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Pharmaceutical Research Nov 2023The oligopeptide/histidine transporters PHT1 and PHT2, two mammalian solute carrier family 15A proteins, mediate the transmembrane transport of histidine and some... (Review)
Review
The oligopeptide/histidine transporters PHT1 and PHT2, two mammalian solute carrier family 15A proteins, mediate the transmembrane transport of histidine and some di/tripeptides via proton gradient. PHT1 and PHT2 are distributed in a variety of tissues but are preferentially expressed in immune cells and localize to the lysosome-related organelles. Studies have reported the relationships between PHT1/PHT2 and immune diseases. PHT1 and PHT2 participate in the regulation of lysosomal homeostasis and lysosome-associated signaling pathways through their transport and nontransport functions, playing important roles in inflammatory diseases. In this review, we summarize recent research on PHT1 and PHT2, aiming to provide reference for their further biological research and as targets for drug design.
Topics: Animals; Biological Transport; Histidine; Mammals; Membrane Transport Proteins; Oligopeptides; Symporters
PubMed: 37610621
DOI: 10.1007/s11095-023-03589-8 -
Molecules (Basel, Switzerland) Nov 2018Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast... (Review)
Review
Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.
Topics: Animals; Humans; Membrane Transport Proteins; Molecular Structure; Pharmaceutical Preparations; Pharmacokinetics; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution
PubMed: 30467304
DOI: 10.3390/molecules23123062 -
Pharmaceutical Research Nov 2023This mini-review describes the role of the solute carrier (SLC)15 family of proton-coupled oligopeptide transporters (POTs) and particularly Pept2 (Slc15A2) and PhT1... (Review)
Review
This mini-review describes the role of the solute carrier (SLC)15 family of proton-coupled oligopeptide transporters (POTs) and particularly Pept2 (Slc15A2) and PhT1 (Slc15A4) in the brain. That family transports endogenous di- and tripeptides and peptidomimetics but also a number of drugs. The review focuses on the pioneering work of David E. Smith in the field in identifying the impact of PepT2 at the choroid plexus (the blood-CSF barrier) as well as PepT2 and PhT1 in brain parenchymal cells. It also discusses recent findings and future directions in relation to brain POTs including cellular and subcellular localization, regulatory pathways, transporter structure, species differences and disease states.
Topics: Symporters; Protons; Biological Transport; Membrane Transport Proteins; Oligopeptides; Brain
PubMed: 37308743
DOI: 10.1007/s11095-023-03550-9 -
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 -
FEMS Microbiology Letters Jun 2018The Tat machinery catalyzes the transport of folded proteins across the cytoplasmic membrane in bacteria and the thylakoid membrane in plants. Transport occurs only in... (Review)
Review
The Tat machinery catalyzes the transport of folded proteins across the cytoplasmic membrane in bacteria and the thylakoid membrane in plants. Transport occurs only in the presence of an electric field (Δψ) and/or a pH (ΔpH) gradient, and thus, Tat transport is considered to be dependent on the proton motive force (pmf). This presents a fundamental and major challenge, namely, that the Tat system catalyzes the movement of large folded protein cargos across a membrane without collapse of ion gradients. Current models argue that the active translocon assembles de novo for each cargo transported, thus providing an effective gating mechanism to minimize ion leakage. A limited structural understanding of the intermediates occurring during transport and the role of the pmf in stabilizing and/or driving this process have hindered the development of more detailed models. A fundamental question that remains unanswered is whether the pmf is actually 'consumed', providing an energetic driving force for transport, or alternatively, whether its presence is instead necessary to provide the appropriate environment for the translocon components to become active. Including addressing this issue in greater detail, we explore a series of additional questions that challenge current models, and, hopefully, motivate future work.
Topics: Bacteria; Gene Products, tat; Hydrogen-Ion Concentration; Membrane Potentials; Membrane Transport Proteins; Protein Folding; Protein Sorting Signals; Protein Transport; Proton-Motive Force
PubMed: 29897510
DOI: 10.1093/femsle/fny123 -
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 -
Frontiers in Cellular and Infection... 2023Copper, a vital element in various physiological processes, is transported from the gastrointestinal tract to tissues and cells through diverse copper transporters.... (Review)
Review
Copper, a vital element in various physiological processes, is transported from the gastrointestinal tract to tissues and cells through diverse copper transporters. Among these transporters, ATP7A and ATP7B play significant roles in regulating systemic copper metabolism and exhibit precise regulation in their intracellular trafficking. These transporters undergo dynamic shuttling between the trans-Golgi network (TGN) and the plasma membrane via the endocytic recycling mechanism, which involves the retromer and other associated factors. Interestingly, the antimicrobial attribute of copper implies a potential connection between microbial infection and copper metabolism. Several microbes, including , , Influenza A virus (IAV) and Zika virus (ZIKV) have been observed to impact the regulatory mechanisms of ATP7A/B, either directly or indirectly, as a means of survival. This review summarizes the key features and trafficking mechanisms of the copper transporters ATP7A/B, and examines the intricate interplay between microbes and copper metabolism. Ultimately, it highlights how microbes can perturb copper homeostasis through interactions with host factors, offering valuable insights into the mechanistic aspects of host-microbe interactions.
