Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In bicarbonate/CO2 buffer, Mn(II) and Fe(II) catalyze the oxidation of amino acids by H2O2 and the dismutation of H2O2. As the Mn(II)/Fe(II) ratio is increased, the yield of carbonyl compounds per mole of leucine oxidized is essentially constant, but the ratio of alpha-ketoisocaproate to isovaleraldehyde formed increases, and the fraction of H2O2 converted to O2 increases. In the absence of Fe(II), the rate of Mn(II)-catalyzed leucine oxidation is directly proportional to the H2O2, Mn(II), and amino acid concentrations and is proportional to the square of the HCO3- concentration. The rate of Mn(II)-catalyzed O2 production in the presence of 50 mM alanine or leucine is about 4-fold the rate observed in the absence of amino acids and accounts for about half of the H2O2 consumed; the other half of the H2O2 is consumed in the oxidation of the amino acids. In contrast, O2 production is increased nearly 18-fold by the presence of alpha-methylalanine and accounts for about 90% of the H2O2 consumed. The data are consistent with the view that H2O2 decomposition is an inner sphere (cage-like) process catalyzed by a Mn coordination complex of the composition Mn(II), amino acid, (HCO3-)2. Oxidation of the amino acid in this complex most likely proceeds by a free radical mechanism involving hydrogen abstraction from the alpha-carbon as a critical step. The results demonstrate that at physiological concentrations of HCO3- and CO2, Mn(II) is able to facilitate Fenton-type reactions.
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PMID:Manganese(II) catalyzes the bicarbonate-dependent oxidation of amino acids by hydrogen peroxide and the amino acid-facilitated dismutation of hydrogen peroxide. 229 94

It has been suggested that the monokine tumor necrosis factor (TNF) (cachectin) is responsible for metabolic abnormalities frequently accompanying malignant neoplasms. The acute metabolic effects of TNF in patients with cancer were studied. Subcutaneous administration of recombinant human TNF led to a rise in the C-reactive protein level (4.4 +/- 1.2 mg/dL vs 11.6 +/- 1.8 mg/dL) and a reduction in the serum zinc level (12.9 +/- 0.8 mumol/L vs 7.3 +/- 0.8 mumol/L [79 +/- 5 mg/dL vs 48 +/- 5 mg/dL]) (values are the mean +/- SEM). Forearm efflux of total amino acids more than doubled after intravenous TNF injection, principally because of increases in release of the gluconeogenic amino acids alanine and glutamine. Concomitantly, the arterial levels of alanine, glutamine, and total amino acids fell, indicating that TNF also stimulated the uptake of amino acids by other tissues. The observed amino acid pattern cannot be explained solely on the basis of measured changes in cortisol, glucagon, or insulin levels. These findings are discussed in relation to known alterations of amino acid metabolism in cancer-associated cachexia.
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PMID:The acute metabolic effects of tumor necrosis factor administration in humans. 368 16

