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Drug Metabolism Reviews Aug 2014Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism and elimination. Many literature works presenting important aspects... (Review)
Review
Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism and elimination. Many literature works presenting important aspects related to stereochemistry of drug metabolism are available. However, there is very little literature on stereoselectivity of chiral drug transport and enantiomer-transporter interaction. In recent years, the experimental research within this field showed good momentum. Herein, an up-to-date review on this topic was presented. Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Proteins (MRP), P-glycoprotein (P-gp), Organic Anion Transporters (OATs), Organic Anion Transporting Polypeptides (OATPs), Organic Cation Transporters (OCTs), Peptide Transport Proteins (PepTs), Human Proton-Coupled Folate Transporter (PCFT) and Multidrug and Toxic Extrusion Proteins (MATEs), have been reported to exhibit either positive or negative enantio-selective substrate recognition. The approaches utilized to study chirality in enantiomer-transporter interaction include inhibition experiments of specific transporters in cell models (e.g. Caco-2 cells), transport study using drug resistance cell lines or transgenic cell lines expressing transporters in wild type or variant, the use of transporter knockout mice, pharmacokinetics association of single nucleotide polymorphism in transporters, pharmacokinetic interaction study of racemate in the presence of specific transporter inhibitor or inducer, molecule cellular membrane affinity chromatography and pharmacophore modeling. Enantiomer-enantiomer interactions exist in chiral transport. The strength and/or enantiomeric preference of stereoselectivity may be species or tissue-specific, concentration-dependent and transporter family member-dependent. Modulation of specific drug transporter by pure enantiomers might exhibit opposite stereoselectivity. Further studies with integrated approaches will open up new horizons in stereochemistry of pharmacokinetics.
Topics: Animals; Biological Transport; Cell Membrane; Humans; Membrane Transport Proteins; Pharmaceutical Preparations; Stereoisomerism; Substrate Specificity
PubMed: 24796860
DOI: 10.3109/03602532.2014.887094 -
Comprehensive Physiology Mar 2018Mammalian members of the proton-coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and... (Review)
Review
Mammalian members of the proton-coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs and couple substrate translocation to the movement of H , with the transmembrane electrochemical proton gradient providing the driving force. Peptide transporters are responsible for the (re)absorption of dietary and/or bacterial di- and tripeptides in the intestine and kidney and maintaining homeostasis of neuropeptides in the brain. These proteins additionally contribute to absorption of a number of pharmacologically important compounds. In this overview article, we have provided updated information on the structure, function, expression, localization, and activities of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4), and PhT2 (SLC15A3). Peptide transporters, in particular, PepT1 are discussed as drug-delivery systems in addition to their implications in health and disease. Particular emphasis has been placed on the involvement of PepT1 in the physiopathology of the gastrointestinal tract, specifically, its role in inflammatory bowel diseases. © 2018 American Physiological Society. Compr Physiol 8:731-760, 2018.
Topics: Amino Acid Sequence; Animals; Biological Transport; Humans; Inflammatory Bowel Diseases; Membrane Transport Proteins; Peptide Transporter 1; Sequence Alignment; Symporters
PubMed: 29687900
DOI: 10.1002/cphy.c170032 -
The Protein Journal Aug 2019The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from... (Review)
Review
The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from other protein transport systems with respect to two key features. Firstly, it accepts cargo proteins with an N-terminal signal peptide that carries the canonical twin-arginine motif, which is essential for transport. Second, the Tat system only accepts and translocates fully folded cargo proteins across the respective membrane. Here, we review the core essential features of folded protein transport via the bacterial Tat system, using the three-component TatABC system of Escherichia coli and the two-component TatAC systems of Bacillus subtilis as the main examples. In particular, we address features of twin-arginine signal peptides, the essential Tat components and how they assemble into different complexes, mechanistic features and energetics of Tat-dependent protein translocation, cytoplasmic chaperoning of Tat cargo proteins, and the remarkable proofreading capabilities of the Tat system. In doing so, we present the current state of our understanding of Tat-dependent protein translocation across biological membranes, which may serve as a lead for future investigations.
Topics: Arginine; Bacillus subtilis; Cell Membrane; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Protein Folding; Protein Sorting Signals; Protein Transport; SEC Translocation Channels; Twin-Arginine-Translocation System
PubMed: 31401776
DOI: 10.1007/s10930-019-09859-y -
Journal of Animal Physiology and Animal... Jan 2022Intestinal absorption of peptides is vital for the overall health and productivity of dairy cows. This study investigated the regulation, uptake and transport of...
Intestinal absorption of peptides is vital for the overall health and productivity of dairy cows. This study investigated the regulation, uptake and transport of dipeptides in bovine intestinal epithelial cells (BIECs). We also evaluated the effects of time, pH, concentration of the dipeptides, temperature, presence of diethylpyrocarbonate (DEPC)-an inhibitor of PepT1, and other dipeptides (Met-Met, Lys-Lys or Met-Lys), on the uptake and transport of Gly-Sar-FITC, which was a common fluorophore-labelled dipeptide. Under controlled experiments, BIECs were treated with 25 μM LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor) and 25 μM Perifosine (a protein kinase B (AKT) inhibitor). The subsequent expression of PepT1 in the BIECs was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. It was found that the uptake and transport of Gly-Sar-FITC were significant high at 37℃ than that at 4℃. The optimal pH for transport and uptake of Gly-Sar-FITC was 6.0-6.5, whereas the two properties decreased significantly in the presence of DEPC, Met-Met, Lys-Lys and Met-Lys (p < 0.05). The apical-to-basolateral transport was also found to be significantly higher than the reverse transport (p < 0.05). PI3K and AKT inhibitors were found to significantly suppress the expression of PepT1, thus impairing uptake and transport of Gly-Sar-FITC. Findings of this study thus suggest that the uptake and transport of Gly-Sar-FITC in BIECs are mediated by PepT1, and the PI3K/AKT signalling pathway regulates the absorption of small peptides.
