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DehydroalanylGly, a new post translational modification resulting from the breakdown of glutathione.
Friedrich MG, Wang Z, Schey KL, Truscott RJW
(2018) Biochim Biophys Acta Gen Subj 1862: 907-913
MeSH Terms: Alanine, Amino Acid Sequence, Crystallins, Dipeptides, Glutathione, Glutathione Disulfide, Humans, Lens, Crystalline, Lysine, Middle Aged, Molecular Structure, Peptides, Protein Conformation, Protein Processing, Post-Translational, Proteins, Tandem Mass Spectrometry, Young Adult
Show Abstract · Added April 3, 2018
BACKGROUND - The human body contains numerous long-lived proteins which deteriorate with age, typically by racemisation, deamidation, crosslinking and truncation. Previously we elucidated one reaction responsible for age-related crosslinking, the spontaneous formation of dehydroalanine (DHA) intermediates from phosphoserine and cysteine. This resulted in non-disulphide covalent crosslinks. The current paper outlines a novel posttranslational modification (PTM) in human proteins, which involves the addition of dehydroalanylglycine (DHAGly) to Lys residues.
METHODS - Human lens digests were examined by mass spectrometry for the presence of (DHA)Gly (+144.0535 Da) adducts to Lys residues. Peptide model studies were undertaken to elucidate the mechanism of formation.
RESULTS - In the lens, this PTM was detected at 18 lysine sites in 7 proteins. Using model peptides, a pathway for its formation was found to involve initial formation of the glutathione degradation product, γ-Glu(DHA)Gly from oxidised glutathione (GSSG). Once the Lys adduct formed, the Glu residue was lost in a hydrolytic mechanism apparently catalysed by the ε-amino group of the Lys.
CONCLUSIONS - This discovery suggests that within cells, the functional groups of amino acids in proteins may be susceptible to modification by reactive metabolites derived from GSSG.
GENERAL SIGNIFICANCE - Our finding demonstrates a novel +144.0535 Da PTM arising from the breakdown of oxidised glutathione.
Copyright © 2018. Published by Elsevier B.V.
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17 MeSH Terms
γ-Aminobutyric acid (GABA) concentration inversely correlates with basal perfusion in human occipital lobe.
Donahue MJ, Rane S, Hussey E, Mason E, Pradhan S, Waddell KW, Ally BA
(2014) J Cereb Blood Flow Metab 34: 532-41
MeSH Terms: Adult, Aspartic Acid, Blood Volume, Cerebrovascular Circulation, Dipeptides, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Neuropsychological Tests, Occipital Lobe, Spin Labels, Young Adult, gamma-Aminobutyric Acid
Show Abstract · Added August 21, 2014
Commonly used neuroimaging approaches in humans exploit hemodynamic or metabolic indicators of brain function. However, fundamental gaps remain in our ability to relate such hemo-metabolic reactivity to neurotransmission, with recent reports providing paradoxical information regarding the relationship among basal perfusion, functional imaging contrast, and neurotransmission in awake humans. Here, sequential magnetic resonance spectroscopy (MRS) measurements of the primary inhibitory neurotransmitter, γ-aminobutyric acid (GABA+macromolecules normalized by the complex N-acetyl aspartate-N-acetyl aspartyl glutamic acid: [GABA(+)]/[NAA-NAAG]), and magnetic resonance imaging (MRI) measurements of perfusion, fractional gray-matter volume, and arterial arrival time (AAT) are recorded in human visual cortex from a controlled cohort of young adult male volunteers with neurocognitive battery-confirmed comparable cognitive capacity (3 T; n=16; age=23±3 years). Regression analyses reveal an inverse correlation between [GABA(+)]/[NAA-NAAG] and perfusion (R=-0.46; P=0.037), yet no relationship between AAT and [GABA(+)]/[NAA-NAAG] (R=-0.12; P=0.33). Perfusion measurements that do not control for AAT variations reveal reduced correlations between [GABA(+)]/[NAA-NAAG] and perfusion (R=-0.13; P=0.32). These findings largely reconcile contradictory reports between perfusion and inhibitory tone, and underscore the physiologic origins of the growing literature relating functional imaging signals, hemodynamics, and neurotransmission.
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15 MeSH Terms
Synthesis and in vitro efficacy of MMP9-activated NanoDendrons.
