Monoamine oxidase -catalyzed oxidation

Using structures, write the reaction for the monoamine oxidase-catalyzed oxidation of benzylamine. 

Monoamine oxidases catalyze oxidative deamination of many primary, secondary, and tertiary amines. They have a wide tissue distribution including brain, liver, and intestine. A variety of endogenous amines, such as catecholamines, and pharmacological substances are metabolized. The products of primary amines are the corresponding aldehydes, ammonia, and hydrogen peroxide. 

Molecular Field Analysis (CoMFA) and Catalyst. An early metabolic study using CoMFA involved the monoamine oxidase-catalyzed oxidation of MPTP analogs (185). A more recent study using the Catalyst algorithm described the pharmacophoric features characteristic of CYP2B6 substrates (186), a simplified representation ofwhich is given in Fig. 13.36. Pharmacophoric features of inhibitors have also been obtained for a number of CYP enzymes using 3D-QSAR methods (187-189). 

Monoamine oxidase is also susceptible to inactivation by olefins such as ally-lamine. An isotope effect of 2.3S on inactivation by [l- Halallylamine and formation of a reduced flavin spectrum are consistent with monoamine oxidase-catalyzed oxidation of the compound (Rando and Eigner, 1977). Because the... 

Peterson LA, Caldera PS, Trevor A, et al. Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP", the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). J Med Chem 1985 28 1432-1436. 

Scheme 18.9 Monoamine oxidase-catalyzed oxidation of amines coupled with catalase disproportionation of hydrogen peroxide to form Oj and water.

Monoamine oxidase catalyzes the deamination of primary amines and some secondary amines, with some notable exceptions. Aromatic amines with unsubstituted a-carbon atoms are preferred, but aromatic substituents influence the binding of these substrates. For example, m-iodobenzylamine is a good substrate, whereas the o-iodo analog is an inhibitor. The mechanism of deamination is as follows hydrolysis of the Schiff base that results from loss of a hydride ion on an a-proton yields an aldehyde, which is then normally oxidized to the carboxylic acid. Aromatic substrates are probably preferred because they can form a charge-transfer complex with the FAD at the active site, properly... 

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. 

Recently Turner and coworkers have sought to extend the deracemization method beyond a-amino acids to encompass chiral amines. Chiral amines are increasingly important building blocks for pharmaceutical compounds that are either in clinical development or currently licensed for use as drugs (Figure 5.7). At the outset of this work, it was known that type II monoamine oxidases were able to catalyze the oxidation of simple amines to imines in an analogous fashion to amino acid oxidases. However, monoamine oxidases generally possess narrow substrate specificity and moreover have been only documented to catalyze the oxidation of simple, nonchiral... 

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

Mabic S, Castagnoli N, Jr. Assessment of structural requirements for the monoamine oxidase-B-catalyzed oxidation of l,4-disubstituted-l,2,3,6-tetrahydropyridine derivatives related to the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. J Med Chem 1996 39( 19) 3694—... 

The reactions presented here must not be confused with oxidative reactions that increase bond order and are catalyzed by oxidoreductases, as discussed elsewhere. Examples of the latter reactions include the cytochrome P450 mediated oxidation of testosterone to 6,7-dehydrotestosterone, and the oxidation of l,2,3,6-tetrahydro-l-methyl-4-phenylpyridine to 2,3-dihydro-1-methy 1-4-phenylpyridinium catalyzed by monoamine oxidase (Chapt. 4 and 9 in [50]). 

This group of enzymes catalyzes the oxidation of amines. Amine oxidase [EC 1.4.3.4], a flavin-containing enzyme (also known as monoamine oxidase, tyramine oxidase, tyraminase, or adrenalin oxidase) catalyzes the reaction of an organic amine R—CH2—NH2) with dioxygen... 

Amine oxidases catalyze the oxidative deamination of both xenobiotic and biogenic amines, and thus have many critical biological functions. Two distinct classes differ in the nature of their prosthetic groups [1]. The flavin-(FAD flavin adenine dinucleotide)-dependent amine oxidases include monoamine oxidases (MAO A and B) and polyamine oxidases. Amine oxidases not containing FAD, the so-called semicarbazide-sensitive amine oxidases (SSAO), include both plasma amine oxidases and tissue amine oxidases. These contain quinonoid structures as redox cofactors that are derived from posttranslationally modified tyrosine or tryptophan side chains, topaoquinone frequently playing this role [2]. 

