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PubMed2002

Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders.

Monoamine oxidase B (MAO B) is a mitochondrial outermembrane flavoenzyme that is a well-known target for antidepressant and neuroprotective drugs. We determined the structure of the human enzyme to 3 A resolution. The enzyme binds to the membrane through a C-terminal transmembrane helix and apolar loops located at various positions in the sequence. The electron density shows that pargyline, an analog of the clinically used MAO B inhibitor, deprenyl, binds covalently to the flavin N5 atom. The active site of MAO B consists of a 420 A(3)-hydrophobic substrate cavity interconnected to an entrance cavity of 290 A(3). The recognition site for the substrate amino group is an aromatic cage formed by Tyr 398 and Tyr 435. The structure provides a framework for probing the catalytic mechanism, understanding the differences between the B- and A-monoamine oxidase isoforms and designing specific inhibitors.

Amino Acid Sequence↗
PubMed2000

Platelet monoamine oxidase activity during surgical intervention under condition of hypothermic perfusion.

Platelet and plasma monoamine oxidase activity was determined at early stages of hypothermic perfusion and circulatory arrest. Monoamine oxidase activity decreased more drastically and restored more slowly against the background of deep (14 degrees C) compared to moderate hypothermia (26-29 degrees C). The decrease in platelet monoamine oxidase activity was accompanied by its increase in the plasma, which attests to mechanical (in tubes) and toxic damage to platelets. The latter is associated with increased partial O(2) pressure in the plasma during hypothermia, which promotes the formation of reactive oxygen species.

Adult↗
PubMed1988

Monoamine oxidase inhibitors and anaesthesia. A review.

There has been a recent renewal of interest in the use of monoamine oxidase inhibitors in psychiatry. The concurrent administration of anaesthetic agents, particularly narcotic analgesics, is often a cause for concern. Although many monoamine oxidase inhibitor-drug interactions have been reported, in practice it is only the interaction with pethidine which has led to fatalities. What is not appreciated is that the monoamine oxidase inhibitor-pethidine interaction has two distinct forms-"excitatory" and "depressive". It is this lack of appreciation that has led to much confusion when dealing with patients taking monoamine oxidase inhibitors.

Anesthesia↗
PubMed1996

The metabolism of tyramine by monoamine oxidase A/B causes oxidative damage to mitochondrial DNA.

Monoamine oxidases A/B (EC 1.4.3.4, MAO), flavoenzymes located on the outer mitochondrial membrane, catalyze the oxidative deamination of biogenic amines, such as dopamine, serotonin, and norepinephrine. In this study, we examined whether the H2O2 formed during the two-electron oxidation of tyramine [4-(2-aminoethyl)phenol] (a substrate for monoamine oxidases A/B) may contribute to the intramitochondrial steady-state concentration of H2O2 ([H2O2]ss) and, thus, be involved in the oxidative impairment of mitochondrial matrix components. Supplementation of intact, coupled rat brain mitochondria with benzylamine, beta-phenylethylamine, or tyramine showed initial rates of H2O2 production ranging from 0.4- to 1.6 nmol H2O2/min/mg protein. ESR analysis of the oxidative deamination of tyramine by intact rat brain mitochondria revealed the formation of hydroxyl (HO.) and carbon-centered radical adducts--the latter probably originating by the (HO.-)-mediated oxidation of mannitol. The signals were substantially enhanced upon addition of FeSO4 and were abolished by catalase. The intramitochondrial [H2O2]ss calculated in terms of glutathione peroxidase activity during the metabolism of tyramine was 48-fold higher (7.71 +/- 0.25 x 10(-7) M) than that obtained during the oxidation of succinate via complex II in the presence of antimycin A (1.64 +/- 0.2 x 10(-8) M). Oxidative damage to the brain mtDNA was assessed by single strand breakage. The ratio of nicked DNA for the preparations treated with tyramine and those without the amine was 1.5 +/- 0.29 (n = 4), 2.12 +/- 0.28 (n = 8, P < or = 0.05), and 3.12 +/- 0.69 (n = 3, P < or = 0.05) at 15, 30, and 60 min, respectively . Preincubation of mitochondria with tranylcypromine (trans-2-phenylcyclopropylamine), an inhibitor to MAO A/B, abolished mtDNA oxidative damage. Catalase inhibited mtDNA strand breakage by approximately 60%. Incubation of intact, coupled rat brain mitochondria with chlorodinitrobenzene (CDNB) depleted mitochondrial GSH by 72%. Tyramine-dependent damage of mtDNA was decreased by 68% in CDNB-treated mitochondria (with 28% remaining GSH). The [H2O2]ss was slightly increased in CDNB-treated mitochondria: 1.38- and 1.28-fold increase during the oxidation of succinate in the presence of antimycin A and during the oxidation of tyramine, respectively. These results suggest that the H2O2 generated during the MAO-catalyzed oxidation of biogenic amines and possibly certain neurotransmitters at the outer mitochondrial membrane contributes to the intramitochondrial [H2O2]ss and may cause oxidative damage to mtDNA. This is effected by the intramitochondrial concentration of GSH and might have potential implications for aging and neurodegenerative processes.