Samuelson LE, Scherer RL, Matrisian LM, McIntyre JO, Bornhop DJ
(2013) Mol Pharm 10: 3164-74
MeSH Terms: Animals, Cell Line, Tumor, Dipeptides, Doxorubicin, Drug Delivery Systems, Humans, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Paclitaxel, Prodrugs, Rats
Show Abstract · Added March 7, 2014
Chemotherapeutics such as doxorubicin (DOX) and paclitaxel (PXL) have dose-limiting systemic toxicities, including cardiotoxicity and peripheral neuropathy. Delivery strategies to minimize these undesirable effects are needed and could improve efficacy, while reducing patient morbidity. Here, DOX and PXL were conjugated to a nanodendron (ND) through an MMP9-cleavable peptide linker, producing two new therapies, ND2(DOX) and ND2(PXL), designed to improve delivery specificity to the tumor microenvironment and reduce systemic toxicity. Comparative cytotoxicity assays were performed between intact ND-drug conjugates and the MMP9 released drug in cell lines with and without MMP9 expression. While ND2(DOX) was found to lose cytotoxicity due to the modification of DOX for conjugation to the ND; ND2(PXL) was determined to have the desired properties for a prodrug delivery system. ND2(PXL) was found to be cytotoxic in MMP9-expressing mouse mammary carcinoma (R221A-luc) (53%) and human breast carcinoma (MDA-MB-231) (66%) at a concentration of 50 nM (in PXL) after 48 h. Treating ND2(PXL) with MMP9 prior to the cytotoxicity assay resulted in a faster response; however, both cleaved and intact versions of the drug reached the same efficacy as the unmodified drug by 96 h in the R221A-luc and MDA-MB-231 cell lines. Further studies in modified Lewis lung carcinoma cells that either do (LLC(MMP9)) or do not (LLC(RSV)) express MMP9 demonstrate the selectivity of ND2(PXL) for MMP9. LLC(MMP9) cells were only 20% viable after 48 h of treatment, while LLC(RSV) were not affected. Inclusion of an MMP inhibitor, GM6001, when treating the LLC(MMP9) cells with ND2(PXL) eliminated the response of the MMP9 expressing cells (LLC(MMP9)). The data presented here suggests that these NDs, specifically ND2(PXL), are nontoxic until activated by MMP9, a protease common in the microenvironment of tumors, indicating that incorporation of chemotherapeutic or cytostatic agents onto the ND platform have potential for tumor-targeted efficacy with reduced in vivo systemic toxicities.
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11 MeSH Terms
Selective mode of action of guanidine-containing non-peptides at human NPFF receptors.
Findeisen M, Würker C, Rathmann D, Meier R, Meiler J, Olsson R, Beck-Sickinger AG
(2012) J Med Chem 55: 6124-36
MeSH Terms: Adamantane, Amino Acid Substitution, Animals, Arginine, Binding Sites, Biological Assay, COS Cells, Cercopithecus aethiops, Dipeptides, Drug Design, Guanidine, HEK293 Cells, Humans, Ligands, Microscopy, Fluorescence, Molecular Conformation, Peptidomimetics, Receptors, G-Protein-Coupled, Receptors, Neuropeptide, Structure-Activity Relationship
Show Abstract · Added January 24, 2015
The binding pocket of both NPFF receptors was investigated, focusing on subtype-selective behavior. By use of four nonpeptidic compounds and the peptide mimetics RF9 and BIBP3226, agonistic and antagonistic properties were characterized. A set of Ala receptor mutants was generated. The binding pocket was narrowed down to the upper part of transmembrane helices V, VI, VII and the extracellular loop 2. Positions 5.27 and 6.59 have been shown to have a strong impact on receptor activation and were suggested to form an acidic, negatively charged binding pocket in both NPFF receptor subtypes. Additionally, position 7.35 was identified to play an important role in functional selectivity. According to docking experiments, the aryl group of AC-216 interacts with position 7.35 in the NPFF(1) but not in the NPFF(2) receptor. These results provide distinct insights into the receptor specific binding pockets, which is necessary for the development of drugs to address the NPFF system.
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20 MeSH Terms
Peptide tyrosine tyrosine levels are increased in patients with urea cycle disorders.
