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Advances in Experimental Medicine and... 2019Solute carrier (SLC) family transporters utilize an electrochemical potential difference or an ion gradient generated by primary active transporters for transporting... (Review)
Review
Solute carrier (SLC) family transporters utilize an electrochemical potential difference or an ion gradient generated by primary active transporters for transporting their substrates across biological membranes. These transporters are categorized as facilitated transporters or secondary active transporters. More than 300 SLC transporters have been identified. SLC transporters related to drug transport mainly include SLC21 gene subfamily (organic anion-transporting polypeptides, OATPs), SLC22A gene subfamily (organic anion transporters, OATs; organic cation transporters, OCTs; or organic cation/carnitine transporters, OCTNs), SLC15A gene subfamily (peptide transporters, PEPTs), and SLC47A gene subfamily (multidrug and toxin extrusion, MATEs). In general, OCTs transport organic cations, OATPs transport large and fairly hydrophobic organic anions, OATs transport the smaller and more hydrophilic organic anions, and PEPTs are responsible for the uptake of di-/tripeptides and peptide-like drugs. MATEs are responsible for efflux of organic cations. These transporters also transport some endogenous substances, indicating that the dysfunction of SLCs not only disrupts homeostasis but also largely impacts on the disposition of their substrate drugs. This chapter will discuss these SLC family transporters, with an emphasis on tissue distribution, substrate specificity, transporter physiology, and clinical significance.
Topics: Animals; Cations; Humans; Peptides; Pharmaceutical Preparations; Solute Carrier Proteins; Substrate Specificity; Tissue Distribution
PubMed: 31571165
DOI: 10.1007/978-981-13-7647-4_3 -
Advances in Experimental Medicine and... 2019Drug transporters are considered to be determinants of drug disposition and effects/toxicities by affecting the absorption, distribution, and excretion of drugs. Drug... (Review)
Review
Drug transporters are considered to be determinants of drug disposition and effects/toxicities by affecting the absorption, distribution, and excretion of drugs. Drug transporters are generally divided into solute carrier (SLC) family and ATP binding cassette (ABC) family. Widely studied ABC family transporters include P-glycoprotein (P-GP), breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRPs). SLC family transporters related to drug transport mainly include organic anion-transporting polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), organic cation/carnitine transporters (OCTNs), peptide transporters (PEPTs), and multidrug/toxin extrusions (MATEs). These transporters are often expressed in tissues related to drug disposition, such as the small intestine, liver, and kidney, implicating intestinal absorption of drugs, uptake of drugs into hepatocytes, and renal/bile excretion of drugs. Most of therapeutic drugs are their substrates or inhibitors. When they are comedicated, serious drug-drug interactions (DDIs) may occur due to alterations in intestinal absorption, hepatic uptake, or renal/bile secretion of drugs, leading to enhancement of their activities or toxicities or therapeutic failure. This chapter will illustrate transporter-mediated DDIs (including food drug interaction) in human and their clinical significances.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Drug Interactions; Food-Drug Interactions; Humans; Neoplasm Proteins; Organic Anion Transporters; Pharmaceutical Preparations
PubMed: 31571167
DOI: 10.1007/978-981-13-7647-4_5 -
Annual Review of Biochemistry Jun 2020ATP-binding cassette (ABC) transporters constitute one of the largest and most ancient protein superfamilies found in all living organisms. They function as molecular... (Review)
Review
ATP-binding cassette (ABC) transporters constitute one of the largest and most ancient protein superfamilies found in all living organisms. They function as molecular machines by coupling ATP binding, hydrolysis, and phosphate release to translocation of diverse substrates across membranes. The substrates range from vitamins, steroids, lipids, and ions to peptides, proteins, polysaccharides, and xenobiotics. ABC transporters undergo substantial conformational changes during substrate translocation. A comprehensive understanding of their inner workings thus requires linking these structural rearrangements to the different functional state transitions. Recent advances in single-particle cryogenic electron microscopy have not only delivered crucial information on the architecture of several medically relevant ABC transporters and their supramolecular assemblies, including the ATP-sensitive potassium channel and the peptide-loading complex, but also made it possible to explore the entire conformational space of these nanomachines under turnover conditions and thereby gain detailed mechanistic insights into their mode of action.
