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PubMed1980

Twin studies and substrate differences in platelet monoamine oxidase activity.

Monoamine oxidase activity was measured in blood platelets of 7 pairs of identical (MZ) twins and a similar number of age- and sex-matched control pairs. Mean intrapair difference in platelet MAO activity was significantly smaller (0.01 less than p less than 0.025) in MZ compared to controls. Kinetic studies of the enzyme revealed mean Km value of 1.0 x 10(-5) mol/l for tryptamine. Platelet MAO activity is higher in women than in men.

Adolescent↗
PubMed1986

Monoamine oxidase inhibitors.

Monoamine oxidase inhibitors offer effective treatment opportunities to an expanded range of depressed and anxious patients, particularly those with atypical depression. The use of these drugs requires heightened physician awareness and patient education, but the risks are less pronounced than was previously thought. Hypotension is the main side effect. Hypertensive reactions can be avoided by strictly proscribing congestion of MAO inhibitors with indirect-action sympathomimetic substances that occur in certain drugs, foods and beverages.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

[Effect of acute and chronic ethanol consumption on rat brain and liver monoamine oxidase activity].

Monoamine oxidase (MAO) activity was studied in hyporthalamus, midbrain, brain stem and liver tissue of rats after single and repeated administration of ethanol using noradrenaline and dopamine as MAO substrates. Small, but statistically significant decrease in the activity MAO of the "A" type was found in rat liver tissue after repeated administration of alcohol. Both single and repeated administrations of ethanol did not affect the enzymatic activity in the brain. Prolonged administration of the MAO inhibitor parnate simultaneously with alcoholization of rats led to inhibition of the MAO activity to the same degree as in control animals treated with the parnate only.

Alcoholic Intoxication↗
PubMed1984

Kinetic aspects of human platelet monoamine oxidase thermolability.

Monoamine oxidase in platelets collected on two different occasions, from twelve apparently healthy subjects, were studied. The influence of human platelet poor plasma (PPP) on MAO thermolability and variation in enzyme activity over time was investigated. A 30-70% reduction of the activity was observed after heat treatment at 52 degrees C for 30 min. Activity of MAO was determined before (C) and after heat treatment (H). No significant differences between the H/C ratios on the two occasions were observed for either Vo, Vmax or Km with or without 10% PPP added to the incubates. A temporal increase of the kinetic parameters was observed. The magnitude of this increase was smaller for vo than for apparent Km and Vmax. Platelet MAO activity regulation by human PPP is discussed.

Adult↗
PubMed1998

Effect of the locus of the oxygen atom in amino ethers on the inactivation of monoamine oxidase B.

Monoamine oxidase is a flavoenzyme that catalyzes the oxidation of a variety of primary, secondary, and tertiary amines. Although primary alkylamines, such as heptylamine, and primary arylalkyl amines, such as phenylethylamine, are excellent substrates for MAO, their analogues having an electron withdrawing group near the aminomethyl methylene group (1-8) are known to inactivate the enzyme. Inactivation has been attributed to the inductive effect of the electron-withdrawing group of these analogues. To determine the extent of the proposed inductive effect of a heteroatom on MAO B inactivation, a series of oxaheptylamine analogues (9-12) were synthesized and tested as inactivators of MAO B. The analogues in which the oxygen atom is closest to the alpha-carbon (9 and 10) inactivate MAO B, but activity slowly returns with time. The analogues with the oxygen atom farther from the alpha-carbon inactivate the enzyme, but activity rapidly returns. These results support the inductive effect hypothesis for inactivation.

Amines↗
PubMed1980

Demographic, biologic, and other variables affecting monoamine oxidase activity.

Monoamine oxidase (MAO) activity has been shown to be influenced by a variety of demographic, biologic, and other variables. Human platelet, plasma, and brain enzyme activities correlate with age and are higher in women. Brain catecholamines tend to decrease with age. The acute effects of ethanol on platelet MAO do not appear to be significant, but chronic ethanol ingestion could influence enzyme activity through a variety of possible mechanisms. Numerous drugs and hormones have been shown to alter platelet and tissue MAO. Heterogeneity of platelet size, density, age, and enzyme activity complicates the study of MAO in clinical populations. Newer platelet isolation techniques may diminish the variability due to platelet sampling. Studies of platelet MAO activity in schizophrenia require that careful attention be given to controlling for variables possibly influencing the blood enzyme activity, such as prior neuroleptic treatment. The limited studies of brain MAO activity in man fail to demonstrate differences between patients with schizophrenia and normal controls.

