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Advances in Experimental Medicine and... 2019Blood-retinal barrier (BRB) includes inner BRB (iBRB) and outer BRB (oBRB), which are formed by retinal capillary endothelial (RCEC) cells and by retinal pigment... (Review)
Review
Blood-retinal barrier (BRB) includes inner BRB (iBRB) and outer BRB (oBRB), which are formed by retinal capillary endothelial (RCEC) cells and by retinal pigment epithelial (RPE) cells in collaboration with Bruch's membrane and the choriocapillaris, respectively. Functions of the BRB are to regulate fluids and molecular movement between the ocular vascular beds and retinal tissues and to prevent leakage of macromolecules and other potentially harmful agents into the retina, keeping the microenvironment of the retina and retinal neurons. These functions are mainly attributed to absent fenestrations of RCECs, tight junctions, expression of a great diversity of transporters, and coverage of pericytes and glial cells. BRB existence also becomes a reason that systemic administration for some drugs is not suitable for the treatment of retinal diseases. Some diseases (such as diabetes and ischemia-reperfusion) impair BRB function via altering tight junctions, RCEC death, and transporter expression. This chapter will illustrate function of BRB, expressions and functions of these transporters, and their clinical significances.
Topics: Blood-Retinal Barrier; Gene Expression; Humans; Membrane Transport Proteins; Retina; Retinal Diseases; Tight Junctions
PubMed: 31571172
DOI: 10.1007/978-981-13-7647-4_10 -
Research in Microbiology 2018Multidrug transporters function in a coordinated mode to provide an essential first-line defense mechanism that prevents antibiotics from reaching lethal concentrations,... (Review)
Review
Multidrug transporters function in a coordinated mode to provide an essential first-line defense mechanism that prevents antibiotics from reaching lethal concentrations, until a number of stable efficient adaptations occur that allow survival. Single-component efflux transporters remove the toxic compounds from the cytoplasm to the periplasmic space where TolC-dependent transporters expel them from the cell. The close interaction between the two types of transporters ensures handling of a wide range of xenobiotics and prevents rapid leak of the hydrophobic substrates back into the cell. In this review, we discuss the concept of the bacterial effluxome of the Gram-negative Escherichia coli that is the entire set of transporters expressed at a given time, under defined conditions. The process of identification of its members and the elucidation of the nature of the interactions throw a novel light on the roles of transporters in bacterial physiology and drug resistance development. We anticipate that the concept of an effluxome where each member contributes to the removal of noxious chemicals from the cell should contribute to improving the present strategy of searching for transport inhibitors as adjuvants of existing antibiotics and provide novel targets for this urgent undertaking.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins
PubMed: 29574104
DOI: 10.1016/j.resmic.2018.02.006 -
Nature Structural & Molecular Biology Jul 2019Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain... (Review)
Review
Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain neurotransmitter homeostasis. As targets of a wide range of compounds, including antidepressants, substances of abuse and drugs for neuropsychiatric and neurodegenerative disorders, their mechanism of action and their modulation by small molecules have long been of broad interest. Recent advances in the structural characterization of dopamine and serotonin transporters have opened the way for structure-based modeling and simulations, which, together with experimental data, now provide mechanistic understanding of their transport function and interactions. Here we review recent progress in the elucidation of the structural dynamics of MATs and their conformational landscape and transitions, as well as allosteric regulation mechanisms.
Topics: Allosteric Regulation; Animals; Binding Sites; Dopamine Plasma Membrane Transport Proteins; Drug Discovery; Humans; Models, Molecular; Norepinephrine Plasma Membrane Transport Proteins; Protein Conformation; Serotonin Plasma Membrane Transport Proteins
PubMed: 31270469
DOI: 10.1038/s41594-019-0253-7 -
Cold Spring Harbor Perspectives in... Jul 2014The cellular uptake of many nutrients and micronutrients governs both their cellular availability and their systemic homeostasis. The cellular rate of nutrient or ion... (Review)
Review
The cellular uptake of many nutrients and micronutrients governs both their cellular availability and their systemic homeostasis. The cellular rate of nutrient or ion uptake (e.g., glucose, Fe(3+), K(+)) or efflux (e.g., Na(+)) is governed by a complement of membrane transporters and receptors that show dynamic localization at both the plasma membrane and defined intracellular membrane compartments. Regulation of the rate and mechanism of endocytosis controls the amounts of these proteins on the cell surface, which in many cases determines nutrient uptake or secretion. Moreover, the metabolic action of diverse hormones is initiated upon binding to surface receptors that then undergo regulated endocytosis and show distinct signaling patterns once internalized. Here, we examine how the endocytosis of nutrient transporters and carriers as well as signaling receptors governs cellular metabolism and thereby systemic (whole-body) metabolite homeostasis.
