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Showing papers on "Monoamine oxidase B published in 1991"


Journal ArticleDOI
TL;DR: The results suggest that MAOA and MAOB are derived from duplication of a common ancestral gene and provide insight on the structural/functional relationship of the enzyme products.
Abstract: Monoamine oxidases A and B [MAOA and MAOB; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4] play important roles in the metabolism of neuroactive, vasoactive amines and the Parkinsonism-producing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Human MAOA and MAOB genes isolated from X chromosome-specific libraries span at least 60 kilobases, consist of 15 exons, and exhibit identical exon-intron organization. Exon 12 codes for the covalent FAD-binding-site and is the most conserved exon; the MAOA and MAOB exon 12 products share 93.9% peptide identity. These results suggest that MAOA and MAOB are derived from duplication of a common ancestral gene and provide insight on the structural/functional relationship of the enzyme products.

259 citations


Journal Article
TL;DR: In this article, cDNA clones that encode the human liver monoamine oxidase A and B have been isolated and compared with the deduced amino acid sequences shows that they are 70% homologous and they appear to be derived from separate genes.

121 citations


Journal ArticleDOI
TL;DR: Both [3H]L-deprenyl binding and monoamine oxidase-B activities in senile dementia of Alzheimer type were higher than in the controls in all brain regions studied, and the increase was highest in the white matter and in the order of 20-50% in the various gray matter regions.

91 citations


Journal Article
TL;DR: In electrophysiological studies, single caudate neuron responses to iontophoretically applied (-)-apomorphine and (+/-)-2-(N-phenethyl-N-propyl) amino-5-hydroxytetralin were potentiated by intracarotid injections of PE and i.p. injections of (-)-deprenyl.
Abstract: This report describes experiments designed to determine whether (-)-deprenyl potentiates dopaminergic transmission and whether its mechanism involves the inhibition of dopamine catabolism. Intraperitoneal administration of (-)-deprenyl (0.5-8 mg kg-1) produced a dose-dependent inhibition of striatal monoamine oxidase type B activity whereas monamine oxidase type A activity in the striatum was inhibited only by 8 mg kg-1 of (-)-deprenyl. Intraperitoneal administration of (-)-deprenyl (0.5-4 mg kg-1) did not alter the striatal concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or homovanillic acid. DOPAC concentrations were decreased by 8 mg kg-1 of (-)-deprenyl. In contrast, administration of clorgyline (2 mg kg-1), a monoamine oxidase type A inhibitor, increased the striatal concentrations of DA and decreased the striatal concentrations of DOPAC and homovanillic acid. The striatal concentrations of 2-phenylethylamine (PE), a putative modulator of striatal DA transmission, were increased by (-)-deprenyl (1-8 mg kg-1) but were unaffected by clorgyline (2 mg kg-1). In electrophysiological studies, single caudate neuron responses to iontophoretically applied (-)-apomorphine and (+/-)-2-(N-phenethyl-N-propyl) amino-5-hydroxytetralin were potentiated by intracarotid injections of PE (30 micrograms kg-1) and i.p. injections of (-)-deprenyl (2 mg kg-1). Both PE and (-)-deprenyl reduced the IT50 of responses to apomorphine and (+/-)-2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin.(ABSTRACT TRUNCATED AT 250 WORDS)

