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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 -
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 -
International Journal of Molecular... Jul 2022Ultrashort peptides (USPs), consisting of 2-7 amino-acid residues, are a group of signaling molecules that regulate gene expression and protein synthesis under normal... (Review)
Review
Ultrashort peptides (USPs), consisting of 2-7 amino-acid residues, are a group of signaling molecules that regulate gene expression and protein synthesis under normal conditions in various diseases and ageing. USPs serve as a basis for the development of drugs with a targeted mechanism of action. The purpose of this review is to systematize the available data on USP transport involving POT and LAT transporters in various organs and tissues under normal, pathological and ageing conditions. The carriers of the POT family (PEPT1, PEPT2, PHT1, PHT2) transport predominantly di- and tripeptides into the cell. Methods of molecular modeling and physicochemistry have demonstrated the ability of LAT1 to transfer not only amino acids but also some di- and tripeptides into the cell and out of it. LAT1 and 2 are involved in the regulation of the antioxidant, endocrine, immune and nervous systems' functions. Analysis of the above data allows us to conclude that, depending on their structure, di- and tripeptides can be transported into the cells of various tissues by POT and LAT transporters. This mechanism is likely to underlie the tissue specificity of peptides, their geroprotective action and effectiveness in the case of neuroimmunoendocrine system disorders.
Topics: Amino Acids; Biological Transport; Membrane Transport Proteins; Organ Specificity; Peptides; Symporters
PubMed: 35887081
DOI: 10.3390/ijms23147733 -
Drug Metabolism and Pharmacokinetics Dec 2007Many types of xenobiotic transporters have been identified. They generally exhibit multispecific recognition of various types of substrates, and mediate membrane... (Review)
Review
Many types of xenobiotic transporters have been identified. They generally exhibit multispecific recognition of various types of substrates, and mediate membrane permeation of therapeutic agents, thereby playing important roles in drug absorption and disposition. It has recently been proposed that protein-protein interactions involving the xenobiotic transporters may affect their function, localization and expression on plasma membranes. So-called adaptor proteins that directly interact with the transporters include PDZ domain-containing proteins (PSD95, Dlg and ZO1). These PDZ adaptors have multiple PDZ domains in their structure, and each PDZ domain can interact with the cytosolic region of the transporters, and so it has been hypothesized that transporters are localized within networks consisting of several transporters and adaptors. Interaction with a PDZ adaptor is essential for the cell-surface localization of at least some xenobiotic transporters, and therefore, such interaction could be required for efficiency and fidelity in the vectorial transport of xenobiotics and therapeutic agents in epithelial cells. This review article summarizes recent evidence on the interactions of xenobiotic transporters with adaptor proteins, and presents a working hypothesis concerning their pharmacological significance.
Topics: Adaptor Proteins, Signal Transducing; Animals; Binding Sites; Biological Transport; Cell Membrane; Humans; Membrane Transport Proteins; PDZ Domains; Pharmacokinetics; Protein Binding; Protein Conformation; Xenobiotics
PubMed: 18159127
DOI: 10.2133/dmpk.22.401 -
International Journal of Molecular... 2012Arsenic and antimony are toxic metalloids, naturally present in the environment and all organisms have developed pathways for their detoxification. The most effective... (Review)
Review
Arsenic and antimony are toxic metalloids, naturally present in the environment and all organisms have developed pathways for their detoxification. The most effective metalloid tolerance systems in eukaryotes include downregulation of metalloid uptake, efflux out of the cell, and complexation with phytochelatin or glutathione followed by sequestration into the vacuole. Understanding of arsenic and antimony transport system is of high importance due to the increasing usage of arsenic-based drugs in the treatment of certain types of cancer and diseases caused by protozoan parasites as well as for the development of bio- and phytoremediation strategies for metalloid polluted areas. However, in contrast to prokaryotes, the knowledge about specific transporters of arsenic and antimony and the mechanisms of metalloid transport in eukaryotes has been very limited for a long time. Here, we review the recent advances in understanding of arsenic and antimony transport pathways in eukaryotes, including a dual role of aquaglyceroporins in uptake and efflux of metalloids, elucidation of arsenic transport mechanism by the yeast Acr3 transporter and its role in arsenic hyperaccumulation in ferns, identification of vacuolar transporters of arsenic-phytochelatin complexes in plants and forms of arsenic substrates recognized by mammalian ABC transporters.
Topics: ATP-Binding Cassette Transporters; Animals; Antimony; Aquaglyceroporins; Arabidopsis; Arsenic; Biological Transport; Glutathione; Humans; Leishmania; Membrane Transport Proteins; Monosaccharide Transport Proteins; Phytochelatins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Xenopus laevis; Zebrafish
PubMed: 22489166
DOI: 10.3390/ijms13033527 -
Biochemical Society Transactions Apr 2020Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an... (Review)
Review
Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an important role in regulating the uptake of nutrients and vitamins from the diet, and in controlling the distribution of their metabolic intermediates within the cell. Several SLC families also play an important role in drug transport and strategies are being developed to hijack SLC transporters to control and regulate drug transport within the body. Through the addition of amino acid and peptide moieties several novel antiviral and anticancer agents have been developed that hijack the proton-coupled oligopeptide transporters, PepT1 (SCL15A1) and PepT2 (SLC15A2), for improved intestinal absorption and renal retention in the body. A major goal is to understand the rationale behind these successes and expand the library of prodrug molecules that utilise SLC transporters. Recent co-crystal structures of prokaryotic homologues of the human PepT1 and PepT2 transporters have shed important new insights into the mechanism of prodrug recognition. Here, I will review recent developments in our understanding of ligand recognition and binding promiscuity within the SLC15 family, and discuss current models for prodrug recognition.