Effect alterations of methamphetamine by pretreatment of amino acids or their salts on ambulatory activity in mice were investigated to confirm a fact that certain amino acids, particularly monosodium L-glutamate, are added to methamphetamine by the street users, and that the amino acids augment the effect of methamphetamine. The ambulatory activity of mouse was measured by a tilting-type round activity cage of 25 cm in diameter. The amino acids or their salts tested were monosodium L-glutamate, monosodium L-aspartate, gamma-amino-butyric acid, L-alanine, L-lysine hydrochloride and L-arginine hydrochloride. A single administration of each chemical at doses of 1 and 2 g/kg i.p. did not induce a marked change in the ambulatory activity in mice. Methamphetamine 2 mg/kg s.c. induced an increase in the ambulatory activity with a peak at 40 min after the administration, and the increased ambulatory activity persisted for 3 hr. The ambulation-increasing effect of methamphetamine was augmented by the pretreatment of monosodium L-glutamate and monosodium L-aspartate at 30 min before the methamphetamine administration, while attenuated by the pretreatment of L-lysine hydrochloride and L-arginine hydrochloride in a dose-dependent manner. Gamma-aminobutyric acid and L-alanine did not affect the effect of methamphetamine. Similar augmentation and attenuation in the ambulation-increasing effect of methamphetamine were induced by the pretreatment of sodium bicarbonate 0.9 g/kg i.p. (urinary alkalizer) and ammonium chloride 0.07 g/kg i.p. (urinary acidifier), respectively. The urinary pH level was elevated by the administration of monosodium L-glutamate, monosodium L-aspartate and sodium bicarbonate, and decreased by L-lysine hydrochloride, L-arginine hydrochloride and ammonium chloride. Gamma-aminobutyric acid and L-alanine did not elicit a marked change in the urinary pH level. The present experiment confirms the fact in human that monosodium L-glutamate augments the effect of methamphetamine. Moreover, the present results suggest that monosodium salts of acidic amino acids augment, and conversely monohydrochloric salts of basic amino acids attenuate the effect of methamphetamine. The alterations of the ambulation-increasing effect of methamphetamine may be due to the urinary excretion rates of the drug through changes in the urinary pH level after the administration of amino acids or their salts.
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PMID:Effect alteration of methamphetamine by amino acids or their salts on ambulatory activity in mice. 687 1

Recoverin is a member of the EF-hand family of calcium-binding proteins involved in the transduction of light by vertebrate photoreceptors. Recoverin also was identified as an autoantigen in the degenerative disease of the retina known as cancer-associated retinopathy (CAR), a paraneoplastic syndrome whereby immunological events lead to the degeneration of photoreceptors in some individuals with cancer. In this study, we demonstrate that recoverin is expressed in the lung tumor of a CAR patient but not in similar tumors obtained from individuals without the associated retinopathy. Recoverin was identified intially by Western blot analysis of the CAR patient's biopsy tissue by using anti-recoverin antibodies generated against different regions of the recoverin molecule. In addition, cultured cells from the biopsy tissue expressed recoverin, as demonstrated by reverse transcription-PCR using RNA extracted from the cells. The immunodominant region of recoverin also was determined in this study by a solid-phase immunoassay employing overlapping heptapeptides encompassing the entire recoverin sequence. Two linear stretches of amino acids (residues 64-70, Lys-Ala-Tyr-Ala-Gln-His-Val; and 48-52, Gln-Phe-Gln-Ser-Ile) made up the major determinants. One of the same regions of the recoverin molecule (residues 64-70) also was uniquely immunopathogenic, causing photoreceptor degeneration upon immunization of Lewis rats with the corresponding peptide. These data demonstrate that the neural antigen recoverin more than likely is responsible for the immunological events associated with vision loss in some patients with cancer. These data also establish CAR as one of the few autoimmune-mediated diseases for which the specific self-antigen is known.
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PMID:Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. 756 96

Hybrid assemblies were prepared in combinations of a synthetic lipid, involving an L-alanine residue interposed between an anionic head group and a hydrophobic double-chain segment, with cage-type cyclophanes having a three-dimensionally extended hydrophobic cavity. Incorporation behavior of the cage-type hosts into the multi- and single-walled vesicules was characterized by highly sensitive differential scanning calorimetry and dynamic light-scattering measurements as well as by gel-filtration chromatography and electronic absorption spectroscopy. Both hosts were found to be completely incorporated into a relatively polar domain close to the vesicular surface. Anionic guest molecules, such as naphthol yellow S, dimethylsulfonazo III, bromopyrogallol red, and orange G, were effectively incorporated into the hydrophobic cavities provided by the cage-type cyclophanes embedded in the single-walled bilayer membrane, as confirmed by circular dichroism spectroscopy; the formation constants for 1:1 host-guest complexes were in the order of 10(4)-10(5) mol.dm-3. This means that the binding affinities of the cage-type hosts are largely retained even when the hosts are incorporated into the vesicle. Moreover, the pyridinium moieties bound to the chiral L-valine residues in the bridging components of the hosts underwent conformational changes upon inclusion of the guest, as confirmed by circular dichroism spectroscopy and molecular mechanics and dynamics calculations.
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PMID:Supramolecular effects and molecular discrimination by macrocyclic hosts embedded in synthetic bilayer membranes. 843 75