Animals↗
PubMed1979

Monoamine oxidase and catechol-O-methyltransferase activity in hamster and rat insulinomas.

Hamster and rat insulinomas were assayed for norepinephrine, dopamine and serotonin concentration and for monoamine oxidase and catechol-o-ethyltransferase (COMT) activity. The concentration of norepinephrine (mean 0.55 mumol/kg, range less than 0.20 to 2.64 mumol/kg) and serotonin (mean 5.22 mucol/kg, rang less than 0.6 to 26.5 mumol/kg) in hamster insulinomas were comparable to previously reported concentrations. Dopamine conentration (mean 0.34 mumol/kg, range less than 0.20 to 0.95 mumol/kg) was only 2 to 2.5% of that reported previously. Monoamine oxidase activity of the hamster and rat insulinomas were comparable to those of normal hamster islets. In contrast, the COMT activity of both insulinomas was much greater than the COMT activity of normal pancreatic islets of both species and was greater than in several other tissues and tumours. The tumour COMT, which was predominantly in the cytosol, was Mg2+ dependent and had a comparable sensitivity to inhibition by tropolone as purified beef-liver COMT. Hamster insulinoma monoamine oxidase was more sensitive than rat insulinoma monoamine oxidase to inhibition by tranylcypromine and deprenyl, while rat insulinoma monoamine oxidase was more sensitive to inhibition by clorgyline and was more heat labile.

Adenoma, Islet Cell↗
PubMed1989

Oxygenation of mitochondrial membranes by the reticulocyte lipoxygenase. Action on monoamine oxidase activities A and B.

Incubation of isolated rat liver mitochondria with the pure rabbit reticulocyte lipoxygenase caused a time-dependent inactivation of the monoamine oxidase activities A and B. Furthermore, a conversion of the monoamine oxidase into a diamine oxidase was observed. The inactivation kinetics for both monoamine oxidase activities A and B showed a biphasic behaviour; a reversible short-term inhibition during the first 5 min of incubation was followed by an irreversible inactivation of the enzyme. The kinetic studies suggest that the slow irreversible inactivation of the monoamine oxidase activities is due to secondary reactions subsequent to the initial attack of the lipoxygenase on the mitochondrial outer membrane. During the interaction of the lipoxygenase with the mitochondria, only about 1.5% of the polyenoic fatty acids present in the mitochondrial membranes were oxygenated. The predominant products formed during the interaction of the lipoxygenase with the mitochondrial membranes are (13S)-hydro(pero)xy-9Z,11E-octadecadienoic acid and (15S)-hydro(pero)xy-5,8,11,13(Z,Z,Z,E)-eicosatetraenoic acid.

