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PubMed1985

Genetic analysis of platelet monoamine oxidase activity in families of schizophrenic patients.

Platelet monoamine oxidase (MAO) has been implicated in the biology of several psychiatric disorders, including schizophrenia. Genetic factors contribute to the variance of MAO activity; however, its mode of inheritance is unknown. To assess the distribution and familial patterns of platelet MAO activity, we studied 73 chronic schizophrenic patients and 219 of their first-degree relatives. The activity distribution was skewed and admixture of two distributions gave a better fit to the data than a single distribution. Single-major-locus hypotheses were tested by pedigree analysis methods for quantitative traits. Using the transmission probability model, the familial transmission of MAO activity was consistent with either recessive or additive inheritance but not with dominant inheritance; the environmental hypothesis was strongly rejected. No effect of genotype on probability of illness was observed suggesting no relationship between the particular major locus tested and schizophrenia. The implications for genetic research in schizophrenia were discussed.

Adolescent↗
PubMed1979

Substrate specificity of monoamine oxidase in pig liver mitochondria.

In pig liver both the A and the B form of monoamine oxidase (MAO) were found to be responsible for the oxidation of 5-hydroxytryptamine (5HT), a substrate oxidised by the A form alone in most other tissues. With increasing concentrations of this substrate, the percentage of the substrate oxidised by the B form increased. The Km value of the A and the B form of MAO for 5HT was 200 microns and 2.2 mM, respectively. It is suggested that the division of the monoamines into A and B form substrates should be done on the basis of the molecular turnover numbers rather than on their activities, and that the substrate specificities of the two forms of MAO should be determined over a large range of substrate concentrations.

Animals↗
PubMed1982

The effect of lithium on platelet monoamine oxidase activity in bipolar and schizoaffective disorders.

Platelet monoamine oxidase (MAO) activity was studied in 33 in-patients with bipolar and schizoaffective disorder who were treated with lithium. Platelet MAO activity was found to increase following 10-41 dys of lithium treatment compared to a prior drug free period, and the increase was positively correlated with the duration of lithium treatment. The increase in platelet MAO activity was not correlated wtih clinical improvement as measured by the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment Scale (GAS). The number of platelets per unit of blood was also significantly correlated with the number of days of lithium treatment. However, the increase in the number of platelets in lithium-treated patients was not correlated with the increase in MAO activity and thus appears not to account for it. These results indicate that studies relating platelet MAO activity to psychiatric diagnosis should be interpreted cautiously if patients are receiving lithium carbonate.

Adult↗
PubMed1994

Novel 4-(aryloxy)tetrahydropyridine analogs of MPTP as monoamine oxidase A and B substrates.

The exceptionally good monoamine oxidase (MAO) substrate properties of several 4-(arylmethyl)-1-methyl-1,2,3,6-tetrahydropyridine derivatives related to the neurotoxin MPTP have prompted studies to evaluate the corresponding properties of tetrahydropyridine derivatives bearing heteroatom-linked groups at C-4. The expected dihydropyridinium metabolites generated from these MAO-A- and MAO-B-catalyzed oxidations of the 4-(aryloxy)tetrahydropyridine analogs were found to undergo rapid hydrolytic cleavage to yield the corresponding arenol and 1-methyl-2,3-dihydro-4-pyridone, a species that could be monitored spectrophotometrically. We have exploited this reaction sequence to probe the active sites of beef liver MAO-B and human placental MAO-A with a variety of 4-(aryloxy)-1-methyl-1,2,3,6-tetrahydropyridine derivatives. The results are discussed in relationship to recently published reports describing the MAO-A vs MAO-B selectivity of various 4-(arylmethyl)tetrahydropyridine derivatives.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1980

Studies on human placental monoamine oxidase using mixed substrates.