89 citations


Journal Article
TL;DR: The data suggest that the stimulatory effect on locomotor activity and dopamine synthesis is not related to a monoamine oxidase-B blocking action of the drug or to a putative effect on DA reuptake, but rather to effects of metabolites of thedrug (e.g., l-methamphetamine).
Abstract: Utilizing behavioral, biochemical and electrophysiological methods, central effects of the monoamine oxidase-B inhibitor deprenyl (selegiline) were analyzed. Administration of deprenyl (3-30 mg/kg, i.p.) caused a dose-dependent increase in the spontaneous locomotor activity. In the striatum, deprenyl (10 and 30 mg/kg) changed the dopa accumulation following 3-hydroxybenzylhydrazine hydrochloride in a biphasic manner. Deprenyl slightly decreased the firing rate of dopamine-containing neurons in substantia nigra, zona compacta. However, increases in locomotor activity and dopa accumulation induced by deprenyl were almost totally prevented by pretreatment with the microsomal liver enzyme inhibitor proadifen hydrochloride (50 mg/kg, i.p., 30 min), indicating that metabolites of the drug are of pharmacological significance for deprenyl's central actions. Furthermore, administration of l-methamphetamine, a major metabolite of deprenyl, affected spontaneous locomotor activity and striatal dopa formation and the firing rate of dopamine-containing neurons in the substantia nigra within the same magnitude as deprenyl itself when given in doses relevant to the formation of l-methamphetamine from deprenyl. However, unlike the effect of deprenyl, the l-methamphetamine-induced increase in locomotor activity and striatal dopa formation was not antagonized by pretreatment with proadifen hydrochloride. The data suggest that the stimulatory effect on locomotor activity and dopamine synthesis is not related to a monoamine oxidase-B blocking action of the drug or to a putative effect on DA reuptake, but rather to effects of metabolites of the drug (e.g., l-methamphetamine). It is proposed that metabolites of deprenyl should not be disregarded to account for the clinical benefits of the drug.

78 citations


Journal ArticleDOI
TL;DR: A tracer kinetic procedure was developed for the measurement of monoamine oxidase type B (MAO-B) activity using L-[11C]deprenyl and positron emission tomography (PET) and it followed that the rate constant for irreversible binding (k3) appeared to be a better index of MAO- B activity than the net influx constant Ki.
Abstract: A tracer kinetic procedure was developed for the measurement of monoamine oxidase type B (MAO-B) activity using L-[11C]deprenyl and positron emission tomography (PET). The kinetic model consisted of two tissue compartments with irreversible binding to the second compartment (three rate constants). In addition, a blood volume component was included. Special attention was given to the accurate measurement of the plasma and whole blood input functions. The method was applied to the measurement of the dose-response curve of a reversible MAO-B inhibitor (Ro 19-6327). From the results, it followed that the rate constant for irreversible binding (k3) appeared to be a better index of MAO-B activity than the net influx constant Ki. Furthermore, regional analysis demonstrated that Ki, but not k3, was flow dependent. This implies that full kinetic analysis is required for an accurate assessment of MAO-B activity.

76 citations


Journal ArticleDOI
TL;DR: This work isolated human genomic clones spanning almost all the MAOA gene from cosmid and phage libraries using a cDNA probe for MAO-A and demonstrated that the longer message has an extension of 2.2 kb in the 3' noncoding region and appears to be generated by the use of two alternative polyadenylation sites.
Abstract: Monoamine oxidases, type A and type B, are principal enzymes for the degradation of biogenic amines, including catecholamines and serotonin. These isozymes have been implicated in neuropsychiatric disorders. Previously, cDNA clones for both MAO-A and MAO-B have been sequenced and the genes encoding them have been localized to human chromosome Xp11.23-Xp11.4. In this work, we isolated human genomic clones spanning almost all the MAOA gene from cosmid and phage libraries using a cDNA probe for MAO-A. Restriction mapping and sequencing show that the human MAOA gene extends over 70 kb and is composed of 15 exons. The exon structure of human MAOA is similar to that described by others for human MAOB. Exon 12 (bearing the codon for cysteine, which carries the covalently bound FAD cofactor) and exon 13 are highly conserved between human MAOA and MAOB genes (92% at the amino acid level). Earlier work revealed two species of MAO-A mRNA, 2.1 kb and 4.5-5.5 kb. We now report on further cDNA isolation and sequencing, which demonstrates that the longer message has an extension of 2.2 kb in the 3' noncoding region. This extended region is contained entirely within exon 15. The two messages therefore appear to be generated by the use of two alternative polyadenylation sites. Results from the present work should facilitate the mutational analysis of functional domains of MAO-A and MAO-B. Knowledge of the gene structure will also help in evaluating the role of genetic variations in MAO-A in human disease through the use of genomic DNA, which is more accessible than the RNA, as a template for PCR-amplification and sequencing.