Animals↗
PubMedDate not supplied

[Cytosol monoamine oxidase in the rat liver].

Cytosolic and particulate monoamine oxidases have been isolated. Cytosolic preparation was free from mitochondrial and microsomal contaminations and also ribosome-bound MAO molecules. Cytosolic MAO had higher affinity for phenylethylamine and exhibited higher sensitivity to acetylenic inhibitors than the mitochondrial enzyme.

Animals↗
PubMed2002

In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations.

This study was conducted to identify enzyme systems eventually catalysing a local cerebral metabolism of citalopram, a widely used antidepressant of the selective serotonin reuptake inhibitor type. The metabolism of citalopram, of its enantiomers and demethylated metabolites was investigated in rat brain microsomes and in rat and human brain mitochondria. No cytochrome P-450 mediated transformation was observed in rat brain. By analysing H2O2 formation, monoamine oxidase A activity in rat brain mitochondria could be measured. In rat whole brain and in human frontal cortex, putamen, cerebellum and white matter of five brains monoamine oxidase activity was determined by the stereoselective measurement of the production of citalopram propionate. All substrates were metabolised by both forms of MAO, except in rat brain, where monoamine oxidase B activity could not be detected. Apparent Km and Vmax of S-citalopram biotransformation in human frontal cortex by monoamine oxidase B were found to be 266 microM and 6.0 pmol min(-1) mg(-1) protein and by monoamine oxidase A 856 microM and 6.4 pmol min(-1) mg(-1) protein, respectively. These Km values are in the same range as those for serotonin and dopamine metabolism by monoamine oxidases. Thus, the biotransformation of citalopram in the rat and human brain occurs mainly through monoamine oxidases and not, as in the liver, through cytochrome P-450.

Animals↗
PubMed2002

Hydrogen peroxide production by monoamine oxidase during ischemia/reperfusion.

Reactive oxygen species have been postulated to play a crucial role in the pathogenesis of renal ischemia-reperfusion injury. However, the intracellular sources of reactive oxygen species during ischemia-reperfusion are still unclear. In the present study, we examined whether catecholamine-degrading enzymes monoamine oxidases contribute to hydrogen peroxide (H(2)O(2)) generation during ischemia-reperfusion using an in vivo rat model of unilateral renal ischemia. The monoamine oxidases were characterized in homogenates of renal cortex by enzyme assay and by Western blot analysis. The monoamine oxidase-dependent H(2)O(2) production was measured by luminol-amplified chemiluminescence assay. Renal monoamine oxidase activity and H(2)O(2) generation by monoamine oxidases were suppressed during ischemia. The monoamine oxidase-dependent H(2)O(2) production was observed during the first 15 min of reperfusion. In addition, enzyme assays showed that monoamine oxidase is also activated in this period. Rat pre-treatment with the irreversible inhibitor of monoamine oxidase, pargyline, prevented H(2)O(2) production. These data suggest that monoamine oxidases are a potential source of H(2)O(2) generation in the early reperfusion following ischemia, which could be involved in renal ischemia-reperfusion injury.

Animals↗
PubMed1990

Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its primary oxidation product, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), are mechanism-based inhibitors of monoamine oxidases A and B. The pseudo-first-order rate constants for inactivation were determined for various analogues of MPTP and MPDP+ and the concentrations in all redox states were measured throughout the reaction. Disproportionation was observed for all the dihydropyridiniums, but non-enzymic oxidation was insignificant. The dihydropyridiniums were poor substrates for monoamine oxidase A and, consequently, inactivated the enzyme only slowly, despite partition coefficients lower than those for the tetrahydropyridines. For monoamine oxidase B, the dihydropyridiniums were more effective inactivators than the tetrahydropyridines. Substitutions in the aromatic ring had no major effect on the inactivation of monoamine oxidase B, but the 2'-ethyl- and 3'-chloro-substituted compounds were very poor mechanism-based inactivators of monoamine oxidase A. It is clear that both oxidation steps can generate the reactive species responsible for inactivation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1982

The nature of the inhibition of rat liver monoamine oxidase types A and B by the acetylenic inhibitors clorgyline, l-deprenyl and pargyline.