The activity of mitochondrial monoamine oxidase (MAO) from human placenta was measured with mixtures of labelled and unlabelled tyramine, serotonin (5-HT), benzylamine and beta-phenylethylamine (PEA). Tyramine deamination was inhibited by benzylamine and PEA but not by 5-HT, while benzylamine deamination was inhibited by tyramine and PEA, but not by 5-HT, 5-HT deamination was inhibited by tyramine, benzylamine and PEA and PEA deamination was inhibited by tyramine, benzylamine and 5-HT. These results suggest that MAO in human placenta has multiple catalytic sites or consists of different enzymes. Probably, tyramine, benzylamine and PEA are deaminated oxidatively at a common catalytic site while 5-HT is deaminated at another catalytic site. Benzylamine deamination was inhibited in a mixed noncompetitive fashion by tyramine and PEA in air, but benzylamine deamination was competitively inhibited by PEA at higher concentrations of oxygen. The deaminations of other substrates were inhibited competitively by other substrates, in air. Reciprocal plots of PEA deamination with benzylamine, 5-HT and tyramine gave hyperbolic curves.

Benzylamines↗
PubMed1986

Comparative lipophilicities of substrates of monoamine oxidase.

Oil/water partition coefficients of various substrates of monoamine oxidase (MAO) and kinetic parameters of MAO-A and -B of rat liver at two pH values, pH 7 and pH 9, were investigated. Octanol, heptane or benzene were chosen for the oil phases. The deamination of the biogenic amines 5-hydroxytryptamine (5-HT), tyramine, 2-phenethylamine (PEA) and benzylamine was studied at pH 7 and pH 9. Results indicated all four substrates were very hydrophilic, and the oil/water partition coefficients of benzylamine and PEA were higher than those of 5-HT and tyramine. The changes in Km and Vmax values at pH 7 and pH 9 indicated that the affinities of MAO-A towards 5-HT and tyramine slightly increased at pH 9 and those of MAO-B towards tyramine and benzylamine also increased at pH 9, while uncharged amines at pH 9 amounted to about a hundred times of those at pH 7. It is concluded that the mitochondrial MAO bound to the membrane may metabolize charged molecules as well as uncharged counterparts.

Animals↗
PubMed2003

Functional variation in promoter region of monoamine oxidase A and subtypes of alcoholism: haplotype analysis.

Monoamine oxidase (MAO) is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines. MAO-A, due to its function in central nervous system, has been one of the important candidate genes involved in the development of neuropsychiatric disorders. A functional polymorphism in the promoter region of the MAO-A gene has been identified. This variation affects the transcriptional efficiency of the gene. To determine the role of this MAO-A functional polymorphism in the development of subtypes of alcoholism, a sample of alcoholics and normal controls were screened with this marker. The allele frequency differences between total alcoholics, Types I and II alcoholics, and normal controls was not significant. Comparison of male alcoholics to male normal controls for the frequencies of two-loci and three-loci haplotypes was statistically significant. After Bonferroni's correction for multiple tests none of the results remained significant at P < 0.05. Our results indicate that MAO-A may play a role in the development of alcoholism but the gene effect is very small.

Alcoholism↗
PubMed2001

[Effect of four mutations (Cr,S,S(H),h) in genes for mink coat color on brain monoamine oxidase].

Activity of A and B types of monoamine oxidase (MAO) has been investigated in the brain stem and brain hemispheres of mink males of five genotypes for coat-color mutations: standard dark-brown (+/+); heterozygous for the semidominant mutation Black crystal (Cr/+); homozygous for the semidominant mutation Black cross, or "95% White" (S/S); heterozygous for the semidominant mutation Shadow (SH/+); and homozygous for the semirecessive mutation hedlum white (h/h). The main changes in the activity of the A and B MAO types occur in the brain hemispheres. A reduced activity of MAO A has been recorded in the hemispheres of Black crystal minks (Cr/+) and an elevated activity, in the hemispheres of Shadow (SH/+) and 95% White (S/S). The activity of MAO B is reduced in the hemispheres of Black crystal and elevated in the hemispheres of hedlum white (h/h). An increased MAO A activity has also been recorded in the brain stem of Shadow minks (SH/+). It is suggested that genes controlling coat color have a pleiotropic effect on sexual behavior in males and the endocrine function of testicles mediated by a putative change in the metabolism of brain neurotransmitters, substrates of MAOs A and B.

