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Biochemical and Biophysical Research... Mar 2023Candida tropicalis is often reported as the second or third most common pathogen causing fungal infections. Antimicrobial peptides (AMPs) have attracted increasing...
Candida tropicalis is often reported as the second or third most common pathogen causing fungal infections. Antimicrobial peptides (AMPs) have attracted increasing attention for their broad-spectrum antimicrobial properties and low cytotoxicity. Our previous studies have shown that CGA-N9, a non-membrane-rupturing AMP, crosses the cell membrane to exert anticandidal activity. We speculate that there are some related transporters that assist in the transmembrane transport of CGA-N9. In this study, the relationship between CGA-N9 lethality kinetics and its real-time transmembrane amount in C. tropicalis cells was investigated. The results demonstrated that there was a positive correlation between its candicidal activity and transmembrane amount. A total of 12 oligopeptide transporter (OPT) coding sequences (CDSs) were cloned from C. tropicalis by using the conservative OPT gene sequences of Candida spp. to design primers and were named C. tropicalis OPTs (CtOPTs). The results of RT‒qPCR demonstrated that the expression levels of CtOPT1, CtOPT9 and CtOPT12 were correlated with the CGA-N9 transmembrane amount in a time-dependent manner. The results of molecular docking demonstrated that CtOPT1, CtOPT9 and CtOPT12 interact strongly with CGA-N9. Therefore, CtOPT1, CtOPT9 and CtOPT12 were predicted to assist in the transmembrane transport of the AMP CGA-N9.
Topics: Candida tropicalis; Antimicrobial Peptides; Molecular Docking Simulation; Membrane Transport Proteins; Oligopeptides; Antifungal Agents
PubMed: 36764112
DOI: 10.1016/j.bbrc.2023.01.083 -
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 -
Pharmaceutical Research Oct 1995The study of peptide transport across the blood-brain barrier (BBB) is a field fraught with conflicting interpretations. This review presents a fairly strong case that... (Review)
Review
The study of peptide transport across the blood-brain barrier (BBB) is a field fraught with conflicting interpretations. This review presents a fairly strong case that peptides can be differentially transported at the BBB. However, minimal transport of peptides could have important impact on central nervous system (CNS) functions since only small amounts are needed for physiologic pharmacologic and/or pathologic effects. Several BBB peptide transport mechanisms (i.e., receptor-mediated, absorptive-mediated, carrier-mediated and non-specific passive diffusion), as well as non-transport processes (i.e., endocytosis without transcytosis, absorption and metabolism) are discussed. It is emphasized that peptide transport systems at the BBB could be important targets for both therapeutic delivery of peptides and the development of certain brain pathologies. Strategies to manipulate peptide BBB transport processes have been discussed including lipidization, chemical modifications of the N-terminal end, coupling of transport with post-BBB metabolism and formation of potent neuroactive peptides, up-regulation of putative peptide transporters, use of chimeric peptides in which non-transportable peptide is chemically linked to a transportable peptide, use of monoclonal antibodies against peptide receptors, and binding of circulating peptides to apolipoproteins. It is suggested that future directions should be directed towards development of molecular strategies to up-regulate specific BBB peptide transporters to enhance brain delivery of peptide neuropharmaceuticals, or to down-regulate transport of peptides with potential role in cerebral pathogenesis.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Capillary Permeability; Cerebrovascular Circulation; Glutathione; Peptides
PubMed: 8584471
DOI: 10.1023/a:1016254514167 -
Involvement of a Na-coupled Oligopeptide Transport System for β-amyloid Peptide (Aβ) in Brain Cells.Pharmaceutical Research May 2020A Na-coupled transport system in mammalian cells is responsible for the uptake of oligopeptides consisting of 5 or more amino acids. Here we investigated if this...
PURPOSE
A Na-coupled transport system in mammalian cells is responsible for the uptake of oligopeptides consisting of 5 or more amino acids. Here we investigated if this transport system is expressed in brain cells and transports the 42-amino-acid β-amyloid peptide (Aβ).
METHODS
The human and mouse neuronal cell lines SK-N-SH and HT22, human microglial cell line HMC-3, and human blood-brain barrier endothelial cell line hCMEC/D3 were used to monitor the uptake of [H]-deltorphin II (a heptapeptide) and fluorescence-labeled Aβ.
RESULTS
All four cell lines exhibited Na-coupled uptake of deltorphin II. Aβ competed with deltorphin II for the uptake. Uptake of fluorescence-labeled Aβ was detectable in these cell lines, and the uptake was Na-dependent and inhibitable by deltorphin II. The Na-coupled uptake disappeared at high concentrations of Aβ due to oligomerization of the peptide. Exposure of the cells to excess iron abolished the uptake. In hCMEC/D3 cells cultured on Transwell filters, the uptake was localized preferentially to the abluminal membrane.
CONCLUSION
A Na-coupled transport system mediates the uptake of Aβ monomers in neuronal and microglial cells. The same system is also responsible for the uptake of Aβ from brain into blood-brain barrier endothelial cells. These findings have relevance to Alzheimer's disease.