Adult↗
PubMed1999

Adaptive changes in postsynaptic dopamine receptors despite unaltered dopamine dynamics in mice lacking monoamine oxidase B.

Monoamine oxidase (MAO) B is considered a key enzyme in dopamine metabolism. The present studies, conducted in MAO B knockout mice, show that lack of MAO B does not alter extracellular levels of dopamine in striatum. Similarly, the synthesis, storage, uptake, and release of dopamine are also unaltered. However, autoradiography revealed a significant up-regulation of the D2-like dopamine receptors in the striatum of MAO B knockout mice. Mutant mice also exhibit a functional supersensitivity of D1-dopamine receptors in the nucleus accumbens. Thus, the agonist SKF 38,393-induced c-Fos immunoreactivity was significantly increased in knockout mice as compared with wild-type controls. In view of the apparently normal basal dopamine dynamics observed in MAO B knockout mice, we hypothesize that a dopamine-independent mechanism underlies adaptations in dopamine receptor function that occur as a consequence of MAO B depletion. Finally, these findings suggest that chronic administration of MAO inhibitors, as occurs in the treatment of Parkinson's disease and depression, may be associated with an increased responsiveness of CNS neurons to dopamine receptor ligands.

Animals↗
PubMed1989

The safety of switching rapidly from tricyclic antidepressants to monoamine oxidase inhibitors.

Monoamine oxidase inhibitors (MAOIs) are increasingly used for patients who do not respond to an initial trial of tricyclic antidepressants (TCAs). Although there are insufficient data documenting the optimal manner for switching a patient from a TCA to an MAOI, standard references advise a drug-free interval of at least 1 week. In clinical practice, however, such a delay may be difficult to observe. In order to explore the safety of a more rapid switch from TCA to MAOI therapy, we survey members of our department (Columbia University) as to their experience with different methods of switching patients from TCAs to MAOIs. Thirty-three respondents reported having switched an estimated 432 patients over the course of 3 years, with 178 patients switched within 4 days of discontinuing TCA therapy, including 63 who had the MAOI added while still being tapered from the TCA. More experienced psychiatrists tended to be less conservative, some using time intervals of 4 days or less. No adverse reactions were reported, including hypertensive and hyperpyrexic crises. This retrospective survey and an accompanying review of the literature suggest that the recommended drug-free interval of a week or more when switching patients from TCAs to MAOIs may be overly conservative.

Antidepressive Agents, Tricyclic↗
PubMed2004

Conserved elements of the cytochrome P-450 superfamily found in monoamine oxidase B.

Monoamine oxidases A and B (MAO A and B) are the major enzymes in mammals that catalyze the oxidative deamination or oxidation of neurotransmitters, peripheral vasoactive amines, and xenobiotics (e.g. MPTP). Although these enzymes are among the most widely studied flavoproteins, their integral association with the outer mitochondrial membrane has deterred knowledge of their structures until recent work yielded the three-dimensional structure of MAO B [Nat. Struct. Biol. 9 (2002) 22]. In our study, we compared the primary sequence in different regions of MAO B to those in selected proteins of known structure, including cytochrome P-450. Using site-directed mutagenesis [Prog. Nucleic Acid Res. Mol. Biol. 65 (2001) 129], we have identified three amino acids residues (Phe 423, Glu 427, and Thr 428) that appear to play a role in generating catalytically active MAO B. However, examination of models of the MAO B structure show that these residues lie outside the substrate binding site. Thus, it appears that Phe 423, Glu 427 and Thr 428 do not directly affect the active site, but they could modulate activity through an independent function such as non-covalent binding of FAD during synthesis of the MAO B polypeptide chain.