71 citations


Journal ArticleDOI
TL;DR: High L-[3H]deprenyl binding was observed in caudate nucleus, putamen, cingulate gyrus and insula cortex, and moderate to low binding was seen in globus pallidus, temporal and parietal cortex and in various thalamus nuclei.

62 citations


Journal ArticleDOI
TL;DR: The results suggest that the activation of dopamine metabolism after transient ischemia was mainly mediated by MAO-A and partly byMAO-B and suggest a possible role of dopamine deamination by MAo in the development of ischemic neuronal necrosis.

62 citations


Journal ArticleDOI
TL;DR: The results suggest that one or more unidentified substances in tobacco smoke are capable of inhibiting brain MAO and perhaps altering the formation of the active metabolite of MPTP.

51 citations


Journal ArticleDOI
TL;DR: Stopped-flow studies demonstrate that the rate of reoxidation of reduced enzyme is enhanced by substrates but not by the product, 1-methyl-4-phenylpyridinium, and that for the A enzyme, the ternary complex with substrate, but not product, is reoxidized at a faster rate than the free, reduced enzyme.
Abstract: Steady-state kinetic data for monoamine oxidase A in crude extracts suggest an exclusively ping-pong mechanism, in contrast to those for monoamine oxidase B, which indicate alternate mechanisms involving either a binary or ternary complex. In this study, with use of purified monoamine oxidase A, steady-state data for the inhibition by D-amphetamine of the oxidation of primary amines indicate the possibility of a ternary complex mechanism for monoamine oxidase A also. Stopped-flow studies demonstrate that the rate of reoxidation of reduced enzyme is enhanced by substrates but not by the product, 1-methyl-4-phenylpyridinium. Thus, for the A enzyme, the ternary complex with substrate, but not product, is reoxidized at a faster rate than the free, reduced enzyme. For both the A and B forms of monoamine oxidase, the mechanism is determined by competition between alternate pathways on the basis of the relative rate constants and dissociation constants.

Journal ArticleDOI
TL;DR: Type B monoamine oxidase immunoreactivity is demonstrated in neuronal cell bodies, fibers and astroglial cells in the cat brain by means of the indirect immunohistochemical method in conjunction with type B monoamines oxidase monoclonal antibody.

Journal ArticleDOI
TL;DR: If a subacute dosing regimen (every 12 hours for 4 days) was utilized, the combination of S-amphetamine with MDAI resulted in a marked long-term decrease in the levels of cortical, hippocampal and striatal 5-HT, 5-HIAA and the number of 5- HT uptake sites.
Abstract: There is increasing evidence linking dopamine (DA) to the long-term serotonergic (5-HT) neurotoxic effects of certain substituted amphetamines such as 3,4-methylenedioxymethamphetamine (MDMA). The present study was undertaken to examine the importance of DA metabolism, uptake inhibition and release in the long-term effects of these drugs by combining various dopaminergic agents with an analogue of MDMA that had low neurotoxic liability, namely 5,6-methylenedioxy-2-aminoindan (MDAI). Monoamine and metabolite levels and the number of 5-HT uptake sites (using [3H]paroxetine binding) were determined 3 hours or 1 week after treatments. Combining the monoamine oxidase inhibitors, clorgyline (MAOA selective) or deprenyl (MAOB selective) with MDAI did not result in any long-term reductions of serotonergic markers. Similarly, combining the DA uptake inhibitor GBR-12909 with MDAI did not result in any long-term changes in monoamine levels at 1 week. In contrast, a single pretreatment or posttreatment with the nonvesicular DA releaser S-amphetamine and MDAI resulted in small but significant long-term changes in monoamine levels. More importantly, if a subacute dosing regimen (every 12 hours for 4 days) was utilized, the combination of S-amphetamine with MDAI resulted in a marked long-term decrease in the levels of cortical, hippocampal and striatal 5-HT, 5-HIAA and the number of 5-HT uptake sites. The results are discussed in terms of the significance of DA and especially nonvesicular DA release in the long-term effects of MDMA-like drugs.