Topics: Biological Transport; Endocytosis; Exocytosis; Glucose; Glucose Transporter Type 4; Homeostasis; Membrane Transport Proteins; Metabolic Networks and Pathways; Models, Biological; Signal Transduction
PubMed: 24984778
DOI: 10.1101/cshperspect.a016964 -
Journal of Molecular Biology Aug 2021The synthesis, folding, and function of membrane transport proteins are critical factors for defining cellular physiology. Since the stability of these proteins evolved... (Review)
Review
The synthesis, folding, and function of membrane transport proteins are critical factors for defining cellular physiology. Since the stability of these proteins evolved amidst the lipid bilayer, it is no surprise that we are finding that many of these membrane proteins demonstrate coupling of their structure or activity in some way to the membrane. More and more transporter structures are being determined with some information about the surrounding membrane, and computational modeling is providing further molecular details about these solvation structures. Thus, the field is moving towards identifying which molecular mechanisms - lipid interactions, membrane perturbations, differential solvation, and bulk membrane effects - are involved in linking membrane energetics to transporter stability and function. In this review, we present an overview of these mechanisms and the growing evidence that the lipid bilayer is a major determinant of the fold, form, and function of membrane transport proteins in membranes.
Topics: Cell Membrane; Lipid Bilayers; Membrane Transport Proteins; Models, Molecular; Protein Folding; Structure-Activity Relationship
PubMed: 34139219
DOI: 10.1016/j.jmb.2021.167103 -
Molecular Microbiology Apr 2021Both isomeric forms of alanine play a crucial role in bacterial growth and viability; the L-isomer of this amino acid is one of the building blocks for protein...
Both isomeric forms of alanine play a crucial role in bacterial growth and viability; the L-isomer of this amino acid is one of the building blocks for protein synthesis, and the D-isomer is incorporated into the bacterial cell wall. Despite a long history of genetic manipulation of Bacillus subtilis using auxotrophic markers, the genes involved in alanine metabolism have not been characterized fully. In this work, we genetically characterized the major enzymes involved in B. subtilis alanine biosynthesis and identified an alanine permease, AlaP (YtnA), which we show has a major role in the assimilation of D-alanine from the environment. Our results provide explanations for the puzzling fact that growth of B. subtilis does not result in the significant accumulation of extracellular D-alanine. Interestingly, we find that in B. subtilis, unlike E. coli where multiple enzymes have a biochemical activity that can generate alanine, the primary synthetic enzyme for alanine is encoded by alaT, although a second gene, dat, can support slow growth of an L-alanine auxotroph. However, our results also show that Dat mediates the synthesis of D-alanine and its activity is influenced by the abundance of L-alanine. This work provides valuable insights into alanine metabolism that suggests that the relative abundance of D- and L-alanine might be linked with cytosolic pool of D and L-glutamate, thereby coupling protein and cell envelope synthesis with the metabolic status of the cell. The results also suggest that, although some of the purified enzymes involved in alanine biosynthesis have been shown to catalyze reversible reactions in vitro, most of them function unidirectionally in vivo.
Topics: Alanine; Amino Acid Transport Systems; Bacillus subtilis; Bacterial Proteins; Biosynthetic Pathways; Membrane Transport Proteins; Transaminases
PubMed: 33155333
DOI: 10.1111/mmi.14640 -
Biochemical Society Transactions Dec 2016Transporters are integral membrane proteins with central roles in the efficient movement of molecules across biological membranes. Many transporters exist as oligomers... (Review)
Review
Transporters are integral membrane proteins with central roles in the efficient movement of molecules across biological membranes. Many transporters exist as oligomers in the membrane. Depending on the individual transport protein, oligomerization can have roles in membrane trafficking, function, regulation and turnover. For example, our recent studies on UapA, a nucleobase ascorbate transporter, from Aspergillus nidulans, have revealed both that dimerization of this protein is essential for correct trafficking to the membrane and the structural basis of how one UapA protomer can affect the function of the closely associated adjacent protomer. Here, we review the roles of oligomerization in many particularly well-studied transporters and transporter families.
