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Trends in Plant Science Jun 2002Recent completion of the Arabidopsis genome revealed that this organism has ten times more peptide transporters than any other sequenced organism (prokaryote or... (Review)
Review
Recent completion of the Arabidopsis genome revealed that this organism has ten times more peptide transporters than any other sequenced organism (prokaryote or eukaryote). These transporters are found in three protein families: the ABC-type transporters; the di- and tripeptide transporters; and the newly described tetra- and pentapeptide oligopetide transporters. The abundance of these transporters suggests that they play diverse and important roles in plant growth and development. Possible substrates for these transporters include glutathione, gamma-glutamyl peptides, hormone-amino acid conjugates, phytosulfokine, peptide-like compounds and peptide phytotoxins. However, the exact role of peptide transport in plants is still undefined.
Topics: ATP-Binding Cassette Transporters; Amino Acid Transport Systems; Arabidopsis; Biological Transport, Active; Genome, Plant; Membrane Transport Proteins; Oligopeptides; Phylogeny; Plant Physiological Phenomena
PubMed: 12049922
DOI: 10.1016/s1360-1385(02)02249-5 -
Advances in Microbial Physiology 1994
Review
Topics: Bacteria; Biological Transport; Cell Wall; Escherichia coli; Fungi; Membrane Transport Proteins; Peptides; Prodrugs; Salmonella typhimurium; Yeasts
PubMed: 7942312
DOI: 10.1016/s0065-2911(08)60176-9 -
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 -
Advanced Drug Delivery Reviews Oct 2004In addition to being the main source of cerebrospinal fluid (CSF) secretion, the choroid plexuses are involved in the supply and distribution of peptides to brain, the... (Review)
Review
In addition to being the main source of cerebrospinal fluid (CSF) secretion, the choroid plexuses are involved in the supply and distribution of peptides to brain, the removal of toxic metabolites, the excretion of xenobiotics, and the delivery of drugs as an alternative route to the blood-brain barrier (BBB). The discovery of proton-coupled oligopeptide transporters in choroid plexus has generated considerable interest regarding their physiologic role at the blood-cerebrospinal fluid interface and their potential for peptide/antagonist pharmacotherapy in the central nervous system. Many of the same factors that affect the disposition of naturally occurring peptides in brain will also affect the disposition of exogenously delivered peptide or peptidomimetic drugs. Therefore, this review addresses three main areas: (1) choroid plexus structure, physiology, and barrier function in relation to peptide transport; (2) polypeptide transport and secretion mechanisms into cerebrospinal fluid; and (3) molecular physiology, expression, and functional activity of proton-coupled oligopeptide transporters in choroid plexus.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Cerebrospinal Fluid; Choroid Plexus; Humans; Membrane Transport Proteins; Peptides
PubMed: 15381333
DOI: 10.1016/j.addr.2004.07.008 -
Pharmacology & Toxicology Jun 2002The apical membrane of small intestinal enterocytes possess an uptake system for di- and tripeptides. The physiological function of the system is to transport small... (Review)
Review
The apical membrane of small intestinal enterocytes possess an uptake system for di- and tripeptides. The physiological function of the system is to transport small peptides resulting from digestion of dietary protein. Moreover, due to the broad substrate specificity of the system, it is also capable of transporting a number of orally administered peptidomimetic drugs. Absorbed peptides may be hydrolysed in the cells due to the high peptidase activity present in the cytosol. Peptidomimetic drugs may, if resistant to the cellular enzyme activity, pass the basolateral membrane via a basolateral peptide transport mechanism and enter the systemic circulation. As the number of new peptide and peptidomimetic drugs are rapidly increasing, the peptide transport system has gained increasing attention as a possible drug delivery system for small peptides and peptide-like compounds. In this paper we give an updated introduction to the transport system and discuss the substrate characteristics of the di/tri-peptide transporter system with special emphasis on chemically modified substrates and prodrugs.
Topics: Animals; Biological Transport; Carrier Proteins; Humans; Intestinal Absorption; Intestinal Mucosa; Molecular Mimicry; Oligopeptides; Peptide Transporter 1; Peptides; Pharmaceutical Preparations; Pharmacokinetics; Prodrugs; Symporters
PubMed: 12403049
DOI: 10.1034/j.1600-0773.2002.900601.x -
Current Opinion in Pharmacology Dec 2013The focus of this review is on the pharmaceutical relevance of the intestinal peptide transporter PepT1. The review is limited to the progress made in the field over the... (Review)
Review
The focus of this review is on the pharmaceutical relevance of the intestinal peptide transporter PepT1. The review is limited to the progress made in the field over the past two years. Much of this progress is being driven by the prevailing view that PepT1 can be used for drug delivery purposes. Studies have indeed shown that several drugs, prodrugs and drug candidates gain entry into the systemic circulation via PepT1. Very recent examples are prodrugs of zanamivir, oseltamivir and didanosine.
