Showing papers on "Polyamine binding published in 2001"
TL;DR: The crystal structure of maize PAO in the reduced state and in complex with three different inhibitors, guazatine, 1,8-diaminooctane, and N(1)-ethyl-N(11)-[(cycloheptyl)methyl]-4,4-diazaundecane, reveals an exact match between the inhibitors and the PAO catalytic tunnel.
Abstract: Polyamine oxidase (PAO) carries out the FAD-dependent oxidation of the secondary amino groups of spermidine and spermine, a key reaction in the polyamine catabolism. The active site of PAO consists of a 30 A long U-shaped catalytic tunnel, whose innermost part is located in front of the flavin ring. To provide insight into the PAO substrate specificity and amine oxidation mechanism, we have investigated the crystal structure of maize PAO in the reduced state and in complex with three different inhibitors, guazatine, 1,8-diaminooctane, and N(1)-ethyl-N(11)-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm). In the reduced state, the conformation of the isoalloxazine ring and the surrounding residues is identical to that of the oxidized enzyme. Only Lys300 moves away from the flavin to compensate for the change in cofactor protonation occurring upon reduction. The structure of the PAO.inhibitor complexes reveals an exact match between the inhibitors and the PAO catalytic tunnel. Inhibitor binding does not involve any protein conformational change. Such lock-and-key binding occurs also in the complex with CHENSpm, which forms a covalent adduct with the flavin N5 atom. Comparison of the enzyme complexes hints at an "out-of-register" mechanism of inhibition, in which the inhibitor secondary amino groups are not properly aligned with respect to the flavin to allow oxidation. Except for the Glu62-Glu170 pair, no negatively charged residues are involved in the recognition of substrate and inhibitor amino groups, which is in contrast to other polyamine binding proteins. This feature may be exploited in the design of drugs specifically targeting PAO.
61 citations
TL;DR: Evidence is provided that polyamines may be involved in learning and memory modulation in the amygdala and co-administration of arcaine and spermidine completely reversed the sperMidine-induced increase of test step-down latencies.
53 citations
TL;DR: The mechanisms underlying NMDA receptor inhibition were investigated using whole-cell voltage-clamp recording in CA1 pyramidal neurons acutely dissociated from rat hippocampus and huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites.
45 citations
TL;DR: It is concluded that the polyamine moiety of 125I-MR44 interacts with the high affinity noncompetitive inhibitor site deep in the channel of the nicotinic acetylcholine receptor, while the aromatic ring of this compound binds in the upper part of the ion channel to a hydrophobic region on the α-subunit that is located in close proximity to the agonist binding site.
24 citations
TL;DR: High-throughput ligand displacement screens of a series of endogenous indoles revealed that tryptamine, serotonin and 5-methoxytryptamine readily displace spermidine and [3H]MK-801 from their respective binding sites in rat brain homogenate, suggesting that certain endogenous indole may act as ligands to one or more polyaminebinding sites in the brain, including those on the N-methyl-D-aspartate receptor complex.
17 citations
TL;DR: In this article, Aminoanthraquinones were identified as potential modulators of N-methyl-D-aspartate (NMDA) receptor function, and they represented a novel class of polyamine binding site ligands with a unique pharmacophore.
Abstract: As part of a drug discovery program using high-throughput radioligand-binding assays, aminoanthraquinones were identified as potential modulators of N-methyl-D-aspartate (NMDA) receptor function. Aminoanthraquinones may represent a novel class of polyamine binding site ligands with a unique pharmacophore and may facilitate the rational design of novel NMDA-receptor modulators.