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American Journal of Physiology. Renal... Dec 2022Kidney function is regulated by the circadian clock. Not only do glomerular filtration rate and urinary excretion oscillate during the day, but the expressions of...
Kidney function is regulated by the circadian clock. Not only do glomerular filtration rate and urinary excretion oscillate during the day, but the expressions of several renal transporter proteins also exhibit circadian rhythms. Interestingly, the circadian regulation of these transporters appears to be sexually dimorphic. Thus, the goal of the present study was to investigate the mechanisms by which the kidney function of the mouse is modulated by sex and time of day. To accomplish this, we developed the first computational models of epithelial water and solute transport along the mouse nephrons that represent the effects of sex and the circadian clock on renal hemodynamics and transporter activity. We conducted simulations to study how the circadian control of renal transport genes affects overall kidney function and how that process differs between male and female mice. Simulation results predicted that tubular transport differs substantially among segments, with relative variations in water and Na reabsorption along the proximal tubules and thick ascending limb tracking that of glomerular filtration rate. In contrast, relative variations in distal segment transport were much larger, with Na reabsorption almost doubling during the active phase. Oscillations in Na transport drive K transport variations in the opposite direction. Model simulations of basic helix-loop-helix ARNT like 1 (BMAL1) knockout mice predicted a significant reduction in net Na reabsorption along the distal segments in both sexes, but more so in males than in females. This can be attributed to the reduction of mean epithelial Na channel activity in males only, a sex-specific effect that may lead to a reduction in blood pressure in BMAL1-null males. How does the circadian control of renal transport genes affect overall kidney function, and how does that process differ between male and female mice? How does the differential circadian regulation of the expression levels of key transporter genes impact the transport processes along different nephron segments during the day? And how do those effects differ between males and females? We built computational models of mouse kidney function to answer these questions.
Topics: Mice; Female; Male; Animals; Sex Characteristics; ARNTL Transcription Factors; Nephrons; Sodium; Circadian Rhythm; Kidney; Membrane Transport Proteins; Water
PubMed: 36264883
DOI: 10.1152/ajprenal.00227.2022 -
Expert Opinion on Drug Metabolism &... May 2020: Transporters and enzymes play an important role in absorption, distribution, clearance and elimination of drugs.: This review provides an overview of the extended... (Review)
Review
: Transporters and enzymes play an important role in absorption, distribution, clearance and elimination of drugs.: This review provides an overview of the extended clearance concept and usefulness of extended clearance classification system (ECCS) in early identification of predominant clearance mechanisms. Clinical studies demonstrating transporter-enzyme interplay, challenges in scaling clearance from in vitro systems, utility of animal models and modeling approaches for evaluating hepatic clearance and drug-drug interactions are reviewed.: Clinical evidence exists supporting organic anion transporting peptide (OATP)1B and drug metabolizing enzymes involvement in clearance of ECCS class 1B drugs. Emerging evidence point toward contribution of organic cation transporter (OCT)1 to hepatic uptake of cationic drugs. Although, limited clinical evidence is presented, preclinical studies and modeling suggests organic anion transporter (OAT)2-enzyme interplay in clearance of class 1A drugs. Data from assays and preclinical models coupled with physiologically based modeling approaches are key for understanding transporter-enzyme interplay, enabling prediction of pharmacokinetics, tissue exposure and drug interactions. Current methodologies incur limitations and emphasis should be placed on the development of physiologically relevant models and characterize animal models to inform mechanistic modeling and improve confidence in prospective predictions.
Topics: Animals; Drug Elimination Routes; Drug Interactions; Humans; Liver; Membrane Transport Proteins; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Pharmaceutical Preparations
PubMed: 32228316
DOI: 10.1080/17425255.2020.1749595 -
Advances in Protein Chemistry and... 2021Iron, the most common metal in the earth, is also an essential component for almost all living organisms. While these organisms require iron for many biological... (Review)
Review
Iron, the most common metal in the earth, is also an essential component for almost all living organisms. While these organisms require iron for many biological processes, too much or too little iron itself poses many issues; this is most easily recognized in human beings. The control of body iron levels is thus an important metabolic process which is regulated essentially by controlling the expression, activity and levels of the iron transporter ferroportin. Ferroportin is the only known iron exporter. The function and activity of ferroportin is influenced by its interaction with the iron-regulatory peptide hepcidin, which itself is regulated by many factors. Here we review the current state of understanding of the mechanisms that regulate ferroportin and its function.
