Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Here, we present the results of continuum electrostatic calculations on a dataset of 222 non-equivalent salt bridges derived from 36 non-homologous high-resolution monomeric protein crystal structures. Most of the salt bridges in our dataset are stabilizing, regardless of whether they are buried or exposed, isolated or networked, hydrogen bonded or non-hydrogen bonded. One-third of the salt bridges in our dataset are buried in the protein core, with the remainder exposed to the solvent. The difference in the dielectric properties of water versus the hydrophobic protein interior cost buried salt bridges large desolvation penalties. However, the electrostatic interactions both between the salt-bridging side-chains, and between the salt bridges and charges in their protein surroundings, are also stronger in the interior, due to the absence of solvent screening. Even large desolvation penalties for burying salt bridges are frequently more than compensated for, primarily by the electrostatic interactions between the salt-bridging side-chains. In networked salt bridges both types of electrostatic interactions, those between the salt-bridging side-chains, and those between the salt bridge and its protein environment, are of similar magnitudes. In particular, a major finding of this work is that salt bridge geometry is a critical factor in determining salt bridge stability. Salt bridges with favorable geometrical positioning of the interacting side-chain charged groups are likely to be stabilizing anywhere in the protein structure. We further find that most of the salt bridges are formed between residues that are relatively near each other in the sequence.
J Mol Biol 1999 Nov 12
PMID:Salt bridge stability in monomeric proteins. 1054 98

Alkyl dihydroxyacetone-phosphate synthase is the second enzyme of the ether-lipid biosynthetic pathway which is responsible for the introduction of the ether linkage between a fatty alcohol and a glycerol present in a subclass of phospholipids, the plasmalogens and possibly in glycolipid membrane anchors. In this study the gene coding for alkyl dihydroxyacetone-phosphate synthase was isolated from Trypanosoma brucei. Southern blot analysis of total genomic DNA suggested the presence of a single copy gene. The analysis, together with sequencing of different cDNA clones showed that the two alleles of the gene differ in only one nucleotide. The gene encodes a protein of 612 amino acids with a calculated molecular mass of 68,891, not counting the initiator methionine. It carries a type-1 peroxisomal targeting signal (a C-terminal tripeptide--AHL) and a calculated overall positive charge of +10. The gene was expressed in a bacterial system and the corresponding protein carrying a His-tag was purified. The recombinant alkyl dihydroxyacetone-phosphate synthase and the enzyme isolated directly from the glycosomes of bloodstream-form trypanosomes have comparable kinetics. The Km for hexadecanol was 42 microM, while approximately 100 microM of palmitoyl dihydroxyacetone phosphate (DHAP) was necessary for optimal activity. Sodium chloride inhibited both the His-tagged protein and the enzyme isolated from the glycosomes of bloodstream-form and insect stage T. brucei.
Mol Biochem Parasitol 1999 Oct 25
PMID:Molecular characterisation of Trypanosoma brucei alkyl dihydroxyacetone-phosphate synthase. 1058 81

The native functional ecdysone receptor complex, a heterodimer of the ecdysone receptor (EcR) and ultraspiracle (USP) proteins, was identified in the fat body of adult female mosquitoes, Aedes aegypti, through electrophoretic mobility shift assays (EMSA) using previously characterized Drosophila ecdysone response elements (EcREs). The use of different salt concentrations during preparation of nuclear extracts enabled us to characterize two distinct subpopulations of the receptor complex, one of which was high salt-sensitive and responsive to exogenous 20-hydroxyecdysone (20E), and the other of which was high salt-resistant and refractory to exogenous 20E. Salt-sensitivity correlated with ligand responsiveness. Developmental EMSA analyses demonstrated that previtellogenic fat body nuclei and nuclei from the termination phase of vitellogenesis with low 20E titer contained solely high-salt-sensitive, ligand responsive complexes, which could be recovered in nuclear extracts (NEs) only by low salt tissue homogenization, suggesting these complexes were unliganded. In contrast, the fat body nuclei from stages of active vitellogenesis with high 20E titer contained almost exclusively high salt-resistant, ligand refractory complexes, implying these complexes were liganded; the nuclei from the intermediate stages, early and late phases of vitellogenesis, contained a mixture of the two subpopulations. The developmental profile of fully activated, ligand refractory receptor complexes closely correlated with that of yolk protein expression, suggesting an intimate involvement of the ecdysone receptor complex in both the induction and maintenance of high level expression of yolk protein genes.
Mol Cell Endocrinol 1999 Oct 25
PMID:Two distinct subpopulations of ecdysone receptor complex in the female mosquito during vitellogenesis. 1061 29