Animals↗
PubMed1991

Human monoamine oxidase A gene determines levels of enzyme activity.

Monoamine oxidase (MAO) is a critical enzyme in the degradative deamination of biogenic amines throughout the body. Two biochemically distinct forms of the enzyme, A and B, are encoded in separate genes on the human X chromosome. In these studies we investigated the role of the structural gene for MAO-A in determining levels of activity in humans, as measured in cultured skin fibroblasts. The coding sequence of the mRNA for MAO-A was determined by first-strand cDNA synthesis, PCR amplification, and direct dideoxy sequencing. Two single-basepair substitutions were observed in cDNAs from cells with a 30-fold difference in activity levels. These two substitutions were in the third base of a triplet codon and hence did not affect the deduced amino acid sequence but did affect the presence or absence of restriction-enzyme sites for EcoRV and Fnu4HI, which could be elucidated on PCR fragments derived from genomic DNA or cDNAs. A third polymorphism for MspI in the noncoding region of the MAOA gene was also evaluated by Southern blot analysis using genomic DNA. Statistically significant associations were observed between the alleles for MAOA and levels of MAO activity in human male fibroblast lines. This association indicates that the MAOA gene itself is a major determinant of activity levels, apparently, in part, through noncoding, regulatory elements.

Base Sequence↗
PubMed2000

Influence of FAD structure on its binding and activity with the C406A mutant of recombinant human liver monoamine oxidase A.

The FAD binding site of human liver monoamine oxidase A (MAO A) has been investigated by mutagenesis of the amino acid site of covalent FAD attachment (Cys-406) to an alanyl residue. Expression of the C406A mutant in Saccharomyces cerevisiae results in the formation of an active enzyme, as found previously with the rat liver enzyme. The activity of this mutant enzyme is labile to solubilization, thus requiring all experiments to be done with membrane preparations. C406A MAO A was expressed in a rib 5(-) strain of S. cerevisiae in the presence of 16 different riboflavin analogues. Inactive apoC406A MAO A is formed by induction of the enzyme in the absence of riboflavin. FAD but not FMN or riboflavin restores catalytic activity with an apparent K(d) of 62 +/- 5 nm. The results from both in vivo and in vitro reconstitution experiments show increased activity levels (up to approximately 7-fold higher) with those analogues exhibiting higher oxidation-reduction potentials than normal flavin and decreased activity levels with analogues exhibiting lower potentials. Analogues with substituents on the pyrimidine ring bind to C406A MAO A more weakly than normal FAD, suggesting specific interactions with the N(3) and N(1) positions. Analogues with substituents in the 7 and 8 positions bind to C406A MAO A with affinities comparable with that of normal FAD. These results are discussed in regard to functional significance of 8alpha-covalent binding of flavins to proteins.

Binding Sites↗
PubMed2004

Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders.

Monoamine oxidase A (MAOA) has been suggested to be involved in human behaviour and physiology due to its key role in the metabolism of several different biological amines including the neurotransmitters serotonin, norepinephrin and dopamine.Recently, a 30 bp repeat in the MAOA gene promoter (uMAOA) has been demonstrated to be polymorphic and to affect transcriptional activity. In the context of an association case-control study design, we analysed the uMAOA polymorphism in 389 unrelated patients affected by severe mood disorders (88 bipolar subjects and 301 major depressive individuals) and in 156 controls. No association was found between the uMAOA locus and bipolar disorder or major depression. However, an increase of high-activity uMAOA alleles was found in major depression female patients presenting a seasonal pattern (chi2=3.013, P=0.05) or psychotic symptoms in their episodes (chi2=2.679, P=0.07). In female bipolar disorder patients, long alleles were associated with longest times of admission (F=4.604, P=0.037). A trend for association with seasonal pattern was also defined in this group (data not corrected for multiple testing). Our results suggest that MAOA gene variation may modulate the expression of some clinical aspects of severe mood disorders, especially in females, and support the existence of a genetic and aetiologic heterogeneity underlying the diagnoses of bipolar disorder and major depression.