Topics: Biological Transport; Cation Transport Proteins; Hepcidins; Humans; Iron
PubMed: 33485480
DOI: 10.1016/bs.apcsb.2020.10.005 -
Cancer Letters Jun 2023The glucose transporter family (GLUT) consists of fourteen members. It is responsible for glucose homeostasis and glucose transport from the extracellular space to the... (Review)
Review
The glucose transporter family (GLUT) consists of fourteen members. It is responsible for glucose homeostasis and glucose transport from the extracellular space to the cell cytoplasm to further cascade catalysis. GLUT proteins are encoded by the solute carrier family 2 (SLC2) genes and are members of the major facilitator superfamily of membrane transporters. Moreover, different GLUTs also have their transporter kinetics and distribution, so each GLUT member has its uniqueness and importance to play essential roles in human physiology. Evidence from many studies in the field of diabetes showed that GLUT4 travels between the plasma membrane and intracellular vesicles (GLUT4-storage vesicles, GSVs) and that the PI3K/Akt pathway regulates this activity in an insulin-dependent manner or by the AMPK pathway in response to muscle contraction. Moreover, some published results also pointed out that GLUT4 mediates insulin-dependent glucose uptake. Thus, dysfunction of GLUT4 can induce insulin resistance, metabolic reprogramming in diverse chronic diseases, inflammation, and cancer. In addition to the relationship between GLUT4 and insulin response, recent studies also referred to the potential upstream transcription factors that can bind to the promoter region of GLUT4 to regulating downstream signals. Combined all of the evidence, we conclude that GLUT4 has shown valuable unknown functions and is of clinical significance in cancers, which deserves our in-depth discussion and design compounds by structure basis to achieve therapeutic effects. Thus, we intend to write up a most updated review manuscript to include the most recent and critical research findings elucidating how and why GLUT4 plays an essential role in carcinogenesis, which may have broad interests and impacts on this field.
Topics: Humans; Cell Membrane; Glucose; Glucose Transport Proteins, Facilitative; Glycolysis; Insulin; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Transport
PubMed: 37061122
DOI: 10.1016/j.canlet.2023.216179 -
Proceedings of the National Academy of... Mar 2023Lysosomes are catabolic organelles involved in macromolecular digestion, and their dysfunction is associated with pathologies ranging from lysosomal storage disorders to...
Lysosomes are catabolic organelles involved in macromolecular digestion, and their dysfunction is associated with pathologies ranging from lysosomal storage disorders to common neurodegenerative diseases, many of which have lipid accumulation phenotypes. The mechanism of lipid efflux from lysosomes is well understood for cholesterol, while the export of other lipids, particularly sphingosine, is less well studied. To overcome this knowledge gap, we have developed functionalized sphingosine and cholesterol probes that allow us to follow their metabolism, protein interactions, and their subcellular localization. These probes feature a modified cage group for lysosomal targeting and controlled release of the active lipids with high temporal precision. An additional photocrosslinkable group allowed for the discovery of lysosomal interactors for both sphingosine and cholesterol. In this way, we found that two lysosomal cholesterol transporters, NPC1 and to a lesser extent LIMP-2/SCARB2, bind to sphingosine and showed that their absence leads to lysosomal sphingosine accumulation which hints at a sphingosine transport role of both proteins. Furthermore, artificial elevation of lysosomal sphingosine levels impaired cholesterol efflux, consistent with sphingosine and cholesterol sharing a common export mechanism.
Topics: Carrier Proteins; Sphingosine; Sterols; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Niemann-Pick C1 Protein; Cholesterol; Membrane Transport Proteins; Lysosomes
PubMed: 36893262
DOI: 10.1073/pnas.2213886120 -
Nature Communications Jan 2020Niemann-Pick C1 (NPC1), a lysosomal protein of 13 transmembrane helices (TMs) and three lumenal domains, exports low-density-lipoprotein (LDL)-derived cholesterol from...
Niemann-Pick C1 (NPC1), a lysosomal protein of 13 transmembrane helices (TMs) and three lumenal domains, exports low-density-lipoprotein (LDL)-derived cholesterol from lysosomes. TMs 3-7 of NPC1 comprise the Sterol-Sensing Domain (SSD). Previous studies suggest that mutation of the NPC1-SSD or the addition of the anti-fungal drug itraconazole abolishes NPC1 activity in cells. However, the itraconazole binding site and the mechanism of NPC1-mediated cholesterol transport remain unknown. Here, we report a cryo-EM structure of human NPC1 bound to itraconazole, which reveals how this binding site in the center of NPC1 blocks a putative lumenal tunnel linked to the SSD. Functional assays confirm that blocking this tunnel abolishes NPC1-mediated cholesterol egress. Intriguingly, the palmitate anchor of Hedgehog occupies a similar site in the homologous tunnel of Patched, suggesting a conserved mechanism for sterol transport in this family of proteins and establishing a central function of their SSDs.