Journal ArticleDOI
TL;DR: Comparison of the kinetic constants of the three enzymes towards dopamine indicated that, although each of them had activity towards this substrate, their relative contributions to the total oxidative deamination would depend on the substrate concentration.

Journal ArticleDOI
TL;DR: It was observed that inhibition of monoamine oxidase type A, and to a lesser degree, type B, increased the magnitude of methamphetamine‐induced neuronal damage and that aged mice were more sensitive to the toxic action of methamphetamine.

Journal ArticleDOI
TL;DR: The most marked difference in the profile was that N2-acetylphenelzine had no effect on whole brain levels of the amino acid neurotransmitters alanine and γ-aminobutyric acid, whereas phenelZine caused dramatic increases.
Abstract: The neurochemical properties of N2-acetyl-phenelzine were compared with those of phenelzine in a rat model N2-Acetylphenelzine is a relatively potent inhibitor of monoamine oxidase-A and -B and causes increases in whole-brain levels of noradrenaline and 5-hydroxytryptamine, and decreases in homovanillic acid, 5-hydroxyindole-3-acetic acid, and 3,4-dihydroxyphenylacetic acid after acute ip administration of the drug Phenelzine is a more potent monoamine oxidase inhibitor than is N2-acetylphenelzine The most marked difference in the profile was that N2-acetylphenelzine had no effect on whole brain levels of the amino acid neurotransmitters alanine and γ-aminobutyric acid, whereas phenelzine caused dramatic increases Acetylation of phenelzine at the N2 position presumably interferes with the inhibition of the transaminase enzymes for γ-aminobutyric acid and alanine

Journal ArticleDOI
TL;DR: The results indicate that two different SSAO activities could be present in the bovine eye, and one of these activities may be related to dopamine metabolism.


Journal ArticleDOI
TL;DR: The findings that alpha-methyl-milacemide has anticonvulsant properties in the bicuculline test but is not a substrate for monoamine oxidase or a source of urinary glycinamide cast doubt on the importance of the oxidation or milacemides to form glycinamide as a major factor in its anticonVulsant action.


Journal ArticleDOI
TL;DR: The results suggest that the degradation of tele-methylhistamine might occur within the intraneuronal structures of histaminergic neurons.

01 Jan 1991
TL;DR: In this paper, the authors show that the human MAOA and MAOBexon12 products share 93.9%peptide identity and reveal that they are derived fromduplication of a commonancestral gene and provide insight on the structureur- al/functional relationship of theenzyme products.
Abstract: Monoamine oxidases A andB (MAOAand MAOB;amine:oxygen oxidoreductase (deaminating) (flavin- contaning), EC1.4.3.4) play important roles inthemetabolism ofneuroactive, vasoactive aminesandtheParkinsonism- producing neurotoxin 1-methyl4-4phenyl-1,2,3,6-tetrahydro- pyridine (MPTP). HumanMAOA andMAOB genes isolated fromX chromosome-specific libraries spanatleast 60kilo- bases, consist of15exons, andexhibit identical exon-intron organization. Exon12codes forthecovalent FAD-binding-site andisthemostconserved exon; theMAOAandMAOBexon12 products share 93.9%peptide identity. These results suggest thatMAOA andMAOB arederived fromduplication ofa commonancestral geneandprovide insight onthestructur- al/functional relationship oftheenzyme products. Monoamine oxidases AandB(MAOAandMAOB;amine:- oxygen oxidoreductase (deaminating) (flavin-containi ng), EC