Topics: ATP-Binding Cassette Transporters; Adenosine Triphosphate; Bacteria; Binding Sites; Biological Transport; Biomechanical Phenomena; Cell Membrane; Drug Resistance, Multiple; Humans; Kinetics; Mitochondria; Models, Molecular; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Substrate Specificity; Xenobiotics
PubMed: 32569521
DOI: 10.1146/annurev-biochem-011520-105201 -
Pharmacology & Therapeutics Dec 2018Drug transporter proteins are critical to the distribution of a wide range of endogenous compounds and xenobiotics such as hormones, bile acids, peptides, lipids,... (Review)
Review
Drug transporter proteins are critical to the distribution of a wide range of endogenous compounds and xenobiotics such as hormones, bile acids, peptides, lipids, sugars, and drugs. There are two classes of drug transporters- the solute carrier (SLC) transporters and ATP-binding cassette (ABC) transporters -which predominantly differ in the energy source utilized to transport substrates across a membrane barrier. Despite their hydrophobic nature and residence in the membrane bilayer, drug transporters have dynamic structures and adopt many conformations during the translocation process. Whereas there is significant literature evidence for the substrate specificity and structure-function relationship for clinically relevant drug transporters proteins, there is less of an understanding in the regulatory mechanisms that contribute to the functional expression of these proteins. Post-translational modifications have been shown to modulate drug transporter functional expression via a wide range of molecular mechanisms. These modifications commonly occur through the addition of a functional group (e.g. phosphorylation), a small protein (e.g. ubiquitination), sugar chains (e.g. glycosylation), or lipids (e.g. palmitoylation) on solvent accessible amino acid residues. These covalent additions often occur as a result of a signaling cascade and may be reversible depending on the type of modification and the intended fate of the signaling event. Here, we review the significant role in which post-translational modifications contribute to the dynamic regulation and functional consequences of SLC and ABC drug transporters and highlight recent progress in understanding their roles in transporter structure, function, and regulation.
Topics: ATP-Binding Cassette Transporters; Animals; Biological Transport; Glycosylation; Humans; Pharmaceutical Preparations; Phosphorylation; Protein Processing, Post-Translational; Solute Carrier Proteins; Ubiquitination; Xenobiotics
PubMed: 29966598
DOI: 10.1016/j.pharmthera.2018.06.013 -
Nature Nov 2021Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism. Mitochondria, as the major site of oxidative...
Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism. Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions. GSH is synthesized exclusively in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remains unknown. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, as a regulator of GSH transport into mitochondria. Loss of SLC25A39 reduces mitochondrial GSH import and abundance without affecting cellular GSH levels. Cells lacking both SLC25A39 and its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron-sulfur clusters. We find that mitochondrial GSH import is necessary for cell proliferation in vitro and red blood cell development in mice. Heterologous expression of an engineered bifunctional bacterial GSH biosynthetic enzyme (GshF) in mitochondria enables mitochondrial GSH production and ameliorates the metabolic and proliferative defects caused by its depletion. Finally, GSH availability negatively regulates SLC25A39 protein abundance, coupling redox homeostasis to mitochondrial GSH import in mammalian cells. Our work identifies SLC25A39 as an essential and regulated component of the mitochondrial GSH-import machinery.
Topics: Animals; Biological Transport; Cell Proliferation; Cells, Cultured; Erythropoiesis; Glutathione; Homeostasis; Humans; Iron-Sulfur Proteins; Mice; Mitochondria; Mitochondrial Membrane Transport Proteins; Oxidation-Reduction; Proteome; Proteomics
PubMed: 34707288
DOI: 10.1038/s41586-021-04025-w -
FEBS Letters Dec 2020Bacterial membrane proteins of the SbmA/BacA family are multi-solute transporters that mediate the uptake of structurally diverse hydrophilic molecules, including...
Bacterial membrane proteins of the SbmA/BacA family are multi-solute transporters that mediate the uptake of structurally diverse hydrophilic molecules, including aminoglycoside antibiotics and antimicrobial peptides. Some family members are full-length ATP-binding cassette (ABC) transporters, whereas other members are truncated homologues that lack the nucleotide-binding domains and thus mediate ATP-independent transport. A recent cryo-EM structure of the ABC transporter Rv1819c from Mycobacterium tuberculosis has shed light on the structural basis for multi-solute transport and has provided insight into the mechanism of transport. Here, we discuss how the protein architecture makes SbmA/BacA family transporters prone to inadvertent import of antibiotics and speculate on the question which physiological processes may benefit from multi-solute transport.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Antigens, Bacterial; Bacterial Proteins; Biological Transport; Escherichia coli Proteins; Membrane Transport Proteins; Mycobacterium tuberculosis; Phosphoric Monoester Hydrolases; Substrate Specificity
PubMed: 32810294
DOI: 10.1002/1873-3468.13912 -
International Journal of Molecular... Feb 2020This editorial aims to summarize the 19 scientific papers that contributed to this Special Issue.
This editorial aims to summarize the 19 scientific papers that contributed to this Special Issue.