The kinetics of inhibition of rat liver mitochondrial monoamine oxidase by clorgyline, l-deprenyl and pargyline are consistent with a mechanism whereby a reversible interaction between the inhibitor and the enzyme active site under conditions of thermodynamic equilibrium is followed by a time-dependent formation of the covalently-bound enzyme-inhibitor adduct. The Ki value for the reversible interaction between clorgyline and monoamine oxidase A is about 1000 times lower than that towards the B-form of the enzyme, and this difference is sufficient to account for most, but not all, of the selectivity of the inhibition caused by this compound. The Ki value of the monoamine oxidase B selective inhibitor l-deprenyl towards that form of the enzyme is only about 40-fold lower than that towards the A-form. However, in this case, the rate of formation of the irreversible adduct is considerably faster for the B-form than for the A-form and this makes a major contribution to the selectivity of this compound. Pargyline shows a Ki value towards monoamine oxidase B that is only 8 times lower than that towards the A-form and in this case the rates of formation of the enzyme-inhibitor adducts are similar. The significance of these results are discussed in terms of the selective inhibition of monoamine oxidase.

Animals↗
PubMed2003

Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures.

Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound enzyme that catalyzes the oxidative deamination of arylalkylamine neurotransmitters and has been a target for a number of clinically used drug inhibitors. The 1.7-A structure of the reversible isatin-MAO-B complex has been determined; it forms a basis for the interpretation of the enzyme's structure when bound to either reversible or irreversible inhibitors. 1,4-Diphenyl-2-butene is found to be a reversible MAO-B inhibitor, which occupies both the entrance and substrate cavity space in the enzyme. Comparison of these two structures identifies Ile-199 as a "gate" between the two cavities. Rotation of the side chain allows for either separation or fusion of the two cavities. Inhibition of the enzyme with N-(2-aminoethyl)-p-chlorobenzamide results in the formation of a covalent N(5) flavin adduct with the phenyl ring of the inhibitor occupying a position in the catalytic site overlapping that of isatin. Inhibition of MAO-B with the clinically used trans-2-phenylcyclopropylamine results in the formation of a covalent C(4a) flavin adduct with an opened cyclopropyl ring and the phenyl ring in a parallel orientation to the flavin. The peptide bond between the flavin-substituted Cys-397 and Tyr-398 is in a cis conformation, which allows the proper orientation of the phenolic ring of Tyr-398 in the active site. The flavin ring exists in a twisted nonplanar conformation, which is observed in the oxidized form as well as in both the N(5) and the C(4a) adducts. An immobile water molecule is H-bonded to Lys-296 and to the N(5) of the flavin as observed in other flavin-dependent amine oxidases. The active site cavities are highly apolar; however, hydrophilic areas exist near the flavin and direct the amine moiety of the substrate for binding and catalysis. Small conformational changes are observed on comparison of the different inhibitor-enzyme complexes. Future MAO-B drug design will need to consider "induced fit" contributions as an element in ligand-enzyme interactions.

Catalytic Domain↗
PubMed1983

The activity of monoamine oxidase -A and -B in brains from chronic alcoholics.

The activity of monoamine oxidase--A was found to be lower in homogenates of hypothalamus and caudate nucleus, but not in cortex of the gyrus cinguli and hippocampus, from chronic alcoholics with respect to homogenates from autopsy cases without histories of alcohol abuse. The activity of monoamine oxidase--B was also lower in the alcoholics, but this could be due to the selective effect of age upon this enzyme form, since the alcoholics were younger than controls. No difference was found for either monoamine oxidase -A or -B activities in brain homogenates from an alcohol preferring (AA) strain of rats, with respect to those from a water preferring (ANA) strain.

