Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N(G)-Amino-l-arginine, N(5)-(1-iminoethyl)-l-ornithine, N(6)-(1-iminoethyl)-l-lysine, and aminoguanidine were studied for the mechanisms by which they produce suicidal inactivation of the neuronal nitric oxide synthase isoform (nNOS). All of the inactivators that were amino acid structural analogs targeted the heme residue at the nNOS active site and led to its destruction as evidenced by the time- and concentration-dependent loss of the nNOS heme fluorescence, which reflects the disruption of the protoporphyrin-conjugated structure. The loss of heme was exclusively associated with the dimeric population of the nNOS. This inactivator-mediated loss of the nNOS heme never reached more than 60%, suggesting that only half of the dimeric heme is involved in catalytic activation of mechanism-based inactivators studied. Aminoguanidine-induced nNOS inactivation produced covalent modification of the nNOS protein chain with a stoichiometry of 0.8 mol of aminoguanidine per mole of the nNOS monomer. Specific covalent modification by aminoguanidine was exclusively associated with the oxygenase domain of the nNOS. The mechanisms by which N(6)-(1-iminoethyl)-l-lysine and aminoguanidine inactivate the nNOS and iNOS do not differ between the isoforms. The selectivity of these inactivators toward the iNOS isoform is a reflection of their much lower partition ratios, which were determined to be 0.16 +/- 0. 1 for N(6)-(1-iminoethyl)-l-lysine and 12 +/- 1.5 for aminoguanidine in case of the iNOS isoform while the same inactivators produced the partition ratios of 17 +/- 2 and 206 +/- 4, respectively, for the nNOS isoform.
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PMID:Studies of neuronal nitric oxide synthase inactivation by diverse suicide inhibitors. 1048 43

C(60)-Fullerene trisamine adducts inhibit neuronal nitric oxide synthase and calcineurin phosphatase activities in a manner completely reversible by calmodulin. As measured by difference spectroscopy, D(3)-trisamine and C(3)-semiamine fullerene adducts displace trifluoperazine bound to calmodulin coincident with their binding. These binding events are complete at a molar ratio of 4 mol added fullerene per mole calmodulin. Trisamine fullerene adducts alter the native electrophoretic mobility of calmodulin, producing a heterogeneity of bands with associated fullerene. D(3)- and C(3)-trisamine fullerene adducts interact with dansylated calmodulin, producing a 50% loss of maximal fluorescence at concentrations of 30 nM. At higher concentrations than those required to inhibit neuronal nitric oxide synthase, trisamine fullerene adducts inhibit nitric oxide formation by the cytokine-inducible nitric oxide synthase isoform. These inhibitions are fully reversible by calmodulin and skeletal muscle troponin C but not by skeletal muscle parvalbumin. Of the trisamine fullerene adducts tested only the C(3)- and D(3)-semiamine adducts inhibit Ca(2+)-dependent nitric oxide production in GH(3) pituitary cells. These observations support the proposal that trisamine C(60)-fullerene adducts are potent calmodulin antagonists, some of which display activity in intact cellular systems.
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PMID:Trisamine C(60)-fullerene adducts inhibit neuronal nitric oxide synthase by acting as highly potent calmodulin antagonists. 1188 98

Using antiserum against the recombinant isoform 3 of mouse brain metallothionein (MT3), the amount of MT3 protein was determined in whole brain homogenates from the Tg2576 transgenic mouse model of Alzheimer's Disease. Twenty-two month old transgenic positive mice showed a 27% decrease of MT3 normalized to the total protein in the extracts compared to same age, control transgenic negative mice. Metallothioneins bind seven molar equivalents of divalent metal ions per mole of protein so metal levels also were measured in these whole brain extracts using inductively coupled plasma atomic absorption (ICP-AA) spectrometry. No significant difference was observed for any metal assayed. Because neuronal nitric oxide synthase (nNOS) is involved in neurodegenerative disease and nitric oxide specifically interacts with MT3, the concentration and total nNOS activity also were evaluated. The transgenic positive mice showed a decrease of 28% in nNOS protein compared to the same age transgenic negative mice. Normalized to the amount of nNOS protein, total NOS activity was higher in the transgenic positive mice. These data showed that protein levels of both MT3 and nNOS were reduced in transgenic positive mice that show many characteristics of Alzheimer's Disease. In vitro studies suggested that MT3 was not a likely candidate for directly affecting nNOS activity in the brain.
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PMID:Metallothionein-3 and neuronal nitric oxide synthase levels in brains from the Tg2576 mouse model of Alzheimer's disease. 1644 95