Amino Acid Sequence↗
PubMed1998

Arginine-42 and threonine-45 are required for FAD incorporation and catalytic activity in human monoamine oxidase B.

Monoamine oxidase B (MAO B) is an integral protein of the outer mitochondrial membrane that is involved in the deamination of vasoactive and neuroactive amines. The oxidation of these amine substrates requires the cofactor FAD, which is covalently bound to Cys-397 of human MAO B. Previously, Glu-34 and Tyr-44 of MAO B have been identified as residues which engage in noncovalent interactions with FAD that are required for subsequent covalent FAD binding and generation of catalytic activity. In this study, we have identified two additional residues, Arg-42 and Thr-45, which form noncovalent contacts with FAD that are prerequisite steps to the covalent attachment of FAD. Arg-42 and Thr-45, along with Tyr-44, comprise part of a highly conserved flavin binding sequence, RXY(T,S), that is found in other flavoproteins, several of which have well-defined X-ray crystal structures. We tested the roles of Arg-42 and Thr-45 in MAO B by constructing mutant MAO B cDNAs which encode amino acid substitutions at these residues and expressed the variant proteins in COS-7 cells. Substitution of Arg-42 or Thr-45 with alanine resulted in complete loss of MAO B activity and FAD incorporation. However, conservative substitutions of Arg-42 with lysine or Thr-45 with serine resulted in MAO B variants that retain both partial activity and partial FAD incorporation. These results indicate that Arg-42 and Thr-45 form critical noncovalent interactions with FAD that are required for the subsequent activation of MAO B by covalent coupling of FAD.

Animals↗
PubMed1995

Flavinylation of monoamine oxidase B.

Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of biogenic and xenobiotic amines. The oxidative step is coupled to the reduction of an obligatory cofactor, FAD, which is covalently linked to the enzyme at Cys397. In this study, we developed a novel riboflavin-depleted (Rib-) COS-7 cell line to study the flavinylation of MAO B. ApoMAO B can be obtained by expressing MAO B cDNA in these cells. We found that MAO B is expressed equally in the presence or absence of FAD and that apoMAO B can be inserted into the outer mitochondrial membrane. Flavinylation of MAO B was achieved by introducing MAO B cDNA and different flavin derivatives simultaneously into Rib- COS-7 cells via electroporation. Since the addition of riboflavin, FMN, or FAD resulted in equal levels of MAO B activity, we conclude that the flavin which initially binds to apoMAO B is FAD. In our previous work, we used site-directed mutagenesis to show that Glu34 in the dinucleotide-binding motif of MAO B is essential for MAO B activity, and we postulated that this residue is involved in FAD binding. In this study, we tested the role of residue 34 in flavin binding by expressing wild-type or mutant MAO B cDNA in Rib- COS-7 cells with the addition of [14C]FAD. We found that Glu34 is essential for both FAD binding and catalytic activity. Thus, FAD binds to MAO B in a dual manner at Glu34 noncovalently and Cys397 covalently. We conclude that Glu34 is critical for the initial non-covalent binding of FAD and is instrumental in delivering FAD to the covalent attachment site at Cys397.

Animals↗
PubMed1991

Structure of the human gene for monoamine oxidase type A.

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.

Amino Acid Sequence↗
PubMed1998

Characterization of a highly conserved FAD-binding site in human monoamine oxidase B.

Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of biogenic and xenobiotic amines. The oxidative step is coupled to the reduction of an obligatory cofactor, FAD, which is covalently linked to the apoenzyme at Cys397. Our previous studies identified two noncovalent flavin-binding regions in MAO B (residues 6-34 and 39-46) (Kwan, S.-W., Lewis, D. A., Zhou, B. P., and Abell, C. W. (1995) Arch. Biochem. Biophys. 316, 385-391; Zhou, B. P., Lewis, D. A., Kwan, S.-W., Kirksey, T. J., and Abell, C. W. (1995) Biochemistry 34, 9526-9531). In these regions, Glu34 and Tyr44 were found to be required for the initial binding of FAD. By comparing sequences with enzymes in the oxidoreductase family, we now have found an additional FAD-binding site in MAO B (residues 222-227), which is highly conserved across species (human, bovine, and rat). This conserved sequence contains adjacent glycine and aspartate residues (Gly226 and Asp227). Based on the x-ray crystal structures of several oxidoreductases (Eggink, G., Engel, H., Vriend, G., Terpstra, P., and Witholt, B. (1990) J. Mol. Biol. 212, 135-142; Van Driessche, G., Kol, M., Chen, Z.-W., Mathews, F. S., Meyer, T. E., Bartsch, R. G., Cusanovich, M. A., and Van Beeumen, J. J. (1996) Protein Sci. 5, 1753-1764), the Gly residue at the end of a beta-strand facilitates a sharp turn and extends the beta-carbonyl group of Asp to interact with the 3'-hydroxyl group of the ribityl chain of FAD. To assess the hypothesis that Gly226 and Asp227 are involved in FAD binding in MAO B, site-specific mutants that encode substitutions at these positions were prepared and expressed in mammalian COS-7 cells. Our results indicate that Gly226 and the beta-carbonyl group of Asp227 are required for covalent flavinylation and catalytic activity of MAO B, but not for noncovalent binding of FAD. Our studies also reveal that mutagenesis at Glu34 and Tyr44 not only interferes with covalent flavinylation and catalytic activity of MAO B, but also with noncovalent binding of FAD. Based on these collective results, we propose that the coupling of FAD to the MAO B apoenzyme is a multistep process.

Amino Acid Sequence↗
PubMed1992

Increase of brain endogenous monoamine oxidase inhibitory activity (tribulin) in experimental audiogenic seizures in rats: evidence for a monoamine oxidase A inhibiting component of tribulin.

Brain tribulin activity in rats with an inherited predisposition to audiogenic epilepsy was studied after seizures of different intensity were induced by an electric bell. Weak seizures (from 0 to 2 arbitrary units) did not produce any changes in endogenous inhibitory activity towards either monoamine oxidase (MAO) A or B. Moderate seizures were characterized by increases in both MAO A and MAO B inhibitory activity (up to 1.9-fold). Complete tonic epileptiform seizures with total areflexia (4 arbitrary units) induced further augmentation (up to 2.5-fold) of MAO A but not of MAO B inhibitory activity. This dissociation between the two inhibitory activities points to the existence of a separate MAO A-inhibiting component of brain tribulin which is different from isatin.

Animals↗
PubMed1999

Quantitative distribution of monoamine oxidase A in brainstem monoamine nuclei is normal in major depression.

An abnormal expression of noradrenergic proteins (e.g., tyrosine hydroxylase, norepinephrine transporters) in the locus coeruleus has recently been demonstrated in subjects with major depression and/or victims of suicide. Monoamine oxidase A (MAO-A) is a key enzyme in the catabolism of biogenic amines and is expressed in brain noradrenergic neurons. In this study, the binding of [3H]Ro41-1049 to MAO-A was measured by quantitative autoradiography at multiple levels along the rostral-caudal axis of the noradrenergic locus coeruleus from subjects with major depression and age- and postmortem interval-matched control subjects who were psychiatrically normal. [3H]Ro41-1049 binding to MAO-A was unevenly distributed along the axis of the locus coeruleus, paralleling an uneven number of neuromelanin-containing (noradrenergic) neurons throughout the nucleus. Accordingly, there was a significant correlation between the number of neuromelanin-containing neurons per section and the specific binding of [3H]Ro41-1049 at any particular level of the locus coeruleus in control subjects (r(2)=0.25; p<0.001) and in subjects with major depression (r(2)=0.14; p<0. 001). Moderate levels of [3H]Ro41-1049 binding were observed in regions surrounding the locus coeruleus, including the central gray and the dorsal and median raphe nuclei. No significant differences in [3H]Ro41-1049 binding to MAO-A were observed at any level of the locus coeruleus, or raphe nuclei, comparing subjects with major depression to psychiatrically normal control subjects. These findings demonstrate that the pathophysiology of major depression is not likely to involve abnormalities in MAO-A.

Adult↗