Aged↗
PubMed2006

Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches.

A new series of 3-, 4-, 7-polysubstituted coumarins have been designed and evaluated for their monoamine oxidase A and monoamine oxidase B (MAO-A and MAO-B) inhibitory potency. Substituents at position 7 consisted of a bridge of different physicochemical nature linking a phenyl ring to the coumarin scaffold. Structure-affinity and structure-selectivity relationships, derived through CoMFA-GOLPE and docking studies, revealed the key physicochemical interactions responsible for the observed MAO-B and MAO-A inhibitory potency and suggested the main structural determinants for high selectivity toward one of the two enzymatic isoforms. The predictive power of our models was proved with the design of a new inhibitor demonstrating an outstanding MAO-B affinity (pIC50 = 8.29) and the highest MAO-B selectivity (DeltapIC50 = 3.39) within the entire series of ligands examined herein.

Animals↗
PubMed1995

Pharmacology of reversible and selective inhibitors of monoamine oxidase type A.

The concept of reversible type A monoamine oxidase (MAO-A) inhibitors as effective antidepressant drugs with a minimal side effect profile has been vindicated in practice. Despite this, the pharmacological basis for their actions is unclear. Studies with the irreversible inhibitor clorgyline have shown that chronic but not acute treatment of rats leads to a significant enhancement of noradrenaline release from peripheral sympathetic nerves and cerebral cortex together with a more effective inhibition of MAO-A, as shown by reduction in levels of deaminated metabolites in cortical microdialysis fluid. Reversible inhibitors, however, do not have a cumulative effect on MAO inhibition and may have different effects on noradrenaline release. Reversible inhibitors did not produce the acute reduction in sympathetic nerve activity seen with clorgyline, which may be one factor in explaining their milder side effect profile. Other aspects of the pharmacology of reversible and irreversible selective inhibitors of MAO-A are reviewed.

Animals↗
PubMed1999

Some peculiar aspects of monoamine oxidase inhibition.

CN- ions enhance the inhibition of monoamine oxidase by the hydrazine derivatives, phenelzine [2-phenylethylhydrazine] and pheniprazine [(1-methyl-2-phenylethyl)hydrazine]. This involves partial competitive activation of the initial noncovalent enzyme-inhibitor complex with no significant effect on the subsequent reaction to give the irreversibly inhibited species. Whereas the maximum effects on pheniprazine inhibition of rat liver MAO-B occurred at about 5 microM cyanide, concentrations of 5 mM were necessary for maximum stimulation of MAO-A inhibition. A comparison of the behaviour of rat and ox MAO revealed considerable differences in their sensitivities to pheniprazine and the potentiating effects of cyanide. Species differences were also evident in the interactions derivatives of milacemide [2-n-pentylaminoacetamide] as substrates and mechanism-based inhibitors of MAO-B. In one case there was evidence for apparently large difference in inhibitor sensitivities between human brain MAO-B from different individuals.

Animals↗
PubMed1983

Neurochemical insights into monoamine oxidase inhibitors, with special reference to deprenyl (selegiline).

Monoamine oxidase (MAO) is distributed in neurons and non-neuronal tissue in the human central nervous system. It occurs there as MAO type A and MAO type B. It is not, however, established where both types are located intra- and/or extra-neuronally. Recently, the use of selective MAO-B blockers has shown beneficial effects in the treatment of Parkinson's disease (PD). Knowledge about the locus of action of MAO inhibitors is therefore of great importance. Our findings indicate that MAO-B inhibitors like deprenyl act by blocking neuronal and extra-neuronal MAO-B. This demonstrates that in the early stages of PD the action of deprenyl improves dopamine neurotransmission and hormonal action, whereas in the advanced stages of the disease, when there is progressive loss of dopaminergic neurons accompanied by gliosis, the drug seems to exert beneficial effects via the hormonal route.

Aged↗