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Biomolecules Jul 2020Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize... (Review)
Review
Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase.
Topics: Biological Transport; Carrier Proteins; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Signal Transduction
PubMed: 32645990
DOI: 10.3390/biom10071008 -
Open Biology Jun 2019Cell nutrition, detoxification, signalling, homeostasis and response to drugs, processes related to cell growth, differentiation and survival are all mediated by plasma... (Review)
Review
Cell nutrition, detoxification, signalling, homeostasis and response to drugs, processes related to cell growth, differentiation and survival are all mediated by plasma membrane (PM) proteins called transporters. Despite their distinct fine structures, mechanism of function, energetic requirements, kinetics and substrate specificities, all transporters are characterized by a main hydrophobic body embedded in the PM as a series of tightly packed, often intertwined, α-helices that traverse the lipid bilayer in a zigzag mode, connected with intracellular or extracellular loops and hydrophilic N- and C-termini. Whereas longstanding genetic, biochemical and biophysical evidence suggests that specific transmembrane segments, and also their connecting loops, are responsible for substrate recognition and transport dynamics, emerging evidence also reveals the functional importance of transporter N- and C-termini, in respect to transport catalysis, substrate specificity, subcellular expression, stability and signalling. This review highlights selected prototypic examples of transporters in which their termini play important roles in their functioning.
Topics: Allosteric Site; Animals; Cell Membrane; Humans; Membrane Transport Proteins; Models, Molecular; Protein Domains; Protein Structure, Secondary; Substrate Specificity
PubMed: 31213137
DOI: 10.1098/rsob.190083 -
Biochimica Et Biophysica Acta.... May 2021Transport proteins are essential for cells in allowing the exchange of substances between cells and their environment across the lipid bilayer forming a tight barrier.... (Review)
Review
Transport proteins are essential for cells in allowing the exchange of substances between cells and their environment across the lipid bilayer forming a tight barrier. Membrane lipids modulate the function of transmembrane proteins such as transporters in two ways: Lipids are tightly and specifically bound to transport proteins and in addition they modulate from the bulk of the lipid bilayer the function of transport proteins. This overview summarizes currently available information at the ultrastructural level on lipids tightly bound to transport proteins and the impact of altered bulk membrane lipid composition. Human diseases leading to altered lipid homeostasis will lead to altered membrane lipid composition, which in turn affect the function of transporter proteins.
Topics: Animals; Biological Transport; Humans; Lipid Bilayers; Membrane Lipids; Membrane Transport Proteins; Protein Binding
PubMed: 33476785
DOI: 10.1016/j.bbadis.2021.166079 -
Plant Physiology Feb 2022
Topics: Biochemical Phenomena; Biological Transport; Cell Membrane; Membrane Transport Proteins; Plant Physiological Phenomena; Signal Transduction
PubMed: 34908141
DOI: 10.1093/plphys/kiab585 -
Pflugers Archiv : European Journal of... Dec 2019Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in... (Review)
Review
Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in endothelial cell membrane of the renal medulla and in other tissues, including the brain, heart, pancreas, colon, bladder, bone marrow, and cochlea. UT-B is responsible for the maintenance of urea concentration, male reproductive function, blood pressure, bone metabolism, and brain astrocyte and cardiac functions. Its deficiency and dysfunction contribute to the pathogenesis of many diseases. Actually, UT-B deficiency increases the sensitivity of bladder epithelial cells to apoptosis triggers in mice and UT-B-null mice develop II-III atrioventricular block and depression. The expression of UT-B in the rumen of cow and sheep may participate in digestive function. However, there is no systemic review to discuss the UT-B functions. Here, we update research approaches to understanding the functions of UT-B.
Topics: Animals; Apoptosis; Epithelial Cells; Humans; Membrane Transport Proteins; Urea; Urinary Bladder; Urea Transporters
PubMed: 31734718
DOI: 10.1007/s00424-019-02323-x -
Biochimica Et Biophysica Acta.... Dec 2020Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal... (Review)
Review
Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal membrane transporters have been associated with inherited disorders. The clinical presentations of these diseases resemble the phenotypes of other LSDs; they are heterogeneous and often present in children with neurodegenerative manifestations. However, for pathomechanistic and therapeutic studies, lysosomal membrane transport defects should be distinguished from LSDs caused by defective hydrolytic enzymes. The involved proteins differ in function, localization, and lysosomal targeting, and the diseases themselves differ in their stored material and therapeutic approaches. We provide an overview of the small group of disorders of lysosomal membrane transporters, emphasizing discovery, pathomechanism, clinical features, diagnostic methods and therapeutic aspects. We discuss common aspects of lysosomal membrane transporter defects that can provide the basis for preclinical research into these disorders.