Topics: Animals; Biological Transport; Humans; Intestinal Mucosa; Membrane Transport Proteins; Pharmaceutical Preparations; Prodrugs
PubMed: 24007794
DOI: 10.1016/j.coph.2013.08.004 -
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 -
Annual Review of Biochemistry 1971
Review
Topics: Amino Acids; Bacillus subtilis; Bacteria; Biological Transport; Biological Transport, Active; Dipeptides; Endopeptidases; Enzyme Activation; Escherichia coli; Lysine; Membrane Transport Proteins; Peptide Hydrolases; Peptides
PubMed: 5001044
DOI: 10.1146/annurev.bi.40.070171.002145 -
Annual Review of Physiology 2004Intestinal protein digestion generates a huge variety and quantity of short chain peptides that are absorbed into intestinal epithelial cells by the PEPT1 transporter in... (Review)
Review
Intestinal protein digestion generates a huge variety and quantity of short chain peptides that are absorbed into intestinal epithelial cells by the PEPT1 transporter in the apical membrane of enterocytes. PEPT1 operates as an electrogenic proton/peptide symporter with the ability to transport essentially every possible di- and tripeptide. Transport is enantio-selective and involves a variable proton-to-substrate stoichiometry for uptake of neutral and mono- or polyvalently charged peptides. Neither free amino acids nor peptides containing four or more amino acids are accepted as substrates. The structural similarity of a variety of drugs with the basic structure of di- or tripeptides explains the transport of aminocephalosporins and aminopenicillins, selected angiotensin-converting inhibitors, and amino acid-conjugated nucleoside-based antiviral agents by PEPT1. The high transport capacity of PEPT1 allows fast and efficient intestinal uptake of the drugs but also of amino acid nitrogen even in states of impaired mucosal functions. Transcriptional and post-transcriptional regulation of PEPT1 occurs in response to alterations in the nutritional status and in disease states, suggesting a prime role of this transporter in amino acid absorption.
Topics: Adaptation, Physiological; Animals; Biological Transport; Carrier Proteins; Cell Membrane; Dietary Proteins; Enterocytes; Humans; Intestinal Mucosa; Peptide Transporter 1; Peptides; Symporters
PubMed: 14977407
DOI: 10.1146/annurev.physiol.66.032102.144149 -
American Journal of Respiratory Cell... Mar 2004The aerosolic administration of peptidomimetic drugs could play a major role in the future treatment of various pulmonary and systemic diseases, because rational drug... (Review)
Review
The aerosolic administration of peptidomimetic drugs could play a major role in the future treatment of various pulmonary and systemic diseases, because rational drug design offers the potential to specifically generate compounds that are transported efficiently into the epithelium by distinct carrier proteins such as the peptide transporters. From the two presently known peptide transporters, PEPT1 and PEPT2, which have been cloned from human tissues, the high-affinity transporter PEPT2 is expressed in the respiratory tract epithelium. The transporter is an integral membrane protein with 12 membrane-spanning domains and mediates electrogenic uphill peptide and peptidomimetic drug transport by coupling of substrate translocation to a transmembrane electrochemical proton gradient serving as driving force. In human airways, PEPT2 is localized to bronchial epithelium and alveolar type II pneumocytes, and transport studies revealed that both peptides and peptidomimetic drugs such as antibiotic, antiviral, and antineoplastic drugs are carried by the system. PEPT2 is also responsible for the transport of delta-aminolevulinic acid, which is used for photodynamic therapy and the diagnostics of pulmonary neoplasms. Based on the recent progress in understanding the structural requirements for substrate binding and transport, PEPT2 becomes a target for a rational drug design that may lead to a new generation of respiratory drugs and prodrugs that can be delivered to the airways via the peptide transporter.
Topics: Animals; Biological Transport; Carrier Proteins; Drug Carriers; Humans; Lung; Lung Diseases; Peptide Transporter 1; Peptides; Respiratory Mucosa; Symporters
PubMed: 14969997
DOI: 10.1165/rcmb.2003-0315TR