated peptide loading and exchange hinges on the conformational dynamics governing the interaction of Tsn and MHC-I with recent structural and functional studies pinpointing the critical sites of direct or allosteric regulation. In this review, we highlight these recent findings and relate them to the extensive molecular and cellular data that are available for these evolutionary interdependent proteins. Furthermore, allotypic differences of MHC-I with regard to the editing and chaperoning function of Tsn are reviewed and related to the mechanistic observations. Finally, evolutionary aspects of the mode of action of Tsn will be discussed, a short comparison with the Tsn-related molecule TAPBPR (Tsn-related protein) will be given, and the impact of Tsn on noncanonical MHC-I molecules will be described.
Topics: Antigen Presentation; Histocompatibility Antigens Class I; Immunoglobulins; Membrane Transport Proteins
PubMed: 36758805
DOI: 10.1016/j.jbc.2023.102987 -
Handbook of Experimental Pharmacology 2021Neuromodulators are critical regulators of the brain's signaling processes, and thus they are popular pharmacological targets for psychoactive therapies. It is clear... (Review)
Review
Neuromodulators are critical regulators of the brain's signaling processes, and thus they are popular pharmacological targets for psychoactive therapies. It is clear that monoamine uptake mechanisms are complicated and subject to multiple uptake mechanisms. Uptake 1 describes uptake of the monoamine via its designated transporter (SERT for serotonin, NET for norepinephrine, and DAT for dopamine), whereas Uptake 2 details multiple transporter types on neurons and glia taking up different types of modulators, not necessarily specific to the monoamine. While Uptake 1 processes have been well-studied over the past few decades, Uptake 2 mechanisms have remained more difficult to study because of the limitations in methods that have the sensitivity and spatiotemporal resolution to look at the subtleties in uptake profiles. In this chapter we review the different experimental approaches that have yielded important information about Uptake 2 mechanisms in vivo. The techniques (scintillation microspectrophotometry, microdialysis, chronoamperometry, and voltammetry) are described in detail, and pivotal studies associated with each method are highlighted. It is clear from these reviewed works that Uptake 2 processes are critical to consider to advance our understanding of the brain and develop effective neuropsychiatric therapies.
Topics: Biological Transport; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Norepinephrine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins
PubMed: 34196807
DOI: 10.1007/164_2021_452 -
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 -
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 -
Biomolecules Jan 2021Cell plasma membrane proteins are considered as gatekeepers of the cell and play a major role in regulating various processes. Transport proteins constitute a subclass... (Review)
Review
Cell plasma membrane proteins are considered as gatekeepers of the cell and play a major role in regulating various processes. Transport proteins constitute a subclass of cell plasma membrane proteins enabling the exchange of molecules and ions between the extracellular environment and the cytosol. A plethora of human pathologies are associated with the altered expression or dysfunction of cell plasma membrane transport proteins, making them interesting therapeutic drug targets. However, the search for therapeutics is challenging, since many drug candidates targeting cell plasma membrane proteins fail in (pre)clinical testing due to inadequate selectivity, specificity, potency or stability. These latter characteristics are met by nanobodies, which potentially renders them eligible therapeutics targeting cell plasma membrane proteins. Therefore, a therapeutic nanobody-based strategy seems a valid approach to target and modulate the activity of cell plasma membrane transport proteins. This review paper focuses on methodologies to generate cell plasma membrane transport protein-targeting nanobodies, and the advantages and pitfalls while generating these small antibody-derivatives, and discusses several therapeutic nanobodies directed towards transmembrane proteins, including channels and pores, adenosine triphosphate-powered pumps and porters.
Topics: Antigens; Cell Membrane; Humans; Membrane Transport Proteins; Models, Biological; Single-Domain Antibodies
PubMed: 33418902
DOI: 10.3390/biom11010063 -
Protein and Peptide Letters 2023Solvent tolerance is a desired feature of microorganisms for their application in biotechnology. Organic solvent-tolerant microorganisms are able to thrive in the... (Review)
Review
BACKGROUND
Solvent tolerance is a desired feature of microorganisms for their application in biotechnology. Organic solvent-tolerant microorganisms are able to thrive in the presence of organic solvents. Several mechanisms have been proposed to elucidate their intrinsic tolerance to organic solvents.
OBJECTIVE
The present review aims to summarize the state of the art of the roles of membrane proteins in microbial organic solvent tolerance. Strategies and challenges for improving the protective function of membrane proteins in organic solvent stress are also proposed.