Topics: Amino Acid Transport Systems, Neutral; Cystinosis; Histiocytosis; Humans; Lysosomal Storage Diseases; Lysosomes; Membrane Transport Proteins; Nucleoside Transport Proteins; Organic Anion Transporters; Sialic Acid Storage Disease; Symporters
PubMed: 32389669
DOI: 10.1016/j.bbamem.2020.183336 -
Biochemical Society Transactions Aug 2020The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope... (Review)
Review
The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope biogenesis in mycobacteria, required for transport of precursors, trehalose monomycolates (TMMs), is the Mycobacterial membrane protein large 3 (MmpL3). Due to its central role in TMM transport, MmpL3 has been an attractive therapeutic target and a key target for several preclinical agents. In 2019, the first crystal structures of the MmpL3 transporter and its complexes with lipids and inhibitors were reported. These structures revealed several unique structural features of MmpL3 and provided invaluable information on the mechanism of TMM transport. This review aims to highlight the recent advances made in the function of MmpL3 and summarises structural findings. The overall goal is to provide a mechanistic perspective of MmpL3-mediated lipid transport and inhibition, and to highlight the prospects for potential antituberculosis therapies.
Topics: Antitubercular Agents; Bacterial Proteins; Biological Transport; Drug Development; Lipids; Membrane Transport Proteins; Mycolic Acids; Protein Conformation
PubMed: 32662825
DOI: 10.1042/BST20190950 -
Journal of Controlled Release :... Nov 2020Bile acids are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum at meals. Apical sodium-dependent bile acid transporter (ASBT), an... (Review)
Review
Bile acids are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum at meals. Apical sodium-dependent bile acid transporter (ASBT), an ileal Na-dependent transporter, plays the leading role of bile acid absorption into enterocytes, where bile acids are delivered to basolateral side by ileal bile acid binding protein (IBABP) and then released by organic solute transporter OSTα/β. The absorbed bile acids are delivered to the liver via portal vein. In this process called "enterohepatic recycling", only 5% of the bile acid pool (~3 g in human) is excreted in feces, indicating the large recycling capacity and high transport efficacy of ASBT-mediated absorption. Therefore, bile acid transporter-mediated oral drug delivery has been regarded as a feasible and potential strategy to improve the oral bioavailability. This review introduces the key factors in enterohepatic recycling, especially the mechanism of bile acid uptake by ASBT, and the development of bile acid-based oral drug delivery for ASBT-targeting, including bile acid-based prodrugs, bile acid/drug electrostatic complexation and bile acid-containing nanocarriers. Furthermore, the specific transport pathways of bile acid in enterocytes are described and the recent finding of lymphatic delivery of bile acid-containing nanocarriers is discussed.
Topics: Bile Acids and Salts; Carrier Proteins; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Organic Anion Transporters, Sodium-Dependent; Pharmaceutical Preparations; Symporters
PubMed: 32711025
DOI: 10.1016/j.jconrel.2020.07.034 -
Genes Nov 2020, , and species are the most frequent cause of severe human fungal infections. Clinically relevant antifungal drugs are scarce, and their effectiveness are hampered by... (Review)
Review
, , and species are the most frequent cause of severe human fungal infections. Clinically relevant antifungal drugs are scarce, and their effectiveness are hampered by the ability of fungal cells to develop drug resistance mechanisms. Drug effectiveness and drug resistance in human pathogens is very often affected by their "transportome". Many studies have covered a panoply of drug resistance mechanisms that depend on drug efflux pumps belonging to the ATP-Binding Cassette and Major Facilitator Superfamily. However, the study of drug uptake mechanisms has been, to some extent, overlooked in pathogenic fungi. This review focuses on discussing current knowledge on drug uptake systems in fungal pathogens, highlighting the need for further studies on this topic of great importance. The following subjects are covered: (i) drugs imported by known transporter(s) in pathogenic fungi; and (ii) drugs imported by known transporter(s) in the model yeast or in human parasites, aimed at the identification of their homologs in pathogenic fungi. Besides its contribution to increase the understanding of drug-pathogen interactions, the practical implications of identifying drug importers in human pathogens are discussed, particularly focusing on drug development strategies.
Topics: ATP-Binding Cassette Transporters; Antifungal Agents; Aspergillus; Biological Transport; Candida albicans; Drug Carriers; Drug Resistance, Fungal; Fungi; Membrane Transport Proteins; Mycoses; Saccharomyces cerevisiae
PubMed: 33182427
DOI: 10.3390/genes11111324 -
Yakugaku Zasshi : Journal of the... 2021
Topics: ATP-Binding Cassette Transporters; Drug Discovery; Humans; Membrane Transport Proteins; Nucleotide Transport Proteins; Organic Anion Transporters; Organic Cation Transport Proteins; Research; Sodium-Glucose Transporter 2
PubMed: 33790115
DOI: 10.1248/yakushi.20-00204-F