In contrast to L-glutamine, lipid emulsions are routinely administered to patients receiving nutritional support. The provision of fat during intravenous feeding is essential, but the potentially toxic byproducts of fatty acid oxidation may have adverse metabolic consequences. In the present study, we have examined the effect of L-glutamine, an inhibitor of fatty acid oxidation, on the development of defective blood glucose regulation caused by a 48-hour infusion of 10% intralipid in rats. Male Sprague-Dawley rats (200-290 g) were anesthetized with sodium pentobarbital, the right femoral vein cannulated, and baseline blood samples were taken. Each rat was placed in a metabolic cage with access to water, in the presence or absence of rodent chow. Two hours after waking, the rats were infused with 10% intralipid with either saline (control), 2% L-glutamine, or 2% L-alanine. After 48 hours, all animals were sacrificed and blood samples were again obtained. The mean +/- SEM plasma glucose levels before and after lipid infusion at the rate of 1 mL/hr in control rats fed ad libitum, were 125 +/- 13 and 170 +/- 5 mg/dL (p < 0.01, n = 7). Similarly, plasma free fatty acids (FFA) in these animals rose from 0.74 +/- 0.11 to 1.34 +/- 0.32 mmol/L (p < 0.05). Plasma insulin levels also increased from 337 +/- 44 to 1278 +/- 88 pg/mL (p < 0.01). Reduction of intralipid dose infusion did not prevent insulin resistance characterized by hyperglycemia and hyperinsulinemia. However, addition of L-glutamine to the high-dose lipid infusion with chow feeding prevented changes in plasma glucose, insulin levels, and FFA but not triglyceride levels. Also, glutamine but not alanine supplementation in intralipid infused rats without chow feeding prevented changes in plasma glucose, insulin, and malondialdehyde levels. In conclusion, these data show that glutamine supplementation during intravenous lipid administration in rats prevents the development of impaired glucose regulation associated with hyperlipidemia.
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PMID:Effect of L-glutamine supplementation on impaired glucose regulation during intravenous lipid administration. 887 24

The pattern of side-chain conservation at the cytoplasmic side of the third transmembrane domain of rhodopsin family G protein-coupled receptors, Asp/Glu-Arg-Tyr/X-X-X-Ile/Val, defines a structural "arginine cage" domain. Previous computational and mutagenesis studies of the GnRH receptor indicated an important contribution of local interactions to the function of this domain. We have investigated the functional importance of the intrahelical position and orientation of the arginine cage using insertional mutagenesis. Introduction of a single Ala proximal to the conserved Asp-Arg of this domain caused loss of detectable ligand binding. Inserting a second Ala, however, restored high-affinity agonist binding. Further insertion of three or four Ala residues at this site generated receptors that bound agonist with an affinity 3- to 10-fold higher than that of the wild-type receptor. Loss of detectable coupling to inositol phosphate turnover in all these mutant receptors confirms that the structure required in this region for efficient signaling is highly constrained. In contrast, the recovery of agonist binding with the progressive insertion of two to four Ala residues indicates that specific orientations of this segment can stabilize high-affinity receptor conformations that are uncoupled from signal transduction.
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PMID:Insertional mutagenesis of the arginine cage domain of the gonadotropin-releasing hormone receptor. 1122 40