RESULTS
Membrane proteins related to transporter, signal transduction, and material and energy metabolism are involved in solvent tolerance. Optimization of the expression level of membrane proteins and engineering of membrane proteins are utilized to tackle the toxicity caused by organic solvents.
CONCLUSIONS
Membrane proteins occupy a strikingly important position in microbial solvent tolerance. Further research on novel methods in membrane proteins, trade-offs among overexpression and toxicity of membrane proteins and solvent yield, and a direct relationship between signaling pathways and solvent tolerance will advance the utilization of organic solvent-tolerant microorganisms in biotechnology.
Topics: Solvents; Membrane Proteins; Membrane Transport Proteins; Energy Metabolism
PubMed: 36573060
DOI: 10.2174/0929866530666221226100221 -
The Protein Journal Aug 2019The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from... (Review)
Review
The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from other protein transport systems with respect to two key features. Firstly, it accepts cargo proteins with an N-terminal signal peptide that carries the canonical twin-arginine motif, which is essential for transport. Second, the Tat system only accepts and translocates fully folded cargo proteins across the respective membrane. Here, we review the core essential features of folded protein transport via the bacterial Tat system, using the three-component TatABC system of Escherichia coli and the two-component TatAC systems of Bacillus subtilis as the main examples. In particular, we address features of twin-arginine signal peptides, the essential Tat components and how they assemble into different complexes, mechanistic features and energetics of Tat-dependent protein translocation, cytoplasmic chaperoning of Tat cargo proteins, and the remarkable proofreading capabilities of the Tat system. In doing so, we present the current state of our understanding of Tat-dependent protein translocation across biological membranes, which may serve as a lead for future investigations.
Topics: Arginine; Bacillus subtilis; Cell Membrane; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Protein Folding; Protein Sorting Signals; Protein Transport; SEC Translocation Channels; Twin-Arginine-Translocation System
PubMed: 31401776
DOI: 10.1007/s10930-019-09859-y -
Handbook of Experimental Pharmacology 2021Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for psychiatric disorders, yet they leave the majority of patients without...
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for psychiatric disorders, yet they leave the majority of patients without full symptom relief. Therefore, a major research challenge is to identify novel targets for the improved treatment of these disorders. SSRIs act by blocking the serotonin transporter (SERT), the high-affinity, low-capacity, uptake-1 transporter for serotonin. Other classes of antidepressant work by blocking the norepinephrine or dopamine transporters (NET and DAT), the high-affinity, low-capacity uptake-1 transporters for norepinephrine and dopamine, or by blocking combinations of SERT, NET, and DAT. It has been proposed that uptake-2 transporters, which include organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT), undermine the therapeutic utility of uptake-1 acting antidepressants. Uptake-2 transporters for monoamines have low affinity for these neurotransmitters, but a high capacity to transport them. Thus, activity of these transporters may limit the increase of extracellular monoamines thought to be essential for ultimate therapeutic benefit. Here preclinical evidence supporting a role for OCT2, OCT3, and PMAT in behaviors relevant to psychiatric disorders is presented. Importantly, preclinical evidence revealing these transporters as targets for the development of novel therapeutics for psychiatric disorders is discussed.
Topics: Antidepressive Agents; Cations; Dopamine Plasma Membrane Transport Proteins; Humans; Mental Disorders; Organic Cation Transport Proteins; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 34282486
DOI: 10.1007/164_2021_473 -
Current Opinion in Structural Biology Aug 2019The Golgi apparatus plays a central role in the secretory pathway as a hub for posttranslational modification, protein sorting and quality control. To date, there is... (Review)
Review
The Golgi apparatus plays a central role in the secretory pathway as a hub for posttranslational modification, protein sorting and quality control. To date, there is little structural or biochemical information concerning the function of transporters that reside within this organelle. The SLC35 family of nucleotide sugar transporters link the synthesis of activated sugar molecules and sulfate in the cytoplasm, with the luminal transferases that catalyse their attachment to proteins and lipids during glycosylation and sulfation. A recent crystal structure of the GDP-mannose transporter has revealed key sequence motifs that direct ligand recognition and transport. Further biochemical studies unexpectedly found a requirement for short chain lipids in activating the transporter, suggesting a possible route for transport regulation within the Golgi.
Topics: Animals; Golgi Apparatus; Humans; Membrane Transport Proteins; Nucleotides; Sugars
PubMed: 30999236
DOI: 10.1016/j.sbi.2019.03.019