Topics: Humans; Copper; Adenosine Triphosphatases; Zika Virus Infection; Cation Transport Proteins; Zika Virus; Copper Transport Proteins; Copper-Transporting ATPases; Peptide Fragments
PubMed: 38106478
DOI: 10.3389/fcimb.2023.1267931 -
Current Opinion in Plant Biology Oct 2023Proteinogenic dipeptides, with few known exceptions, are products of protein degradation. Dipeptide levels respond to the changes in the environment, often in a... (Review)
Review
Proteinogenic dipeptides, with few known exceptions, are products of protein degradation. Dipeptide levels respond to the changes in the environment, often in a dipeptide-specific manner. What drives this specificity is currently unknown; what likely contributes is the activity of the different peptidases that cleave off the terminal dipeptide from the longer peptides. Dipeptidases that degrade dipeptides to amino acids, and the turnover rates of the "substrate" proteins/peptides. Plants can both uptake dipeptides from the soil, but dipeptides are also found in root exudates. Dipeptide transporters, members of the proton-coupled peptide transporters NTR1/PTR family, contribute to nitrogen reallocation between the sink and source tissues. Besides their role in nitrogen distribution, it becomes increasingly clear that dipeptides may also serve regulatory, dipeptide-specific functions. Dipeptides are found in protein complexes affecting the activity of their protein partners. Moreover, dipeptide supplementation leads to cellular phenotypes reflected in changes in plant growth and stress tolerance. Herein we will review the current understanding of dipeptides' metabolism, transport, and functions and discuss significant challenges and future directions for the comprehensive characterization of this fascinating but underrated group of small-molecule compounds.
Topics: Dipeptides; Biological Transport; Amino Acids; Nitrogen
PubMed: 37311365
DOI: 10.1016/j.pbi.2023.102395 -
Biomaterials Science Nov 2022Intracellular delivery of macromolecules is a critical procedure for biological research and drug discovery, including proteins, peptides, vaccines, antibodies and... (Review)
Review
Intracellular delivery of macromolecules is a critical procedure for biological research and drug discovery, including proteins, peptides, vaccines, antibodies and genes. The penetration of macromolecule therapeutics through the cell membrane to intracellular targets is a prerequisite for their biological activity, but most delivery systems rely on the endocytic pathway to enter the cell and confront an inability to escape from the lysosome. A profound understanding of the cellular internalization of transporting carriers can (i) optimize the design of drug delivery systems, (ii) maintain the biological activity of biomolecular drugs, (iii) improve the efficiency of intracellular macromolecule transport and release, (iv) bring new opportunities for the discovery of macromolecule therapeutics and treatment of refractory disease. This article summarizes the uptake pathway of intracellular delivery vehicles for macromolecule drugs, hoping to provide ideas and references for macromolecule therapeutics delivery systems.
Topics: Drug Delivery Systems; Macromolecular Substances; Peptides; Biological Transport; Proteins
PubMed: 36214257
DOI: 10.1039/d2bm01348g -
Microbiology (Reading, England) Dec 2022Peptide transporters play important nutritional and cell signalling roles in which are pronounced during stationary phase adaptations and development. Three...
Peptide transporters play important nutritional and cell signalling roles in which are pronounced during stationary phase adaptations and development. Three high-affinity ATP-binding cassette (ABC) family transporters are involved in peptide uptake - the oligopeptide permease (Opp), another peptide permease (App) and a less well-characterized dipeptide permease (Dpp). Here we report crystal structures of the extracellular substrate binding proteins, OppA and DppE, which serve the Opp and Dpp systems, respectively. The structure of OppA was determined in complex with endogenous peptides, modelled as Ser-Asn-Ser-Ser, and with the sporulation-promoting peptide Ser-Arg-Asn-Val-Thr, which bind with values of 0.4 and 2 µM, respectively, as measured by isothermal titration calorimetry. Differential scanning fluorescence experiments with a wider panel of ligands showed that OppA has highest affinity for tetra- and penta-peptides. The structure of DppE revealed the unexpected presence of a murein tripeptide (MTP) ligand, l-Ala-d-Glu--DAP, in the peptide binding groove. The mode of MTP binding in DppE is different to that observed in the murein peptide binding protein, MppA, from , suggesting independent evolution of these proteins from an OppA-like precursor. The presence of MTP in DppE points to a role for Dpp in the uptake and recycling of cell wall peptides, a conclusion that is supported by analysis of the genomic context of , which revealed adjacent genes encoding enzymes involved in muropeptide catabolism in a gene organization that is widely conserved in .
Topics: Bacillus subtilis; Peptidoglycan; Bacterial Proteins; Oligopeptides; Membrane Transport Proteins; Escherichia coli; ATP-Binding Cassette Transporters
PubMed: 36748525
DOI: 10.1099/mic.0.001274