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Molecules (Basel, Switzerland) Jan 2023Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier... (Review)
Review
Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical compositions has recently been used as a means to enhance their targeting and absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.
Topics: Membrane Transport Proteins; Biological Transport; Solute Carrier Proteins; Drug Delivery Systems; Prodrugs
PubMed: 36770817
DOI: 10.3390/molecules28031151 -
Scientific Reports Aug 2022Membrane transporters are an important group of proteins in physiology and disease. Their functions make them common drug targets, but their location in the lipid...
Membrane transporters are an important group of proteins in physiology and disease. Their functions make them common drug targets, but their location in the lipid bilayers poses a tremendous challenge to researchers. The current stage of development of structural biology, in addition to new research tools, has largely facilitated the acquisition of knowledge about transporters and mechanisms. This Collection presents recent studies, covering bioenergetics, structure and functional characterization of various transporters, lipids-protein interactions, and novel research tool development.
Topics: ATP-Binding Cassette Transporters; Biological Transport; Cell Membrane; Membrane Transport Proteins; Protein Conformation
PubMed: 35918457
DOI: 10.1038/s41598-022-17524-1 -
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 -
Biological & Pharmaceutical Bulletin 2018
Topics: Amino Acid Transport Systems; Animals; Carrier Proteins; GABA Plasma Membrane Transport Proteins; Humans; Membrane Transport Proteins
PubMed: 30270316
DOI: 10.1248/bpb.b18-ctf4110 -
Critical Reviews in Biochemistry and... 2015All living cells require membrane proteins that act as conduits for the regulated transport of ions, solutes and other small molecules across the cell membrane. Ion... (Review)
Review
All living cells require membrane proteins that act as conduits for the regulated transport of ions, solutes and other small molecules across the cell membrane. Ion channels provide a pore that permits often rapid, highly selective and tightly regulated movement of ions down their electrochemical gradient. In contrast, active transporters can move moieties up their electrochemical gradient. The secondary active transporters (such as SLC superfamily solute transporters) achieve this by coupling uphill movement of the substrate to downhill movement of another ion, such as sodium. The primary active transporters (including H(+)/K(+)-ATPases and Na(+)/K(+)-ATPases) utilize ATP hydrolysis as an energy source to power uphill transport. It is well known that proteins in each of these classes work in concert with members of the other classes to ensure, for example, ion homeostasis, ion secretion and restoration of ion balance following action potentials. More recently, evidence is emerging of direct physical interaction between true ion channels, and some primary or secondary active transporters. Here, we review the first known members of this new class of macromolecular complexes that we term "chansporters", explore their biological roles and discuss the pathophysiological consequences of their disruption. We compare functional and/or physical interactions between the ubiquitous KCNQ1 potassium channel and various active transporters, and examine other newly discovered chansporter complexes that suggest we may be seeing the tip of the iceberg in a newly emerging signaling modality.
Topics: Animals; Biological Transport; Humans; Ion Channels; Ion Pumps; Membrane Transport Proteins; Protein Subunits; Solute Carrier Proteins
PubMed: 27098917
DOI: 10.3109/10409238.2016.1172553 -
Cell Mar 2017The subfamily C ATP-binding cassette (ABCC) transporters mediate multidrug resistance and ion conductance regulation. Recent atomic or near-atomic resolution structures...
The subfamily C ATP-binding cassette (ABCC) transporters mediate multidrug resistance and ion conductance regulation. Recent atomic or near-atomic resolution structures of three physiologically significant ABCC transporters (MRP1, SUR1, and CFTR), determined by using single-particle cryo-electron microscopy (cryo-EM), reveal structural details that help explain the wide functional diversity of this ABC transporter subfamily.
Topics: ATP-Binding Cassette Transporters; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins
PubMed: 28283067
DOI: 10.1016/j.cell.2017.02.033 -
Environment International May 2019Arsenic is a non-essential, environmentally ubiquitous toxic metalloid. In response to this pervasive environmental challenge, organisms evolved mechanisms to confer... (Review)
Review
Arsenic is a non-essential, environmentally ubiquitous toxic metalloid. In response to this pervasive environmental challenge, organisms evolved mechanisms to confer resistance to arsenicals. Inorganic pentavalent arsenate is taken into most cells adventitiously by phosphate uptake systems. Similarly, inorganic trivalent arsenite is taken into most cells adventitiously, primarily via aquaglyceroporins or sugar permeases. The most common strategy for tolerance to both inorganic and organic arsenicals is by efflux that extrude them from the cytosol. These efflux transporters span across kingdoms and belong to various families such as aquaglyceroporins, major facilitator superfamily (MFS) transporters, ATP-binding cassette (ABC) transporters and potentially novel, yet to be discovered families. This review will outline the properties and substrates of known arsenic transport systems, the current knowledge gaps in the field, and aims to provide insight into the importance of arsenic transport in the context of the global arsenic biogeocycle and human health.
Topics: Animals; Arsenic; Arsenicals; Biological Transport; Humans; Membrane Transport Proteins
PubMed: 30852446
DOI: 10.1016/j.envint.2019.02.058 -
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 -
The FEBS Journal Mar 2018Trypanosoma brucei comprise the causative agents of sleeping sickness, T. b. gambiense and T. b. rhodesiense, as well as the livestock-pathogenic T. b. brucei. The... (Review)
Review
Trypanosoma brucei comprise the causative agents of sleeping sickness, T. b. gambiense and T. b. rhodesiense, as well as the livestock-pathogenic T. b. brucei. The parasites are transmitted by the tsetse fly and occur exclusively in sub-Saharan Africa. T. brucei are not only lethal pathogens but have also become model organisms for molecular parasitology. We focus here on membrane transport proteins of T. brucei, their contribution to homeostasis and metabolism in the context of a parasitic lifestyle, and their pharmacological role as potential drug targets or routes of drug entry. Transporters and channels in the plasma membrane are attractive drug targets as they are accessible from the outside. Alternatively, they can be exploited to selectively deliver harmful substances into the trypanosome's interior. Both approaches require the targeted transporter to be essential: in the first case to kill the trypanosome, in the second case to prevent drug resistance due to loss of the transporter. By combining functional and phylogenetic analyses, we were mining the T. brucei predicted proteome for transporters of pharmacological significance. Here, we review recent progress in the identification of transporters of lipid precursors, amino acid permeases and ion channels in T. brucei.
Topics: Animals; Antiprotozoal Agents; Humans; Insect Vectors; Membrane Transport Proteins; Phylogeny; Protozoan Proteins; Trypanosoma brucei brucei; Trypanosomiasis, African; Tsetse Flies
PubMed: 29063677
DOI: 10.1111/febs.14302 -
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