HNS-32 (N1,N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazulene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS-32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anesthetized rats in vivo and compared with those of mexiletine. Saline or drugs were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of total number of premature ventricular complexes (PVC) from 2091+/-225 to 656+/-116 and 286+/-69 beats/30 min (p < 0.05), the ventricular tachycardia (VT) duration from 183+/-33 to 28+/-9 and 4+/-2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936+/-159 beats/30 min (p < 0.05), 39+/-22 sec (p < 0.05), 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect them. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126+/-34 to 37+/-12 and 3+/-2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 16+/-9 sec (p < 0.05), 80 (n.s.), 50 (p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced the heart rate in a dose-dependent manner, from 399+/-14 to 350+/-8 and 299+/-10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antiarrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.
Mol Cell Biochem 2000 Feb
PMID:Effects of HNS-32, a novel antiarrhythmic drug, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats. 1082 31

The alpha-amylases in the salivary glands of Lygus hesperus Knight and L. lineolaris (Palisot de Beauvois) were isolated and purified by ion exchange chromatography, and by isoelectric focusing, respectively. The alpha-amylase from L. hesperus had an isoelectric point (pI) of 6.25, and a pH optimum of 6.5. The specific activity of alpha-amylases in the salivary glands of L. hesperus was 1.2 U/mg/ml. The alpha-amylase from L. lineolaris had a pI of 6.54, and a pH optimum of 6.5. The specific activity of alpha-amylase from L. lineolaris was 1.7 U/mg/ml. The activity of alpha-amylase in both species was significantly inhibited by alpha-amylase inhibitor from wheat and also by EDTA and SDS. Sodium chloride enhanced alpha-amylase activity for both species. The enzyme characteristics and relative activities are discussed in the context of differences phytophagous versus zoophagous habits in these two congeneric species.
Comp Biochem Physiol B Biochem Mol Biol 2000 May
PMID:Partial characterization of alpha-amylase in the salivary glands of Lygus hesperus and L. lineolaris. 1082 60

The molecular mechanism(s) by which chemically complex air pollution particles mediate their adverse health effects is not known. We have examined the ability of combustion and ambient air particles to induce pulmonary matrilysin expression due to the well-documented role of matrix metalloproteinases in tissue injury and repair responses. Rats were exposed to saline, residual oil fly ash (2.5 mg/rat), or ambient air particles (2.5 mg/rat) via intratracheal instillation and examined 3-72 h after exposure. Saline-exposed animals had low levels of matrilysin mRNA, whereas the animals exposed to either complex particle showed an early induction of pulmonary matrilysin gene expression as well as of the 19-kDa activated form of matrilysin. Immunocytochemistry and in situ hybridization analyses identified the alveolar macrophages and monocytes as primary sources of air pollution particle-induced matrilysin expression. Matrilysin gene induction and protein activation by combustion and ambient air particles correlated with the early histopathological changes produced by these particles. These results demonstrate the ability of combustion and ambient air particles to induce pulmonary matrilysin expression and suggest a role for this matrix metalloproteinase in the initiation of lung injury produced by these particles.
Am J Physiol Lung Cell Mol Physiol 2000 Jul
PMID:Induction of pulmonary matrilysin expression by combustion and ambient air particles. 1089 14

Water flux rates and osmotic responses of Kemp's Ridley sea turtles (Lepidochelys kempi) acutely exposed to fresh water were quantified. Salt-water adapted turtles were exposed to fresh water for 4 d before being returned to salt water. During the initial salt water phase, absolute and relative water flux rates were 1.2+/-0.1 l d(-1) and 123.0+/-6.8 ml kg(-1) d(-1), respectively. When turtles were exposed to fresh water, rates increased by approximately 30%. Upon return to salt water, rates decreased to original levels. Plasma osmolality, Na(+), K(+), and Cl(-) decreased during exposure to fresh water, and subsequently increased during the return to salt water. The Na(+):K(+) ratio was elevated during the fresh water phase and subsequently decreased upon return to salt water. Aldosterone and corticosterone were not altered during exposure to fresh water. Elevated water flux rates during fresh water exposure reflected an increase in water consumption, resulting in a decrease in ionic and osmotic concentrations. The lack of a change in adrenocorticoids to acute fresh water exposure suggests that adrenal responsiveness to an hypo-osmotic environment may be delayed in marine turtles when compared to marine mammals.
Comp Biochem Physiol A Mol Integr Physiol 2000 Sep
PMID:Effects of acute fresh water exposure on water flux rates and osmotic responses in Kemp's ridley sea turtles (Lepidochelys kempi). 1099 20