The pores of glutamate receptors and K(+) channels share sequence homology, suggesting a conserved secondary structure. Scanning mutagenesis with substitution of alanine and tryptophan in GluR6 channels was performed based on the structure of KcsA. Our assay used disruption of voltage-dependent polyamine block to test for changes in the packing of pore-forming regions. Alanine scanning from D567 to R603 revealed reduced rectification resulting from channel block in two regions. A periodic pattern from F575 to M589 aligned with the pore helix in KcsA, whereas a cluster of sensitive positions around Q590, a site regulated by RNA editing, mapped to the selectivity filter in KcsA. Tryptophan scanning from D567 to R603 revealed similar patterns, but with a complete disruption of spermine block for 7 out of the 37 positions and a pM dissociation constant for Q590W. Molecular modeling with KcsA coordinates showed that GluR6 pore helix mutants disrupting polyamine block pack against M1 and M2, and are not exposed in the ion channel pore. In the selectivity filter, tryptophan creates an aromatic cage consistent with the pM dissociation constant for Q590W. A scan with glutamate substitution was used to map the cytoplasmic entrance to the pore based on charge neutralization experiments, which established that E594 was uniquely required for high affinity polyamine block. In E594Q mutants, introduction of glutamate at positions S593-L600 restored polyamine block at positions corresponding to surface-exposed residues in KcsA. Our results reinforce proposals that the pore region of glutamate receptors contains a helix and pore loop analogous to that found in K(+) channels. At the cytoplasmic entrance of the channel, a negatively charged amino acid, located in an extended loop with solvent-exposed side chains, is required for high affinity polyamine block and probably attracts cations via a through space electrostatic mechanism.
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PMID:Structural similarities between glutamate receptor channels and K(+) channels examined by scanning mutagenesis. 1127 54

The function of p53 correlates with its 'wildtype' conformation, specifically recognized by antibodies PAb1620 and PAb246, and many cancer-associated mutations cause loss of this conformation. The epitopes of these antibodies were identified using hybrid p53 proteins created by a new method. Plasmids carrying homologous genes cut at appropriate sites recombined efficiently when transformed into RecE(+) E. coli. PAb1620 and PAb246 recognize mouse but not chicken p53; we created mouse-chicken hybrids of the p53 core domain and tested antibody reactivity. PAb246 binding mapped to residues 201-212, while PAb1620 required both residues 145-157 and 201-212 (human p53 numbering used throughout). An alanine-scan showed that the key residues for PAb246 and PAb1620 are completely distinct: PAb246 recognizes residues 202-204 (Tyr-Pro-Glu) while PAb1620 recognizes residues Arg156, Leu206, Arg209, and Gln/Asn210, the last two residues being essential. Both antibody epitopes are far from the p53 interface with DNA, but near the epitope of the 'mutant' conformation antibody PAb240. These epitope locations may help in dissecting the interactions of p53, including those with E6/E6-AP and in its DNA-bound state.
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PMID:The 'wildtype' conformation of p53: epitope mapping using hybrid proteins. 1140 27

Activation of the muscarinic acetylcholine receptors requires agonist binding followed by a conformational change, but the ligand binding and conformation-switching residues have not been completely identified. Systematic alanine-scanning mutagenesis has been used to assess residues 142-164 in transmembrane helix 4 and 402-421 in transmembrane helix 7 of the M(1) muscarinic acetylcholine receptor. Several inward-facing amino acid side chains in the exofacial parts of transmembrane helices 4 and 7 contribute to acetylcholine binding. Alanine substitution of the aromatic residues in this group reduced signaling efficacy, suggesting that they may form part of a charge-stabilized aromatic cage, which triggers rotation and movement of the transmembrane helices. The mutation of adjacent residues modulated receptor activation, either reducing signaling or causing constitutive activation. In the buried endofacial section of transmembrane helix 7, alanine substitution mutants of the conserved NSXXNPXXY motif displayed strongly reduced signaling efficacy, despite having increased or unchanged acetylcholine affinity. These residues may have dual functions, forming intramolecular contacts that stabilize the receptor in the inactive ground state, but that are broken, allowing them to form new intramolecular bonds in the activated state. This conformational rearrangement is critical to produce a G protein binding site and may represent a key mechanism of receptor activation.
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PMID:Transmembrane domains 4 and 7 of the M(1) muscarinic acetylcholine receptor are critical for ligand binding and the receptor activation switch. 1144 Oct 14


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