Adult↗
PubMed2004

[Neuroprotective effect of monoamine oxidase monoclonal antibody against vasogenic brain edema in rats].

OBJECTIVE: To observe the therapeutic effect of monoamine oxidase (MAO) monoclonal antibody (mAb) for vasogenic brain edema (VBE) in rats. METHODS: A total of 75 Wistar rats were randomized into non-edema, non-treated edema, saline-treated edema, mannitol-treated edema and MAO mAb-treated groups. Rat models of VBE were established by intraperitoneal injection of phenylephrine in the latter 4 groups. Brain water content in the gray and white matter was measured respectively with a moisture analyzer, and the permeability of the blood-brain barrier (BBB) determined by Evan's blue (EB) extravasation method. RESULTS: MAO mAb administration significantly reduced the brain water content in the gray and white matter as well as the permeability of BBB (P<0.01), Which was especially effective for the white matter, producing results comparable with those of the non-edema group (P>0.05). MAO mAb markedly alleviated brain edema, with better dehydrating effect on the white matter than mannitol (P<0.01), which reduced the water content of the brain gray and white matter undiscriminatingly and showed poor effect on the permeability of BBB. CONCLUSION: The pathogenesis of BBB permeability changes in VBE is related to the activity of monoamine oxidase, and MAO mAb has selective therapeutic effect on VBE, which is especially obvious on brain white matter.

Animals↗
PubMed2006

Distinct structure and activity of monoamine oxidase in the brain of zebrafish (Danio rerio).

Monoamine oxidase (MAO) is a mitochondrial flavoprotein involved in the metabolism of, e.g., aminergic neurotransmitters and the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). We have reported earlier MPTP-related alterations of brain catecholaminergic system in zebrafish (Danio rerio) brain. Here we describe the structural and functional properties of zebrafish MAO and the distribution of MAO mRNA and activity in zebrafish brain. The gene is located in chromosome 9 and consists of 15 exons. The amino acid composition of the active center resembles both human MAO-A and MAO-B. The enzyme displayed the highest substrate specificity for tyramine, followed by serotonin, phenylethylamine, MPTP, and dopamine; isoform-specific antagonists blocked the activity of the enzyme with equal potency. Zebrafish MAO mRNA, which was present in several tissues, and enzyme displayed differential distribution in the brain; dopaminergic cell clusters had low to moderate levels of MAO activity, whereas the highest levels of MAO activity were detected in noradrenergic and serotonergic cell groups and the habenulointerpeduncular pathway, including its caudal projection to the medial ventral rhombencephalon. The results of this study confirm the presence of functionally active MAO in zebrafish brain and other tissues and characterize the neural systems that express MAO and areas of intense activity in the brain. They also suggest that MPTP toxicity not related to MAO may affect the zebrafish brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Mutagenesis at a highly conserved tyrosine in monoamine oxidase B affects FAD incorporation and catalytic activity.

Monoamine oxidase B (MAO B), an integral protein of the outer mitochondrial membrane, catalyzes the oxidative deamination of various neuroactive and vasoactive amines. A covalently bound FAD cofactor at Cys-397 of human MAO B is required for the oxidation of the amine substrates. In addition to the covalent binding site, MAO B also contains a noncovalent FAD binding region (residues 6-34) known as the dinucleotide binding motif. Previously, we have shown that Glu-34 is required for catalytic activity, presumably by forming a hydrogen bond between the carboxylate group of glutamate and the 2'-hydroxyl group of ribose in the AMP moiety of FAD. In this work, we have identified a third FAD binding site in MAO B (residues 39-46) by sequence comparisons to other flavoenzymes. The conserved sequence contains a tyrosine residue (Tyr-44) which, based on the X-ray crystal structure of ferredoxin-NADP+ reductase, is postulated to participate in FAD binding through van der Waals contact with the isoalloxazine ring and a hydrogen bond to the 3'-hydroxy of the ribityl moiety. To test the postulated role of this tyrosine residue, site-directed mutants that encode substitutions at Tyr-44 were prepared and expressed in mammalian COS-7 cells. Variant MAO B enzymes were then characterized with respect to enzymatic activity and [14C]FAD incorporation. Substitution of tyrosine with phenylalanine had no effect on MAO B activity or the level of [14C]FAD incorporation compared to the wild-type enzyme, indicating that the hydroxyl group of the tyrosine residue was not essential at residue 44.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1984