Topics: Biological Transport; Cell Membrane; Fungal Proteins; Kinetics; Membrane Transport Proteins; Models, Molecular; Mutation; Protein Conformation; Protein Multimerization
PubMed: 27913684
DOI: 10.1042/BST20160217 -
Research in Microbiology 2018
Topics: Bacteria; Bacterial Proteins; Membrane Transport Proteins
PubMed: 30223033
DOI: 10.1016/j.resmic.2018.09.001 -
MBio Feb 2023Flucytosine (5-FC) is an antifungal agent commonly used for treatment of cryptococcosis and several other systemic mycoses. In fungi, cytosine permease and cytosine...
Flucytosine (5-FC) is an antifungal agent commonly used for treatment of cryptococcosis and several other systemic mycoses. In fungi, cytosine permease and cytosine deaminase are known major players in flucytosine resistance by regulating uptake and deamination of 5-FC, respectively. Cryptococcus species have three paralogs each of cytosine permease ( and ) and cytosine deaminase ( and ). As in other fungi, we found and to be the primary cytosine deaminase and permease gene, respectively, in C. neoformans H99 (VNI), C. gattii R265 (VGIIa) and WM276 (VGI). However, when various amino acids were used as the sole nitrogen source, C. neoformans and C. gattii diverged in the function of and Though there was some lineage-dependent variability, the two genes functioned as the secondary permease and deaminase, respectively, only in C. gattii when the nitrogen source was arginine, asparagine, or proline. Additionally, the expression of genes, excluding , was under nitrogen catabolic repression in the presence of NH. Functional analysis of and gene deletion constructs demonstrated that these two genes regulate the expression of each permease and deaminase genes individually. Furthermore, the expression levels of and under different amino acids corroborated the 5-FC susceptibility in or background. Thus, the mechanism of 5-FC resistance in C. gattii under diverse nitrogen conditions is orchestrated by two transcription factors of GATA family, cytosine permease and deaminase genes. 5-FC is a commonly used antifungal drug for treatment of cryptococcosis caused by Cryptococcus neoformans and C. gattii species complexes. When various amino acids were used as the sole nitrogen source for growth, we found lineage dependent differences in 5-FC susceptibility. Deletion of the classical cytosine permease () and deaminase () genes caused increased 5-FC resistance in all tested nitrogen sources in C. neoformans but not in C. gattii. Furthermore, we demonstrate that the two GATA family transcription factor genes and are involved in the nitrogen-source dependent 5-FC resistance by regulating the expression of the paralogs of cytosine permease and deaminase genes. Our study not only identifies the new function of paralogs of the cytosine permease and deaminase and the role of their regulatory transcription factors but also denotes the differences in the mechanism of 5-FC resistance among the two etiologic agents of cryptococcosis under different nitrogen sources.
Topics: Flucytosine; Nitrogen; Cytosine Deaminase; Antifungal Agents; Cryptococcus neoformans; Cryptococcus gattii; Cryptococcosis; Amino Acids; Membrane Transport Proteins; Transcription Factors; Microbial Sensitivity Tests
PubMed: 36656038
DOI: 10.1128/mbio.03451-22 -
Trends in Cell Biology Sep 2017The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate... (Review)
Review
The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate cellular chemistry by metabolism. The mammalian MCS comprises the transporters of the 53-member canonical SLC25A family and a lesser number of identified noncanonical transporters. The recent discovery and investigations of the mitochondrial pyruvate carrier (MPC) illustrate the diverse effects a single mitochondrial carrier may exert on cellular function. However, the transport selectivities of many carriers remain unknown, and most have not been functionally investigated in mammalian cells. The mechanisms coordinating their function as a unified system remain undefined. Increased accessibility to molecular genetic and metabolomic technologies now greatly enables investigation of the MCS. Continued investigation of the MCS may reveal how mitochondria encode complex regulatory information within chemical thermodynamic gradients. This understanding may enable precision modulation of cellular chemistry to counteract the dysmetabolism inherent in disease.
Topics: Animals; Biological Transport; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Monocarboxylic Acid Transporters
PubMed: 28522206
DOI: 10.1016/j.tcb.2017.04.004