Mitchell S, Welch-Burke T, Dumitrescu L, Lomenick JP, Murdock DG, Crawford DC, Summar M
(2012) Mol Genet Metab 106: 39-42
MeSH Terms: Adult, Anorexia, Appetite, Body Mass Index, Child, Dipeptides, Humans, Infant, Newborn, Retrospective Studies, Urea Cycle Disorders, Inborn
Show Abstract · Added December 10, 2013
Nutritional management is essential for patients with inborn errors of metabolism, such as urea cycle disorders (UCDs). Lack of appetite is common in these patients and can lead to underconsumption of calories, catabolism, and subsequently loss of metabolic control. The etiology of anorexia in these patients is largely unexplored. The neuroendocrine hormone peptide tyrosine tyrosine (PYY), secreted postprandially from endocrine cells of the ileum and colon, induces feelings of satiety and decreases food intake. While plasma PYY levels have been characterized in a number of populations, they have not been examined in UCD patients. In a retrospective study, plasma PYY concentrations were measured in UCD (n=42) patients and controls (n=28) via an ELISA to determine if levels of this anorexigenic hormone are altered in this patient population. Median PYY levels were significantly higher in UCD patients compared to controls (p=3.5×10(-5)). Body mass index was significantly associated with increased PYY levels in controls (p=0.02), while UCD diagnosis subtype was associated with PYY levels (p=1×10(-3)) in cases. Median PYY levels were significantly lower in ornithine carbamoyltransferase deficient patients compared with all other UCD subtypes (p=9×10(-3)), but significantly higher compared to controls (p=1.6×10(-3)). Overall, this study demonstrates that UCD cases have increased PYY levels compared to controls, suggesting that regulation of PYY may be altered in these patients. These observations may lead to a better understanding of the development of anorexia in UCD patients.
Copyright © 2012 Elsevier Inc. All rights reserved.
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10 MeSH Terms
Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates δ-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer.
Lu JP, Zhang J, Kim K, Case TC, Matusik RJ, Chen YH, Wolfe M, Nopparat J, Lu Q
(2010) Mol Cancer 9: 304
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Catenins, Cell Line, Tumor, Dipeptides, E2F1 Transcription Factor, Electrophoretic Mobility Shift Assay, Flow Cytometry, Homeodomain Proteins, Humans, Immunohistochemistry, Immunoprecipitation, In Vitro Techniques, Male, Mice, Microscopy, Fluorescence, Prostatic Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor HES-1
Show Abstract · Added November 28, 2012
BACKGROUND - Neuronal synaptic junction protein δ-catenin (CTNND2) is often overexpressed in prostatic adenocarcinomas but the mechanisms of its activation are unknown. To address this question, we studied the hypothesis that Hes1, human homolog of Drosophila Hairy and enhancer of split (Hes) 1, is a transcriptional repressor of δ-catenin expression and plays an important role in molecular carcinogenesis.
RESULTS - We identified that, using a δ-catenin promoter reporter assay, Hes1, but not its inactive mutant, significantly repressed the upregulation of δ-catenin-luciferase activities induced by E2F1. Hes1 binds directly to the E-boxes on δ-catenin promoter and can reduce the expression of δ-catenin in prostate cancer cells. In prostate cancer CWR22-Rv1 and PC3 cell lines, which showed distinct δ-catenin overexpression, E2F1 and Hes1 expression pattern was altered. The suppression of Hes1 expression, either by γ-secretase inhibitors or by siRNA against Hes1, increased δ-catenin expression. γ-Secretase inhibition delayed S/G2-phase transition during cell cycle progression and induced cell shape changes to extend cellular processes in prostate cancer cells. In neuroendocrine prostate cancer mouse model derived allograft NE-10 tumors, δ-catenin showed an increased expression while Hes1 expression was diminished. Furthermore, E2F1 transcription was very high in subgroup of NE-10 tumors in which Hes1 still displayed residual expression, while its expression was only moderately increased in NE-10 tumors where Hes1 expression was completely suppressed.
CONCLUSION - These studies support coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression.
1 Communities
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20 MeSH Terms
Distinct subdomains of the KCNQ1 S6 segment determine channel modulation by different KCNE subunits.
