Human brain monoamine oxidase type B: Mechanism of deamination as probed by steady-state methods
(Impact Factor: 3.02).
04/1985; 24(8):1821-6. DOI: 10.1021/bi00329a003
Recently, evidence has been published which suggests that [Husain, M., Edmondson, D. E., & Singer, T.P. (1982) Biochemistry 21, 595-600] monoamine oxidase [amine:oxygen oxidoreductase (MAO), EC 184.108.40.206] deaminates phenylethylamine and benzylamine via two distinct kinetic pathways which involve either binary or ternary complex formation, respectively. These conclusions were drawn largely from stopped-flow kinetic analysis performed on purified enzyme removed from its native membrane and in the presence of the inhibitory detergent Triton X-100. In this study, d-amphetamine and alternative substrates were used as steady-state probes of the kinetics of deamination by the B form of human brain MAO using native membrane-bound enzyme. Initial velocity studies showed mixed-type patterns for amphetamine inhibition of phenylethylamine, tryptamine, and tyramine when either amine or oxygen was the varied substrate. Slope and intercept vs. amphetamine concentration replots were linear in all cases except for phenylethylamine (hyperbolic); Ki values obtained from linear replots of slope or intercept values were comparable. In contrast, amphetamine was a competitive inhibitor of benzylamine deamination when amine concentration was varied and uncompetitive when oxygen concentration was varied; slope and intercept replots were linear for both. When benzylamine was the alternative substrate inhibitor and tyramine and tryptamine deamination was measured, mixed-type inhibition patterns were obtained when either amine or oxygen concentration was varied; replots of slope and intercept were linear in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)
Available from: Sabine Windhorst
- "The consequence is a reduction in enzymatic activity, but the inhibitor does not directly affect substrate binding. A mixed inhibition is a mixture of competitive and non-competitive inhibition; in presence of inhibitor V max decreases and K m increases    . "
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ABSTRACT: Ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A (ITPKA) in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities; it bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals by phosphorylating InsP3. Thus, in order to inhibit the metastasis-promoting activity of ITPKA, both its actin bundling and its InsP3kinase activity has to be blocked. In this study, we performed a high throughput screen in order to identify specific and membrane-permeable substances against the InsP3kinase activity. Among 34144 small molecules, 237 compounds (0.7%) were identified as potential InsP3kinase inhibitors. After determination of IC50-values, the three compounds with highest specificity and highest hydrophobicity (EPPC-3, BAMB-4, MEPTT-3) were further characterized. Only BAMB-4 was nearly completely taken up by H1299 cells and remained stable after cellular uptake, thus exhibiting a robust stability and a high membrane permeability. Determination of the inhibitor type revealed that BAMB-4 belongs to the group of mixed type inhibitors. Taken together, for the first time we identified a highly membrane-permeable inhibitor against the InsP3kinase activity of ITPKA providing the possibility to partly inhibit the metastasis-promoting effect of ITPKA in lung tumor cells.
Biochemical and Biophysical Research Communications 08/2013; 439(2). DOI:10.1016/j.bbrc.2013.08.053 · 2.30 Impact Factor
Available from: Dale E Edmondson
- "8- (3-Chlorostyryl)-caffeine inhibition of zMAO is the only exception and is the only " dual cavity spanning " MAO B reversible inhibitor observed to bind. The reversible MAO inhibitor d-amphetamine (Green and El Hait 1980;Sowa, et al. 2004) functions as an uncompetitive inhibitor of zMAO catalyzed kynuramine oxidation although it competitively inhibits human MAO A (Vintém et al., 2005) and can function either as a competitive or as a mixed inhibitor of human MAO B depending on the substrate (Pearce and Roth, 1985). "
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ABSTRACT: A comparative investigation of substrate specificity and inhibitor binding properties of recombinant zebrafish (Danio rerio) monoamine oxidase (zMAO) with those of recombinant human monoamine oxidases A and B (hMAO A and hMAO B) is presented. zMAO oxidizes the neurotransmitter amines (serotonin, dopamine and tyramine) with k(cat) values that exceed those of hMAO A or of hMAO B. The enzyme is competitively inhibited by hMAO A selective reversible inhibitors with the exception of d-amphetamine where uncompetitive inhibition is exhibited. The enzyme is unreactive with most MAO B-specific reversible inhibitors with the exception of chlorostyrylcaffeine. zMAO catalyzes the oxidation of para-substituted benzylamine analogs exhibiting (D)k(cat) and (D)(k(cat)/K(m)) values ranging from 2 to 8. Structure-activity correlations show a dependence of log k(cat) with the electronic factor σ(p) with a ρ value of +1.55±0.34; a value close to that for hMAO A but not with MAO B. zMAO differs from hMAO A or hMAO B in benzylamine analog binding correlations where an electronic effect (ρ=+1.29±0.31) is observed. These data demonstrate zMAO exhibits functional properties similar to hMAO A as well as exhibits its own unique behavior. These results should be useful for studies of MAO function in zebrafish models of human disease states.
Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 02/2011; 159(2):78-83. DOI:10.1016/j.cbpb.2011.02.002 · 1.55 Impact Factor
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ABSTRACT: We previously reported that qualitative changes in dietary fat influence certain monoaminergic mediated behaviours such as pain sensitivity and thermoregulation in a cold environment after an amphetamine challenge. The purpose of this study was to further explore the behavioural consequences of alterations in dietary fat intake by examining another behaviour known to be mediated by the monoamines--food intake regulation--and to begin investigating a biochemical link between dietary fat composition and behaviour. Rats were stabilized to 20% (w/w) soybean oil (SBO) or lard diets for 10 days and then allowed to select for protein (PRO) and carbohydrate (CHO) intake. While total food intake was unchanged, rats fed the SBO diet selected lower PRO (3.1 +/- 0.6 vs. 4.9 +/- 0.6 g/day, SBO vs. lard, respectively) and higher CHO (9.6 +/- 0.7 vs. 7.8 +/- 1.2) intakes than those consuming the lard based diet. Comparable differences were seen in a second trial. Current evidence suggests that the regulation of PRO and CHO intake is under serotonergic control. Therefore to determine whether dietary fat is mediating its effect on macronutrient selection via alterations in serotonin (5HT) metabolism, brain stem concentrations of 5HT and its metabolite 5-hydroxyindole acetic acid (5HIAA) and whole brain (minus brain stem) mitochondrial monoamine oxidase (MAO) activity were measured in a separate set of animals fed the SBO or lard diets for 28 days. Vmax of MAO was decreased in rats fed the SBO diets (20.2 +/- 7.4 vs. 27.9 +/- 8.9 nmol/mg prot/20') compared to those fed the lard diets. Km was unaltered by dietary fat fed. The change in activity of MAO was insufficient to alter steady-state levels of 5HT or 5HIAA. We propose that changes in neuronal functioning, induced by altered dietary fat, contributed to the differences seen in PRO and CHO selection.
Pharmacology Biochemistry and Behavior 06/1987; 27(1):1-6. DOI:10.1016/0091-3057(87)90468-0 · 2.78 Impact Factor
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