MAO-catalyzed oxidation

FIGURE 4.34 Postulated mechanisms for MAO-catalyzed oxidation of primary amines, (A) SET (B) HAT mechanism, and (C) polar mechanism. 

A single electron transfer (SET) mechanism involving initial transfer of an electron from the FAD cofactor has been proposed for MAO-catalyzed oxidations [10]. An alternative polar nucleophilic mechanism has also received support [11]. 

In the late 1960s, different types of cyclopropylamines, the A/-substituted cyclopropylamines, were reported [111]. One of the most interesting compounds in the new class was A/-[2-o-chlorophenoxy]-ethyl]-cyclopropylamine (Lilly 51641) (42). This compound noncompetitively inhibited the MAO-catalyzed oxidation of serotonin, tyramine, phenylethylamine, and tryptamine in vitro and increased the serotonin concentration in the whole rat brain in vitro. In structure-activity studies on a series of m- and p-aromatic substituted A/-(phenoxyethyl)cyclopropylamines (43), the degree of inhibition correlated well with a and % values [112]. 

Identification of 74 on incubation of MAO with 69 confirmed the initial formation of the 1-phenylcyclobutylaminium radical. That a variety of cyclopropylamines and cyclobutylamines inactivate MAO and result in ring-opened adducts is consistent with the intermediacy of the aminyl radicals. These results strongly suggest that the MAO-catalyzed oxidation of amines involves one-electron transfer as the first step. 

Silverman s studies on mechanism based MAO inactivation have provided overwhelming support for the role of electron transfer in the MAO catalyzed dealkylation of amines. It must be mentioned however that spectroscopic attempts for detecting the radical ion intermediates have hitherto been unsuccessful. Yasanobu and coworkers could not find EPR spectral evidence for radical intermediates in MAO-catalyzed oxidation of benzylamine [205]. Miller et al. failed to observe the flavin semiquinone or an amine-flavin adduct in rapid-scan-stopped flow spectroscopy [206]. The only time-dependent absorption change observed in this study was the bleaching of the oxidized flavin. Furthermore, no influence of a magnetic field up to 6500 G was observed on the rate of MAO B reduction. The reaction rates of systems with kinetically significant radical pair intermediates are known to be altered... 

Evidence for radical intermediates in the MAO-catalyzed oxidation of amine substrates and inhibitors is supported by the inactivation of MAO by cyclopropyl-... 

Monoamine oxidase (MAO) is a mammalian flavin-containing enzyme that catalyzes oxidation of primary amines. While the neurotransmitter amines are... 

Studies with various subcellular fractions are useful to ascertain which enzyme systems are involved in the metabolism of a chug candidate. In the absence of added cofactors, oxidative reactions such as oxidative deamination that are supported by mitochondria or by Ever microsomes contaminated with mitochondria membranes (as is the case with microsomes prepared from frozen liver samples) are likely catalyzed by monoamine oxidase (MAO), whereas oxidative reactions supported by cytosol are likely catalyzed by aldehyde oxidase and/or xanthine oxidase (a possible role for these enzymes in the metabolism of... 

Destruction of the cubane structure could also however occur via carbanion intermediates. T0 rule out this possibility Silverman et al. studied the MAO-catalyzed reactions of cinnamylamine-2,3-oxide [202]. 

In the course of studies directed towards the development of photoaffinity labels for monoamine oxidase (MAO) isozymes, Shih and colleagues found that 4-fluoro-3-nitrophenyl azide (FNPA) (16) exhibited some interesting properties as an inhibitor of this enzyme [80]. MAO catalyzes the oxidative... 

The relationship of MAO and MPTP has neurobiological relevance beyond MPTP neurotoxicity. Types A and B MAO catalyze the a-carbon oxidative deamination of monoamine neurotransmitters and other aromatic amines. These genetically dissimilar isozymes show differential selectivity for specific substrates and inhibitors (63). Most intraneuro-nal MAO is mitochondrial and type A, and oxidizes primary amines to aldehydes, which are then converted by aldehyde reductases to alcohols or carboxylic acids, including dihy-droxyphenylatic acid (DOPAC) from DA Additional 3-0-methylation yields the majorfmal human metabolite of DA, homovanillic acid (HVA see Fig. 12.4). 

In the MAO-catalyzed reaction, intermediate structure 10 is converted directly to structure 12. As shown in figure 2, the electron acceptor for the cytochrome P450-catalyzed reaction is the perferryl 0X0 species (Fe O), while the electron acceptor for the MAO-catalyzed reaction is the oxidized flavin moiety (FAD). 

Scheme 17. Mechanism for MAO-catalyzed monoamine oxidation proposed by Silverman (95).

MAO catalyzes the oxidative deamination of catecholamines, 5-hydroxytryptamine (serotonin), and other monoamines, both primary such as NE, and secondary such as EP. It is one of several oxidase-type enzymes whose coenzyme is the flavin-adenine-dinucleotide (FAD) covalently bound as a prosthetic group (Fig. 9-3). The isoalloxazine ring system is viewed as the catalytically functional component of the enzyme. In a narrow view N-5 and C-4a is where the redox reaction takes place (i.e., +H+, +le or -H+, -le), although the whole chromophoric N-5-C-4a-C-4-N-3-C-2-N-l region undoubtedly participates. Figure 9-3 is a proposed structure of MAO isolated from pig brain (Salach et al., 1976).4... 

In MAO, the flavin is covalently attached to the enzyme at the S-a-position via an active site cysteine residue. MAO catalyzes the oxidation of several primary, secondary, and tertiary alkyl and arylalkyl amines to the corresponding imines, which are subsequently hydrolyzed nonenzymatically to the corresponding aldehydes or ketones. MAO A and MAO B are 70% identical in sequence but vary in substrate specificity. ... 

Histone modifications, such as phosphorylation, acetylation, and methylation, regulate gene expression. " Histone lysine methylation was considered a static modification, until relatively recently, when histone demethylases were discovered." One such enzyme is ESDI, which belongs to the amine oxidase superfamily. ESDI catalyzes the demethylation of mono- and disubstituted Eys 4 of histone H3" in a reductive halfreaction very similar to those catalyzed by DAAO and MAO by oxidizing the amino group of the methylated lysine to the corresponding imino product, which hydrolyzes nonenzymatically to formaldehyde (Equation (2)). 

Monoamine oxidase (MAO) and diamine oxidase catalyze oxidative deamination of amines to the aldehydes in the presence of oxygen. The aldehyde products can be metabolized further to the corresponding alcohol or acid by aldehyde oxidase or dehydrogenase. 

An enzyme found mainly in nerve tissue and in the liver and lungs, MAO catalyzes the oxidative deamination of various amines, including epinephrine, NE, dopamine, and 5-HT. At least two isoforms of MAO exist,... 

Scheme 2.14 Enzyme-catalyzed oxidative C—C coupling reactions reported by Kroutil. MAO = monoamine oxidase.

Recently, one of the evolved MAO-N variants has been shown to catalyze the enantioselective oxidation of O-methyl-N-hydroxylamines (e.g. 16) yielding the corresponding -oxime (17) and recovered (R)-hydroxylamine (16) in enantiomeri-cally pure form (Figure 5.11) [21]. 

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