No reliable pathologic criteria have been identified that predict clinical behavior in adrenal and extra-adrenal pheochromocytomas (PHEOs). Reliable prognostic markers for the prediction of clinical outcome are needed to assign optimal treatment for potentially malignant tumors. In this report, we evaluated several molecular markers (topoisomerase II alpha, E-cadherin, HER-2/neu, and retinoblastoma (RB) gene protein) that have not been previously studied in PHEOs. Paraffin-embedded, formalin-fixed tissue blocks from 50 cases of PHEO (30 benign and 20 malignant, 31 adrenal and 19 extra-adrenal) were obtained from University of Utah Health Sciences Center, Salt Lake City, and the Medical College of Wisconsin, Milwaukee. Gross (tumor size, weight, local extension, cyst formation, hemorrhage, necrosis), microscopic (pleomorphism, hyaline globules, intranuclear inclusion, mitotic count, capsular and vascular invasion, ganglionic/neuronal differentiation), and immunohistochemical features (topoisomerase II alpha, p53, MIB-1, E-cadherin, RB, and HER-2/neu) were studied. With the exception of vascular invasion (P = 0.025), there were no unequivocal gross or microscopic characteristics that distinguished benign from malignant lesions (P approximately = 0.11-0.71). Topoisomerase III and MIB-1 indices in malignant lesions were significantly higher than those observed in benign lesions (P = 0.012 and 0.019). Differences in p53 expression were not statistically significant (P = 0.082). Loss in RB protein product expression was significantly more common in malignant lesions (P = 0.001), E-cadherin loss and HER-2/-neu overexpression were not observed in any of the benign or malignant lesions. We studied the immunohistochemical expression of topoisomerase II alpha, MIB-1, p53, RB gene protein product, E-cadherin, and HER-2/neu in a series of adrenal and extra-adrenal PHEOs. Overexpression of topoisomerase II alpha and MIB-1 and loss of RB protein product were more common in malignant lesions, whereas p53, E-cadherin, and HER-2/neu do not seem to have diagnostic utility in the prediction of biologic behavior in these neoplasms.
Appl Immunohistochem Mol Morphol 2000 Dec
PMID:Prognostic value of immunohistochemical expression of topoisomerase alpha II, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu in adrenal and extra-adrenal pheochromocytomas. 1112 18

The disequilibrium pH is defined as any discrepancy between the measured pH and the pH which would exist if CO2-HCO3-H+ reactions were at equilibrium. Measurement of the disequilibrium pH can be used to assess the status of CO2-HCO3--H+ reactions and, in combination with carbonic anhydrase (CA) or CA inhibitor treatments, may also be used to localize CA. Renal physiologists have used disequilibrium experiments to determine that HCO3- reabsorption in the kidney tubule occurs via proton secretion, and that CA activity is available to ultrafiltrate CO2-HCO3-H+ reactions in the proximal convoluted tubule, but not the distal tubule. Disequilibrium experiments were also used in investigating the availability of CA to CO2-HCO3--H+ reactions in water at the fish gill; the opposing results obtained in two studies have not yet been resolved. Respiratory physiologists have used the disequilibrium technique in vivo and with saline-perfused preparations to assess the availability of CA to plasma CO2-HCO3--H+ reactions following gas exchange. Saline-perfused preparations enable direct localization of CA activity, while in vivo measurements encompass the numerous factors affecting CO2-HCO3--H+ equilibration in a multi-phase solution. Given the many organs in which membrane-bound CA activity has now been identified, the usefulness of the disequilibrium pH technique has increased beyond its original applications in renal and pulmonary physiology.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:The disequilibrium pH: a tool for the localization of carbonic anhydrase. 1125 90

This study was conducted to investigate the hepatic extraction of plasma free amino acids in anesthetized Single Comb White Leghorn (SCWL) males (Gallus domesticus). SCWL males were anesthetized and implanted with cannulae in the carotid artery, hepatic vein, hepatic portal vein and the left hepatic duct. Free amino acids in plasma and bile were determined before, during and after 30-min infusions of Saline (control), DL-Methionine (DL-Met) or DL-2-hydroxy-4-methylthio-butanoic acid (DL-HMB) into the hepatic portal vein. Hepatic extraction rates (HER) of amino acids were calculated based on the concentration of amino acids in plasma multiplied by estimations of blood flow in the hepatic portal vein, hepatic artery and hepatic vein. For the non-essential amino acids, alanine had the highest HER (46%). The liver also removed more than 20% of hepatic inflow of tyrosine and asparagine with substantial extraction (14-18%) of serine, glycine and glutamine, also. In contrast, less than 5% of hepatic inflow of glutamate and cystine were removed by liver. For the essential amino acids, HER for methionine, histidine and phenylalanine were 30, 14 and 17%, respectively, with less than 5% for branched-chain amino acids, lysine, arginine and threonine. Biliary secretion of amino acids represented a small percentage (<0.2%) of total hepatic extraction turnover of the amino acids. Infusion of methionine sources, DL-Met and DL-HMB, had no effect on hepatic metabolism of amino acids other than methionine. The results demonstrated for the first time, the hepatic extraction of circulating free amino acids in avian species in vivo.
Comp Biochem Physiol B Biochem Mol Biol 2001 Sep
PMID:The hepatic extraction of plasma free amino acids and response to hepatic portal venous infusion of methionine sources in anesthetized SCWL males (Gallus domesticus). 1154 94


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