Deamination. Amine groups can be removed oxidatively via a deamination reaction, which may be catalyzed by cytochromes P-450. Other enzymes, such as monoamine oxidases, may also be involved in deamination reactions (see below). The product of deamination of a primary amine is the corresponding ketone. For example, amphetamine is metabolized in the rabbit to phenylacetone (Fig. 4.27). The mechanism probably involves oxidation of the carbon atom to yield a carbinolamine, which can rearrange to the ketone with loss of ammonia. Alternatively, the reaction may proceed via phenylacetoneoxime, which has been isolated as a metabolite and for which there are several possible routes of formation. The phenylacetoneoxime is hydrolyzed to phenylacetone. Also N-hydroxylation of amphetamine may take place and give rise to phenylacetone as a metabolite. This illustrates that there may be several routes to a particular metabolite. 

Degradation of catecholamines The catecholamines are inacti vated by oxidative deamination catalyzed by monoamine oxidase (MAO), and by O-methylation carried out by catechol-O-methyl-transferase (COMT, Figure 21.15). The two reactions can occur in either order. The aldehyde products of the MAO reaction are axi dized to the corresponding acids. The metabolic products of these reactions are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine. 

Monoamine oxidase (MAO) serves as a marker enzyme for outer membrane. There is some MAO activity in the inner membrane and therefore also in SMPs however, a high level of monoamine oxidase in the SMP preparation indicates a large contamination by outer membrane. Mitochondrial monoamine oxidase is an FAD-dependent enzyme that catalyzes the oxidation of amines to aldehydes (Equation E10.2). A convenient assay for this enzyme uses benzylamine as substrate and monitors the rate of ben-zaldehyde production at 250 nm. 

Amine oxidases catalyze the oxidation of amines, diamines, and polyamines. According to their ability to recognize one of those substrates preferentially, amine oxidases may be divided into monoamine oxidases, diamine oxidases, and polyamine oxidases, respectively. Several different enzymes fall into the amine oxidase class, and the classification of some of them still remains ambiguous. The term monoamine oxidase (flavin-containing, EC 1.4.3.4) was introduced to contrast with copper-containing amine oxidases (EC 1.4.3.6). 

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... 

Superoxide is also a product of various enzyme reactions catalyzed by the flavin oxidases (e.g., xanthine oxidase and monoamine oxidase). In addition, 07 is a product of the noncatalytic oxidation of oxyhemoglobin, of which about 3% is converted each day to methemoglobin. Moreover, 02 is readily formed in phagocytic cells (i.e., neutrophils and monocytes) during the respiratory burst. Furthermore, in addition to the Fenton reaction, the Haber-Weiss reaction results in the conversion of 02 to the potent HO via the following reactions (H3) ... 

Monoamine oxidases (MAO-A and MAO-B) are mitochondrial enzymes that oxidatively deaminate endogenous biogenic amine neurotransmitters such as dopamine, serotonin, norepinephrine, and epinephrine. MAOs are like EMOs in that they catalyze the oxidation of drugs to produce drug metabolites that are identical in chemical structures to those formed by CYPs. Because the resulting structures are... 

Electron-transfer reactions of amines are of significant importance in biochemical systems. Enzymes known to catalyze the oxidative dealkylation of amines include monoamine oxidase [16, 17], cytochrome-P450 [18, 184-186], horseradish peroxidase [187], hemoproteins [188, 189], and chloroperoxidase [187, 188]. N-dealkylation of amines by peroxidases are generally accepted to occur via one-electron transfer, whereas the role of electron transfer in reactions catalyzed by enzymes such as monoamine oxidase [16, 17] and cytochrome P-450 [18, 184, 185] is currently a topic of debate. 

Monoamine oxidase, which exists in two distinct forms, referred to as MAO A and MAO B, is one of the enzymes responsible for the degradation of biologically important amines. Compounds that block the catalytic action of MAO A, which is selective for the degradation of norepinephrine and serotinin, have antidepressant effects whereas compounds that inhibit MAO B, which degrades dopamine in the brain, are useful for treating Parkinson s disease [190, 191]. Both MAO A and MAO B contain flavin co-enzyme attached at the 8-a-position to an enzyme-active cysteine residue (54). A one-electron transfer mechanism (Scheme 15) for the oxidations catalyzed by MAO was first proposed by Silverman [192] and Krantz [193,194]. 

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... 

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