Topics: Animals; Biological Transport; Crystallography, X-Ray; Drug Design; Humans; Oligopeptides; Peptide Transporter 1; Prodrugs; Symporters; Valacyclovir; Valganciclovir
PubMed: 32219385
DOI: 10.1042/BST20180302 -
Nutrients Mar 2018With the global population rising, the need for sustainable and resource-efficiently produced proteins with nutritional and health promoting qualities has become urgent.... (Review)
Review
With the global population rising, the need for sustainable and resource-efficiently produced proteins with nutritional and health promoting qualities has become urgent. Proteins are important macronutrients and are involved in most, if not all, biological processes in the human body. This review discusses these absorption mechanisms in the small intestine. To study intestinal transport and predict bioavailability, cell lines are widely applied as screening models and often concern Caco-2, HT-29, HT-29/MTX and T84 cells. Here, we provide an overview of the presence and activities of peptide- and amino acid transporters in these cell models. Further, inter-laboratory differences are discussed as well as the culture micro-environment, both of which may influence cell culture phenotype and performance. Finally, the value of new developments in the field, including culturing cells in 3-dimensional systems under shear stress (i.e., gut-on-chips), is highlighted. In particular, their suitability in screening novel food proteins and prediction of the nutritional quality needed for inclusion in the human diet of the future is addressed.
Topics: Amino Acid Transport Systems; Biological Availability; Caco-2 Cells; Cadherins; Carrier Proteins; Cell Line, Tumor; Cell Membrane Permeability; Dietary Proteins; HT29 Cells; Humans; Intestinal Absorption; Intestinal Mucosa; Intestines; Membrane Transport Proteins; Nerve Tissue Proteins; Peptide Transporter 1; Peptides
PubMed: 29518965
DOI: 10.3390/nu10030322 -
Current Opinion in Structural Biology Aug 2017The POT family of membrane transporters use the inwardly directed proton electrochemical gradient to drive the uptake of essential nutrients into the cell. Originally... (Review)
Review
The POT family of membrane transporters use the inwardly directed proton electrochemical gradient to drive the uptake of essential nutrients into the cell. Originally discovered in bacteria, members of the family have been found in all kingdoms of life except the archaea. A remarkable feature of the family is their diverse substrate promiscuity. Whereas in mammals and bacteria they are predominantly di- and tri-peptide transporters, in plants the family has diverged to recognize nitrate, plant defence compounds and hormones. This promiscuity has led to the development of peptide-based pro-drugs that use PepT1 and PepT2, the mammalian homologues, to improve oral drug delivery. Recent crystal structures from bacterial and plant members of the family have revealed conserved features of the ligand-binding site and provided insights into post-translational regulation. Here I review the current understanding of transport, ligand promiscuity and regulation within the POT family.
Topics: Animals; Disulfides; Humans; Membrane Transport Proteins; Peptides; Protein Transport; Protons
PubMed: 27865112
DOI: 10.1016/j.sbi.2016.10.018 -
Biochimica Et Biophysica Acta Mar 2015Cellular uptake of small peptides is an important physiological process mediated by the PTR family of proton-coupled peptide transporters. In bacteria peptides can be... (Review)
Review
BACKGROUND
Cellular uptake of small peptides is an important physiological process mediated by the PTR family of proton-coupled peptide transporters. In bacteria peptides can be used as a source of amino acids and nitrogen. Similarly in humans peptide transport is the principle route for the uptake and retention of dietary protein in the form of short di- and tri-peptides for cellular metabolism.
SCOPE OF THE REVIEW
Recent crystal structures of bacterial PTR family transporters, combined with biochemical studies of transport have revealed key molecular details underpinning ligand promiscuity and the mechanism of proton-coupled transport within the family.
MAJOR CONCLUSIONS
Pairs of salt bridge interactions between transmembrane helices work in tandem to orchestrate alternating access transport within the PTR family. Key roles for residues conserved between bacterial and eukaryotic homologues suggest a conserved mechanism of peptide recognition and transport that in some cases has been subtly modified in individual species.
GENERAL SIGNIFICANCE
Physiological studies on PepT1 and PepT2, the mammalian members of this family, have identified these transporters as being responsible for the uptake of many pharmaceutically important drug molecules, including antibiotics and antiviral medications and demonstrated their promiscuity can be used for improving the oral bioavailability of poorly absorbed compounds. The insights gained from recent structural studies combined with previous physiological and biochemical analyses are rapidly advancing our understanding of this medically important transporter superfamily. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
Topics: Amino Acid Sequence; Bacterial Proteins; Biological Transport; Membrane Transport Proteins; Models, Molecular; Molecular Sequence Data; Oligopeptides; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid
PubMed: 24859687
DOI: 10.1016/j.bbagen.2014.05.011