Topics: Animals; Biological Transport; Caco-2 Cells; Cattle; Dipeptides; Epithelial Cells; Female; Humans; Peptide Transporter 1; Phosphatidylinositol 3-Kinases; Symporters
PubMed: 33834547
DOI: 10.1111/jpn.13546 -
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 -
Pflugers Archiv : European Journal of... Apr 2024Secretin is a key hormone of the intestinal phase of digestion which activates pancreatic, bile duct and Brunner gland HCO secretion. Recently, the secretin receptor... (Review)
Review
Secretin is a key hormone of the intestinal phase of digestion which activates pancreatic, bile duct and Brunner gland HCO secretion. Recently, the secretin receptor (SCTR) was also found in the basolateral membrane of the beta-intercalated cell (B-IC) of the collecting duct. Experimental addition of secretin triggers a pronounced activation of urinary HCO excretion, which is fully dependent on key functional proteins of the B-IC, namely apical pendrin and CFTR and the basolateral SCTR. Recent studies demonstrated that the SCTR knock-out mouse is unable to respond to an acute base load. Here, SCTR KO mice could not rapidly increase urine base excretion, developed prolonged metabolic alkalosis and exhibited marked compensatory hypoventilation. Here, we review the physiological effects of secretin with distinct focus on how secretin activates renal HCO excretion. We describe its new function as a hormone for HCO homeostasis.
Topics: Mice; Animals; Secretin; Cell Membrane; Sulfate Transporters; Biological Transport; Homeostasis; Bicarbonates
PubMed: 38221598
DOI: 10.1007/s00424-024-02906-3 -
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 -
FEMS Yeast Research Jun 2016ABC (ATP-binding cassette) and MFS (major facilitator superfamily) exporters, belonging to two different superfamilies, are one of the most prominent contributors of... (Review)
Review
ABC (ATP-binding cassette) and MFS (major facilitator superfamily) exporters, belonging to two different superfamilies, are one of the most prominent contributors of multidrug resistance (MDR) in yeast. While the role of ABC efflux pump proteins in the development of MDR is well documented, the MFS transporters which are also implicated in clinical drug resistance have not received due attention. The MFS superfamily is the largest known family of secondary active membrane carriers, and MFS exporters are capable of transporting a host of substrates ranging from small molecules, including organic and inorganic ions, to complex biomolecules, such as peptide and lipid moieties. A few of the members of the drug/H(+) antiporter family of the MFS superfamily function as multidrug transporters and employ downhill transport of protons to efflux their respective substrates. This review focuses on the recent developments in MFS of Candida and highlights their role in drug transport by using the example of the relatively well characterized promiscuous Mdr1 efflux pump of the pathogenic yeast C. albicans.
Topics: Antifungal Agents; Antiporters; Biological Transport, Active; Candida; Drug Resistance, Fungal
PubMed: 27188885
DOI: 10.1093/femsyr/fow043 -
Current Opinion in Plant Biology Aug 2022The nitrate and peptide transporter family (NPF) is one of the largest transporter families in the plant kingdom. The name of the family reflects the substrates (nitrate... (Review)
Review
The nitrate and peptide transporter family (NPF) is one of the largest transporter families in the plant kingdom. The name of the family reflects the substrates (nitrate and peptides) identified for the two founding members CHL1 and PTR2 from Arabidopsis thaliana almost 30 years ago. However, since then, the NPF has emerged as a hotspot for transporters with a wide range of crucial roles in plant specialized metabolism. Recent prominent examples include 1) controlling accumulation of antinutritional glucosinolates in Brassica seeds, 2) deposition of heat-stress tolerance flavonol diglucosides to pollen coats 3) production of anti-cancerous monoterpene indole alkaloid precursors in Catharanthus roseus and 4) detoxification of steroid glycoalkaloids in ripening tomatoes. In this review, we turn the spotlight on the emerging role of the NPF in plant specialized metabolism and its potential for improving crop traits through transport engineering.
Topics: Anion Transport Proteins; Arabidopsis; Gene Expression Regulation, Plant; Membrane Transport Proteins; Nitrates; Peptides; Plant Proteins; Plants
PubMed: 35709542
DOI: 10.1016/j.pbi.2022.102243 -
American Journal of Physiology. Renal... Nov 2018The ability to detect and track single molecules presents the advantage of visualizing the complex behavior of transmembrane proteins with a time and space resolution... (Review)
Review
The ability to detect and track single molecules presents the advantage of visualizing the complex behavior of transmembrane proteins with a time and space resolution that would otherwise be lost with traditional labeling and biochemical techniques. Development of new imaging probes has provided a robust method to study their trafficking and surface dynamics. This mini-review focuses on the current technology available for single-molecule labeling of transmembrane proteins, their advantages, and limitations. We also discuss the application of these techniques to the study of renal transporter trafficking in light of recent research.
Topics: Animals; Expressed Sequence Tags; Humans; Kidney; Luminescent Proteins; Membrane Transport Proteins; Microscopy, Fluorescence; Protein Transport; Recombinant Proteins; Single Molecule Imaging; Single-Domain Antibodies
PubMed: 30043625
DOI: 10.1152/ajprenal.00082.2017