Some interrelated properties of A and B form monoamine oxidase in monkey brain mitochondria.

The multiplicity of monoamine oxidase (MAO) in monkey brain was studied by comparing the relationship between the selective substrates of MAO and the pH-activity curves obtained using these substrates. When mitochondrial and A-form MAO were used as the enzyme preparations with serotonin (5-HT) and norepinephrine (NE), preferential substrates for A-form MAO, the pH optima were 8.8 and 7.8 with 5-HT and 8.5 and 7.2 with NE. These substrates were also oxidized by B-form MAO after changing the pH of the incubation medium (shift to alkaline); these pH optima were 9.0 and 8.2, respectively. When common substrates of MAO were used (tyramine, octopamine, dopamine and tryptamine), the pH activity curves obtained were all broad and bell-shaped with pH optima for the 3 species of enzyme (mitochondria, A-form and B-form MAO) at 8.0, 7.8, and 8.0 with tyramine; 8.3, 7.5, and 8.5 with octopamine; 7.8, 7.5, and 8.5 with dopamine; and 8.0, 8.3, and 6.9 with tryptamine, respectively. The pH optima were 6.6 with beta-phenylethylamine (beta-PEA) and 9.0 with benzylamine, preferential substrates for B-form MAO, for either mitochondria or B-form MAO. The Km values obtained for tryptamine and beta-PEA were lower than those for the other substrates of MAO, regardless of the enzyme preparations. The Km and Vmax values of both forms MAO for 5-HT and NE were similar to those of the A-form MAO. The differences in the Km and Vmax values of the A-form MAO and B-form MAO for common substrates were comparable. Tyramine, octopamine and dopamine were substrates for both forms MAO, with only a slight preference for B-form MAO over A-form MAO. However, tryptamine may be deaminated predominantly by A-form MAO.

Animals↗
PubMed1993

The effect of side chain substitution at positions 2 and 3 of the heterocyclic ring of N-acetylenic analogues of tryptamine as monoamine oxidase inhibitors.

N-Acetylenic analogues of tryptamine in which the side chain is located at position 2 of the indole ring are compared with those in which the side chain is located at position 3, in terms of their actions as inhibitors of monoamine oxidases A and B. IC50 values at 0 and 30 min of pre-incubation were determined. Time-dependence and irreversible inhibition confirmed that all of them behave as mechanism-based inhibitors. The kinetic constants of each inhibition step were determined for both monoamine oxidase forms and compared between them. In all cases the first-order rate constants for the covalent adduct formation were similar to inhibitor selectivity which is derived solely from differences in affinities for non-covalent binding to the A and B enzymes. Those compounds where the acetylenic side chain was substituted at position 2 of the heterocyclic ring and selective inhibitors of monoamine oxidase A were more potent than those with the side chain in position 3.

Acetylene↗
PubMedDate not supplied

[Mitochondrial monoamine oxidase in progressive Duchenne muscular dystrophy].

In children with progressive Duchenne muscular dystrophy distinct impairment in activity, of mitochondrial monoamine oxidase from skeletal muscles correlated with the step of myodystrophic process. The decrease in activity of monoamine oxidase in mitochondria of skeletal muscles, occurred with simultaneous increase in intensity of amines deamination in a medium surrounding the organelles, might de due to "leakage" of the enzyme as a result of deterioration of mitochondrial membranes permeability developed in the disease.

Adolescent↗