Topics: Adaptor Proteins, Signal Transducing; Amino Acids; Biological Transport; Cationic Amino Acid Transporter 1; Glutamate Plasma Membrane Transport Proteins; Humans; Large Neutral Amino Acid-Transporter 1; Proteins
PubMed: 32059365
DOI: 10.3390/ijms21041212 -
The Journal of Biological Chemistry Jul 2022An ever-increasing number of proteins have been shown to translocate across various membranes of bacterial as well as eukaryotic cells in their folded states as a part... (Review)
Review
An ever-increasing number of proteins have been shown to translocate across various membranes of bacterial as well as eukaryotic cells in their folded states as a part of physiological and/or pathophysiological processes. Herein, we provide an overview of the systems/processes that are established or likely to involve the membrane translocation of folded proteins, such as protein export by the twin-arginine translocation system in bacteria and chloroplasts, unconventional protein secretion and protein import into the peroxisome in eukaryotes, and the cytosolic entry of proteins (e.g., bacterial toxins) and viruses into eukaryotes. We also discuss the various mechanistic models that have previously been proposed for the membrane translocation of folded proteins including pore/channel formation, local membrane disruption, membrane thinning, and transport by membrane vesicles. Finally, we introduce a newly discovered vesicular transport mechanism, vesicle budding and collapse, and present evidence that vesicle budding and collapse may represent a unifying mechanism that drives some (and potentially all) of folded protein translocation processes.
Topics: Bacteria; Bacterial Proteins; Eukaryota; Membrane Transport Proteins; Peroxisomes; Protein Folding; Protein Sorting Signals; Protein Transport; Twin-Arginine-Translocation System
PubMed: 35671825
DOI: 10.1016/j.jbc.2022.102107 -
Research in Microbiology 2019The CydDC family of ABC transporters export the low molecular weight thiols glutathione and cysteine to the periplasm of a variety of bacterial species. The CydDC... (Review)
Review
The CydDC family of ABC transporters export the low molecular weight thiols glutathione and cysteine to the periplasm of a variety of bacterial species. The CydDC complex has previously been shown to be important for disulfide folding, motility, respiration, and tolerance to nitric oxide and antibiotics. In addition, CydDC is thus far unique amongst ABC transporters in that it binds a haem cofactor that appears to modulate ATPase activity. CydDC has a diverse impact upon bacterial metabolism, growth, and virulence, and is of interest to those working on membrane transport mechanisms, redox biology, aerobic respiration, and stress sensing/tolerance during infection.
Topics: ATP-Binding Cassette Transporters; Adenosine Triphosphatases; Anti-Bacterial Agents; Biological Transport; Cysteine; Escherichia coli; Escherichia coli Proteins; Glutathione; Heme; Oxidation-Reduction; Periplasm
PubMed: 31279084
DOI: 10.1016/j.resmic.2019.06.003 -
Biochimica Et Biophysica Acta Mar 2015ABC transporters ubiquitously found in all kingdoms of life move a broad range of solutes across membranes. Crystal structures of four distinct types of ABC transport... (Review)
Review
BACKGROUND
ABC transporters ubiquitously found in all kingdoms of life move a broad range of solutes across membranes. Crystal structures of four distinct types of ABC transport systems have been solved, shedding light on different conformational states within the transport process. Briefly, ATP-dependent flipping between inward- and outward-facing conformations allows directional transport of various solutes.
SCOPE OF REVIEW
The heterodimeric transporter associated with antigen processing TAP1/2 (ABCB2/3) is a crucial element of the adaptive immune system. The ABC transport complex shuttles proteasomal degradation products into the endoplasmic reticulum. These antigenic peptides are loaded onto major histocompatibility complex class I molecules and presented on the cell surface. We detail the functional modules of TAP, its ATPase and transport cycle, and its interaction with and modulation by other cellular components. In particular, we emphasize how viral factors inhibit TAP activity and thereby prevent detection of the infected host cell by cytotoxic T-cells.
MAJOR CONCLUSIONS
Merging functional details on TAP with structural insights from related ABC transporters refines the understanding of solute transport. Although human ABC transporters are extremely diverse, they still may employ conceptually related transport mechanisms. Appropriately, we delineate a working model of the transport cycle and how viral factors arrest TAP in distinct conformations.
GENERAL SIGNIFICANCE
Deciphering the transport cycle of human ABC proteins is the major issue in the field. The defined peptidic substrate, various inhibitory viral factors, and its role in adaptive immunity provide unique tools for the investigation of TAP, making it an ideal model system for ABC transporters in general. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
Topics: ATP-Binding Cassette Transporters; Adaptive Immunity; Animals; Antigen Presentation; Biological Transport; Endoplasmic Reticulum; Humans; Models, Molecular; Peptides; Protein Conformation
PubMed: 24923865
DOI: 10.1016/j.bbagen.2014.05.022