Topics: Amyloid beta-Peptides; Animals; Biological Transport; Blood-Brain Barrier; Cell Line; Endothelial Cells; Humans; Kinetics; Membrane Transport Modulators; Membrane Transport Proteins; Mice; Models, Biological; Oligopeptides; Peptide Fragments; Sodium
PubMed: 32419062
DOI: 10.1007/s11095-020-02835-7 -
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 -
Current Drug Metabolism Feb 2004Proton-coupled peptide transporters, localized at brush-border membranes of intestinal and renal epithelial cells, play important roles in protein absorption and the... (Review)
Review
Proton-coupled peptide transporters, localized at brush-border membranes of intestinal and renal epithelial cells, play important roles in protein absorption and the conservation of peptide-bound amino nitrogen. These transporters also have significant pharmacological and pharmacokinetic relevance to the transport of various peptide-like drugs such as beta-lactam antibiotics. The identification and molecular characterization of H(+)/peptide cotransporters (PEPT1 and PEPT2) have facilitated the clarification of many aspects of these transporters such as the structure/function relationship and regulation. Recent findings that intestinal PEPT1 can transport l-valine ester prodrugs such as valacyclovir provided a major step forward toward the development of novel drug delivery systems. It has been demonstrated that peptide transporters, which have a similar substrate specificity to PEPT1 and PEPT2, but possess other distinct functional properties, are localized at basolateral membranes of intestinal and renal epithelial cells. This review highlights the recent advances in our knowledge of the cellular and molecular nature of PEPT1, PEPT2 and the basolateral peptide transporters.
Topics: Animals; Biological Transport; Carrier Proteins; Humans; Organ Specificity; Peptide Transporter 1; Peptides; Pharmaceutical Preparations; Pharmacokinetics; Protein Conformation; Symporters
PubMed: 14965252
DOI: 10.2174/1389200043489153 -
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 -
Methods in Enzymology 1998
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP Binding Cassette Transporter, Subfamily B, Member 3; ATP-Binding Cassette Transporters; Amino Acid Sequence; Bacterial Proteins; Binding, Competitive; Biological Transport; Cell Line; Cell Membrane Permeability; Cells, Cultured; Chromatography, Affinity; Glycosylation; Humans; Kinetics; Major Histocompatibility Complex; Melanoma; Molecular Sequence Data; Peptides; Streptolysins; Tumor Cells, Cultured
PubMed: 9711596
DOI: 10.1016/s0076-6879(98)92057-2 -
Biochemistry and Cell Biology =... Dec 2016Cholesterol plays an important role in determining the biophysical properties of membranes in mammalian cells, and the concentration of cholesterol in membranes is... (Review)
Review
Cholesterol plays an important role in determining the biophysical properties of membranes in mammalian cells, and the concentration of cholesterol in membranes is tightly regulated. Cholesterol moves among membrane organelles by a combination of vesicular and nonvesicular transport pathways, but the details of these transport pathways are not well understood. In this review, we discuss the mechanisms for nonvesicular sterol transport with an emphasis on the role of STARD4, a small, soluble, cytoplasmic sterol transport protein. STARD4 can rapidly equilibrate sterol between membranes, especially membranes with anionic lipid headgroups. We also discuss the sterol transport in late endosomes and lysosomes, which is mediated by a soluble protein, NPC2, and a membrane protein, NPC1. Homozygous mutations in these proteins lead to a lysosomal lipid storage disorder, Niemann-Pick disease type C. Many of the disease-causing mutations in NPC1 are associated with degradation of the mutant NPC1 proteins in the endoplasmic reticulum. Several histone deacetylase inhibitors have been found to rescue the premature degradation of the mutant NPC1 proteins, and one of these is now in a small clinical trial.
Topics: Biological Transport; Carrier Proteins; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Membrane Transport Proteins; Niemann-Pick C1 Protein; Sterols
PubMed: 27421092
DOI: 10.1139/bcb-2015-0154 -
Biology Letters Aug 2011Protein digestion products are transported from the intestinal lumen into the enterocyte both in the form of free amino acids (AAs), by a large variety of brush border...
Protein digestion products are transported from the intestinal lumen into the enterocyte both in the form of free amino acids (AAs), by a large variety of brush border membrane AA transporters, and in the form of di/tripeptides, by a single brush border membrane transporter known as PEPtide Transporter 1 (PEPT1). Recent data indicate that, at least in teleost fish, PEPT1 plays a significant role in animal growth by operating, at the gastrointestinal level, as part of an integrated response network to food availability that directly supports body weight. Notably, PEPT1 responds to both fasting and refeeding and is involved in a phenomenon known as compensatory growth (a phase of accelerated growth when food levels are restored after a period of growth depression). In particular, PEPT1 expression decreases during fasting and increases during refeeding, which is the opposite of what observed so far in mammals and birds. These findings in teleost fish document, to our knowledge, for the first time in a vertebrate model, a direct correlation between the expression of an intestinal transporter, such as PEPT1, primarily involved in the uptake of dietary protein degradation products and animal growth.
Topics: Animals; Biological Transport; Fishes; Peptide Transporter 1; Peptides; Symporters
PubMed: 21389019
DOI: 10.1098/rsbl.2010.1164