Vanoye CG, Welch RC, Daniels MA, Manderfield LJ, Tapper AR, Sanders CR, George AL
(2009) J Gen Physiol 134: 207-17
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, CHO Cells, Cricetinae, Cricetulus, Dipeptides, KCNQ1 Potassium Channel, Molecular Sequence Data, Protein Structure, Tertiary
Show Abstract · Added November 21, 2018
Modulation of voltage-gated potassium (KV) channels by the KCNE family of single transmembrane proteins has physiological and pathophysiological importance. All five KCNE proteins (KCNE1-KCNE5) have been demonstrated to modulate heterologously expressed KCNQ1 (KV7.1) with diverse effects, making this channel a valuable experimental platform for elucidating structure-function relationships and mechanistic differences among members of this intriguing group of accessory subunits. Here, we specifically investigated the determinants of KCNQ1 inhibition by KCNE4, the least well-studied KCNE protein. In CHO-K1 cells, KCNQ1, but not KCNQ4, is strongly inhibited by coexpression with KCNE4. By studying KCNQ1-KCNQ4 chimeras, we identified two adjacent residues (K326 and T327) within the extracellular end of the KCNQ1 S6 segment that determine inhibition of KCNQ1 by KCNE4. This dipeptide motif is distinct from neighboring S6 sequences that enable modulation by KCNE1 and KCNE3. Conversely, S6 mutations (S338C and F340C) that alter KCNE1 and KCNE3 effects on KCNQ1 do not abrogate KCNE4 inhibition. Further, KCNQ1-KCNQ4 chimeras that exhibited resistance to the inhibitory effects of KCNE4 still interact biochemically with this protein, implying that accessory subunit binding alone is not sufficient for channel modulation. These observations indicate that the diverse functional effects observed for KCNE proteins depend, in part, on structures intrinsic to the pore-forming subunit, and that distinct S6 subdomains determine KCNQ1 responses to KCNE1, KCNE3, and KCNE4.
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Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer.
Meyer zu Schwabedissen HE, Tirona RG, Yip CS, Ho RH, Kim RB
(2008) Cancer Res 68: 9338-47
MeSH Terms: Breast, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Chromatin Immunoprecipitation, Dipeptides, Estrogens, Estrone, Female, Humans, Neoplasm Staging, Organic Anion Transporters, Pregnane X Receptor, Promoter Regions, Genetic, Pyridines, RNA, Messenger, Receptors, Cytoplasmic and Nuclear, Receptors, Estrogen, Receptors, Steroid, Rifampin, Transcription Factors
Show Abstract · Added March 5, 2014
The ligand-activated nuclear receptor pregnane X receptor (PXR) is known to play a role in the regulated expression of drug metabolizing enzymes and transporters. Recent studies suggest a potential clinically relevant role of PXR in breast cancer. However, the relevant pathway or target genes of PXR in breast cancer biology and progression have not yet been fully clarified. In this study, we show that mRNA expression of organic anion transporter polypeptide 1A2 (OATP1A2), a transporter capable of mediating the cellular uptake of estrogen metabolites, is nearly 10-fold greater in breast cancer compared with adjacent healthy breast tissues. Immunohistochemistry revealed exclusive expression of OATP1A2 in breast cancer tissue. Interestingly, treatment of breast cancer cells in vitro with the PXR agonist rifampin induced OATP1A2 expression in a time-dependent and concentration-dependent manner. Consistent with its role as a hormone uptake transporter, induction of OATP1A2 was associated with increased uptake of estrone 3-sulfate. The rifampin response was abrogated after small interfering RNA targeting of PXR. We then identified a PXR response element in the human OATP1A2 promoter, located approximately 5.7 kb upstream of the transcription initiation site. The specificity of PXR-OATP1A2 promoter interaction was confirmed using chromatin immunoprecipitation. Importantly, we used a novel potent and specific antagonist of PXR (A-792611) to show the reversal of the rifampin effect on the cellular uptake of E(1)S. These data provide important new insights into the interplay between a xenobiotic nuclear receptor PXR and OATP1A2 that could contribute to the pathogenesis of breast cancer and may also prove to be heretofore unrecognized targets for breast cancer treatment.
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21 MeSH Terms
Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1.