Topics: Animals; Antifungal Agents; Binding Sites; Biological Transport; CHO Cells; Cell Line; Cholesterol; Cricetinae; Cricetulus; Cryoelectron Microscopy; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Itraconazole; Niemann-Pick C1 Protein; Patched-1 Receptor; Protein Domains
PubMed: 31919352
DOI: 10.1038/s41467-019-13917-5 -
Proceedings of the National Academy of... Oct 2023Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the...
Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the existing layer of PG is remodeled and PG fragments are released. Enterics such as go to great lengths to internalize and reutilize PG fragments. is estimated to break down one-third of its cell wall, yet only loses ~0 to 5% of meso-diaminopimelic acid, a PG-specific amino acid, per generation. Two transporters were identified early on to possibly be the primary permease that facilitates PG fragment recycling, i) AmpG and ii) the Opp ATP binding cassette transporter in conjunction with a PG-specific periplasmic binding protein, MppA. The contribution of each transporter to PG recycling has been debated. Here, we have found that AmpG and MppA/Opp are differentially regulated by carbon source and growth phase. In addition, MppA/Opp is uniquely capable of high-affinity scavenging of muropeptides from growth media, demonstrating that AmpG and MppA/Opp allow for different strategies of recycling PG fragments. Altogether, this work clarifies environmental contexts under which utilizes distinct permeases for PG recycling and explores how scavenging by MppA/Opp could be beneficial in mixed communities.
Topics: Membrane Transport Proteins; Escherichia coli; Peptidoglycan; Bacterial Proteins; Bacteria; Cell Wall
PubMed: 37871219
DOI: 10.1073/pnas.2308940120 -
Cells Sep 2022Peptide transporter 2 (PepT2) in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining... (Review)
Review
Peptide transporter 2 (PepT2) in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining neuropeptide homeostasis in the brain. It is also of significant medical and pharmacological significance in the absorption and disposing of peptide-like drugs, including angiotensin-converting enzyme inhibitors, β-lactam antibiotics and antiviral prodrugs. Understanding the structure, function and regulation of PepT2 is of emerging interest in nutrition, medical and pharmacological research. In this review, we provide a comprehensive overview of the structure, substrate preferences and localization of PepT2 in mammals. As PepT2 is expressed in various organs, its function in the liver, kidney, brain, heart, lung and mammary gland has also been addressed. Finally, the regulatory factors that affect the expression and function of PepT2, such as transcriptional activation and posttranslational modification, are also discussed.
Topics: Amino Acids; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Bacterial Agents; Antiviral Agents; Biology; Mammals; Membrane Transport Proteins; Peptides; Prodrugs; Symporters; beta-Lactams
PubMed: 36139448
DOI: 10.3390/cells11182874 -
Bioconjugate Chemistry Nov 2022Synthetic calcium transporters are few despite their potential biological significance. Herein, we report small alanine-derived peptides containing pyridyl-triazole...
Synthetic calcium transporters are few despite their potential biological significance. Herein, we report small alanine-derived peptides containing pyridyl-triazole motifs for inducing calcium selectivity. The peptides are decorated with hydrophobic alkyl chains to facilitate membrane insertion. The most efficient peptide scaffold has an EC value of 0.09 mol % and functions as a calcium carrier.
Topics: Ionophores; Calcium; Peptides; Biological Transport; Ion Transport
PubMed: 36345049
DOI: 10.1021/acs.bioconjchem.2c00396 -
Proteins Jul 2022Oligopeptide permease A (OppA) plays an important role in the nutrition of cells and various signaling processes. In archaea, OppA is a major protein present in membrane...
Oligopeptide permease A (OppA) plays an important role in the nutrition of cells and various signaling processes. In archaea, OppA is a major protein present in membrane vesicles of Thermococcales. Because there being no crystal structures of archaeal OppAs determined to date, we report the crystal structure of archaeal OppA from Thermococcus kodakaraensis (TkOppA) at 2.3 Å resolution by the single-wavelength anomalous dispersion method. TkOppA consists of three domains similarly to bacterial OppAs, and the inserted regions not present in bacterial OppAs are at the periphery of the core region. An endogenous pentapeptide was bound in the pocket of domains I and III of TkOppA by hydrogen bonds of main-chain atoms of the peptide and hydrophobic interactions. No hydrogen bonds of side-chain atoms of the peptide were observed; thus, TkOppA may have low peptide selectivity but some preference for residues 2 and 3. TkOppA has a relatively large pocket and can bind a nonapeptide; therefore, it is suitable for the binding of large peptides similarly to OppAs of Gram-positive bacteria.
Topics: Bacterial Proteins; Carrier Proteins; Lipoproteins; Membrane Transport Proteins; Oligopeptides; Peptides; Thermococcus
PubMed: 35170084
DOI: 10.1002/prot.26324