Journal ArticleDOI
TL;DR: Comparison of the nucleic acid sequences of the cDNAs for MAO-A andMAO-B shows that the different forms of MA0 are the products of two related but different genes, lending support to the idea that these genes may have arisen from duplication of a single ancestral gene.
Abstract: The two forms of monoamine oxidase (MAO) are defined by their substrate and inhibitor affinities [ 11. This specificity must be reflected in the amino acid sequences and molecular structure of the active sites. A precise knowledge of those amino acid residues that form the active sites of MAO-A and MAO-B may enable new specific inhibitors of MA0 to be rationally designed. Until recently the only approach to identifying those amino acid residues important for enzymic specificity was by protein chemical methods and from the large amounts of data describing the substrate and inhibitor specificities of the two forms. However, the recent isolation of cDNA clones for both forms of MA0 from several different species initiates a molecular biological approach to structural and functional studies [ 2-41. The translated protein sequences of MAO-A and MAO-B cDNAs showed that the two isoenzymes differed in size, the MAO-A cDNA coded for a protein of 527 amino acid residues (M 59700 Da) and MAO-B cDNA coded for a protein of 520 residues (M 58 800 Da). This difference in size is in agreement with biochemical data obtained from the comparison of ['HI pargyline-labelled polypeptides on denaturing polyacrylamide gels [ 5 ] . The hydrophobicity profile of the two forms are very similar, suggesting that they share a similar structure. Comparison of the nucleic acid sequences of the cDNAs for MAO-A and MAO-B shows that the different forms of MA0 are the products of two related but different genes. In humans and probably in other mammals the two genes are closely linked on the X-chromosome [6] lending support to the idea that these genes may have arisen from duplication of a single ancestral gene. Lower vertebrates

Journal ArticleDOI
TL;DR: Enzymic systems involved with metabolism of foreign chemicals, xenobiotics, have been studied in Parkinson's disease and pathways involved with N‐methylation of pyridines are different from controls leading to a rise in potentially toxic N‐ methylated derivatives.
Abstract: Enzymic systems involved with metabolism of foreign chemicals, xenobiotics, have been studied in Parkinson's disease. Enzymes involved with sulphur oxidation and methylation are under-active. Cysteine levels are high and sulphate levels low. Differences in the activity of the enzyme monoamine oxidase-B are evident. Pathways involved with N-methylation of pyridines are different from controls leading to a rise in potentially toxic N-methylated derivatives.

Journal ArticleDOI
TL;DR: Xenobiotic enzymic systems have been studied in Parkinson's disease and platelet monoamine oxidage-B activity is increased by the use of phenylethylamine but decreased by theUse of dopamine as substrate.
Abstract: Xenobiotic enzymic systems have been studied in Parkinson9s disease. Platelet monoamine oxidage-B activity is increased by the use of phenylethylamine but decreased by the use of dopamine as substrate. Enzymes involved with sulfur oxidation and methylation are underactive.

Journal ArticleDOI
TL;DR: Comparison of molecular activities and Km values for MAO A and B showed that with the exception of benzylamine and beta-phenylethylamine,MAO A oxidizes the other tested substrates faster than MAO B over a wide range of concentrations.

Journal ArticleDOI
TL;DR: 2-Propyl-1-aminopentane was found to be readily deaminated by monoamine oxidase B in the liver of the rat and semicarbazide-sensitive amine oxidase in the aorta of the rats, and could be subsequently converted to valproic acid in the presence of aldehyde dehydrogenase and beta-NAD cofactor in vitro as well as in vivo.

Journal ArticleDOI
TL;DR: In this paper, 2-propylpentylglycinamide (2-PPG) was found to be readily deaminated by rat liver monoamine oxidase B in vitro and in vivo.
Abstract: 2-Propylpentylglycinamide (2-PPG), a branched aliphatic amine derivative, was found to be readily deaminated by rat liver monoamine oxidase B in vitro and in vivo. The deamination leads to production of 2-propyl-1-pentaldehyde, which can be subsequently converted to valproic acid (VPA), and glycinamide, which is then subsequently converted to glycine. Absorption and biotransformation of a single ip dose of 2-PPG into blood as well as transfer of the drug and its metabolite into the brain were rapid processes. Although VPA (an anticonvulsant) and glycine (an inhibitory neurotransmitter) can be detected in the brain following administration of 2-PPG, its anticonvulsant action cannot be determined. 2-PPG at relatively low doses exhibited distinct tremor effects. Furthermore, 2-PPG appeared to potentiate the convulsant effect induced by pentylenetetrazol.

Journal ArticleDOI
TL;DR: The results indicate that p-CMP is a short-acting, probably reversible, MAOB-selective inhibitor and 5-FMT has the same characteristics of selectivity for MAOA in central serotonergic neurons.