McLaughlin JN, Shen L, Holinstat M, Brooks JD, Dibenedetto E, Hamm HE
(2005) J Biol Chem 280: 25048-59
MeSH Terms: Actins, Adenosine Diphosphate, Amides, Calcium, Cells, Cultured, Chelating Agents, Dipeptides, Dose-Response Relationship, Drug, Egtazic Acid, Electric Impedance, Endothelium, Vascular, Enzyme Inhibitors, GTP-Binding Protein alpha Subunits, G12-G13, GTP-Binding Protein alpha Subunits, Gq-G11, GTP-Binding Proteins, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Ligands, Matrix Metalloproteinase Inhibitors, Microcirculation, Models, Biological, Models, Theoretical, Peptides, Pertussis Toxin, Protease Inhibitors, Protein Binding, Protein-Serine-Threonine Kinases, Pyridines, Receptor, PAR-1, Signal Transduction, Thrombin, Time Factors, rho-Associated Kinases
Show Abstract · Added December 10, 2013
Thrombin activates protease-activated receptor-1 (PAR-1) by cleavage of the amino terminus to unmask a tethered ligand. Although peptide analogs can activate PAR-1, we show that the functional responses mediated via PAR-1 differ between the agonists. Thrombin caused endothelial monolayer permeability and mobilized intracellular calcium with EC(50) values of 0.1 and 1.7 nm, respectively. The opposite order of activation was observed for agonist peptide (SFLLRN-CONH(2) or TFLLRNKPDK) activation. The addition of inactivated thrombin did not affect agonist peptide signaling, suggesting that the differences in activation mechanisms are intramolecular in origin. Although activation of PAR-1 or PAR-2 by agonist peptides induced calcium mobilization, only PAR-1 activation affected barrier function. Induced barrier permeability is likely to be Galpha(12/13)-mediated as chelation of Galpha(q)-mediated intracellular calcium with BAPTA-AM, pertussis toxin inhibition of Galpha(i/o), or GM6001 inhibition of matrix metalloproteinase had no effect, whereas Y-27632 inhibition of the Galpha(12/13)-mediated Rho kinase abrogated the response. Similarly, calcium mobilization is Galpha(q)-mediated and independent of Galpha(i/o) and Galpha(12/13) because pertussis toxin Y-27632 and had no effect, whereas U-73122 inhibition of phospholipase C-beta blocked the response. It is therefore likely that changes in permeability reflect Galpha(12/13) activation, and changes in calcium reflect Galpha(q) activation, implying that the pharmacological differences between agonists are likely caused by the ability of the receptor to activate Galpha(12/13) or Galpha(q). This functional selectivity was characterized quantitatively by a mathematical model describing each step leading to Rho activation and/or calcium mobilization. This model provides an estimate that peptide activation alters receptor/G protein binding to favor Galpha(q) activation over Galpha(12/13) by approximately 800-fold.
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34 MeSH Terms
A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin.
Zhou YP, Sreenan S, Pan CY, Currie KP, Bindokas VP, Horikawa Y, Lee JP, Ostrega D, Ahmed N, Baldwin AC, Cox NJ, Fox AP, Miller RJ, Bell GI, Polonsky KS
(2003) Metabolism 52: 528-34
MeSH Terms: Animals, Calcium, Calpain, Cell Separation, Cysteine Proteinase Inhibitors, Dipeptides, Energy Metabolism, Glucose, In Vitro Techniques, Insulin, Islets of Langerhans, Leucine, Mice, Mice, Inbred C57BL, Mitochondria, NADP, Oxidation-Reduction
Show Abstract · Added March 30, 2013
Genetic variation in the gene for a cytosolic cysteine protease, calpain-10, increases the susceptibility to type 2 diabetes apparently by altering levels of gene expression. In view of the importance of altered beta-cell function in the pathophysiology of type 2 diabetes, the present study was undertaken to define the effects on insulin secretion of exposing pancreatic islets to calpain inhibitors for 48 hours. Exposure of mouse islets to calpain inhibitors (ALLN, ALLM, E-64-d, MDL 18270, and PD147631) of different structure and mechanism of action for 48 hours reversibly suppresses glucose-induced insulin secretion by 40% to 80%. Exposure of islets to inhibitors of other proteases, ie, cathepsin B and proteasome, did not affect insulin secretion. The 48-hour incubation with calpain inhibitors also attenuates insulin secretory responses to the mitochondrial fuel alpha-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca(2+)](i)) responses to glucose or KIC in islets. In summary, long-term inhibition of islet calpain activity attenuates insulin secretion possibly by limiting the rate of glucose metabolism. A reduction of calpain activity in islet could contribute to the development of beta-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.
Copyright 2003 Elsevier Inc. All rights reserved.
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17 MeSH Terms