Oxidative deamination mechanism

The beneficial effect of deprenyl in Parkinson s disease was su ested to be in part due to its effect on increasing the levels of SOD activity in several brain regions (Carrillo et al., 1993). Deprenyl is known to inhibit monoamine oxidase type B, which results in a reduction in hydrogen peroxide formation by blockade of the oxidative deamination of dopamine. That is believed to be the major mechanism of action of this drug in inhibiting the progression of Parkinson s disease. 

While most alkaloids do not contain aldehydes when they enter mammalian, microbial, or plant tissues, this functional group may become important when formed as a metabolite of alcohols (via alcohol dehydrogenase) or amines (via oxidative dealkylation and oxidative deamination). Aldehyde dehydrogenases catalyze oxidation of aldehydes to the corresponding carboxylic acids. The physical properties, catalytic mechanism, and specificity of this group of enzymes has been reviewed (99). The general reaction catalyzed by aldehyde dehydrogenase is seen in Eq. (9). 

The experiments described above indicated amino acids were oxidatively deaminated in liver and their a-amino groups converted to urea. A start on investigations of the mechanism of urea biosynthesis was made by Schultzen and Nenki (1869) who concluded that amino acids gave rise to cyanate which might combine with ammonia from proteins to produce urea. Von Knieren (1873) demonstrated that when he drank an ammonium chloride solution, or gave it to a dog, there was an increase in the formation of urea, without any rise in urinary ammonia. His results were consistent with the cyanate theory but did not eliminate the possibility that urea arose from ammonium carbonate which could be dehydrated to urea ... 

The process of oxidative deamination is the most important mechanism whereby all monoamines are inactivated (i.e. the catecholamines, 5-HT and the numerous trace amines such as phenylethylamine and tryptamine). Monoamine oxidase occurs in virtually all tissues, where it appears to be bound to the outer mitochondrial membrane. Whereas there are several specific and therapeutically useful monoamine oxidase inhibitors, inhibitors of catechol-O-methyltransferase have found little application. This is mainly due to the fact that at most only 10% of the monoamines released from the nerve terminal are catabolized by this enzyme. The main pathways involved in the catabolism of the catecholamines are shown in Figure 2.16. 

The mechanism of antidepressive action of this series of drugs is likely associated with their inhibition of the oxidizing deamination process of the neurotransmitters norepinephrine, epinephrine, dopamine, and serotonin, which participate in the transmission of nerve excitement in the CNS. A major drawback of these drugs is the high toxicity associated with their inhibition of not only MAO, but also a number of other nonspecific enzymes. 

Several analogous systems which have been previously studied, may be reexamined in view of the mechanism suggested for the copper-catalyzed oxidative deamination. It was reported by Nyilasi that copper and cobalt ions catalyze the... 

We don t observe oxidative deamination in the absence of oxidants. We may boil ethylenediamine with copper indefinitely without any chemical changes taking place. This observation is in addition to the lack of chloride-induced deamination, which conflicts with the hydride transfer mechanism. Moreover, if this mechanism did occur, it would imply a copper-induced exchange of hydrogen between the methylene group and water. 

The reaction mechanism has been further investigated using cr-amino acids (96).8,62 In aqueous ethanol these amine derivatives exist as zwitterions in equilibrium with varying amounts of the uncharged molecules,6Ja which are oxidatively deaminated, via unstable imino acids (98), to stable detectable aldehydes (100). When ethanolic solutions of 2-(2-pyridyl)isatogen (90b) and 96a or 96b are refluxed under nitrogen,... 

Dr. Flaig. The mechanism of the reaction between amino acids and oxidized lignin decomposition products can be described by the scheme of Trautner, which involves oxidative deamination. 

Reactions at the a-carbon atom are affected by the presence of 02. First, by rapidly removing the reducing species, it blocks reductive deamination. This is thought to explain the protective effect of 02 on alanine destruction 26). Secondly, 02 also probably alters the mechanism of oxidative deamination though the products (NH3 and the carbonyl group) are the same 39). 

Flavin-containing mitochondrial MAO-A and MAO-B catalyze the oxidative deamination of neurotransmitters, such as dopamine, serotonin, and norepinephrine in the central nervous system and peripheral tissues. The enzymes share 73% sequence homology and follow the same kinetic and chemical mechanism but have different substrate and inhibitor specificities. Chemical modification experiments provide evidence that a histidine residue is essential for the catalysis. There is also strong evidence that two cysteine residues are present in the active site of MAO. 

Akagawa M, Sasaki T, Suyama K (2002), Oxidative deamination of lysine residue in plasma protein of diabetic rats. Novel mechanism via the Maillard reaction, Eur. J. Biochem. 269 5451-5458. 

K. Suyama, M. Akagawa, and T. Sasaki, Oxidative deamination of lysine residue in plasma protein from diabetic rat a-dicarbonyl-mediated mechanism, in G, 2002, 243-248. 

Capsaicin and capsaicinoids undergo Phase I metabolic bioconversion to catechol metabolites via hydroxylation of the vanillyl ring moiety (Lee and Kumar, 1980 Miller et al, 1983). Metabohsm involves oxidative, in addition to non-oxidative, mechanisms. An example of oxidative conversion involves the liver mixed-function oxidase system to convert capsaicin to an electrophilic epoxide, a reactive metabolite (Olajos, 2004). Surh and Lee (1995) have also demonstrated the formation of a phenoxy radical and quinine product the quinine pathway leads to formation of a highly reactive methyl radical (Reilly et al, 2003). The alkyl side chain of capsaicin also undergoes rapid oxidative deamination (Wehmeyer et al, 1990) or hydroxylation (Surh et al, 1995 Reilly et al, 2003) to hydroxycapsaicin as a detoxification pathway. An example of nonoxidative metabolism of capsaicin is hydrolysis of the acid-amide bond to yield vanillylamide and fatty acyl groups (Kawada et al, 1984 Oi et al, 1992). 

Scheme 11. Mechanism for the formation of metabolite J via oxidative deamination. (Reprinted from reference 131, with permission of the American Society for Pharmacology and Experimental Therapeutics.)...

DAAO is one of the most extensively studied flavoprotein oxidases. The homodimeric enzyme catalyzes the strictly stere-ospecihc oxidative deamination of neutral and hydrophobic D-amino acids to give a-keto acids and ammonia (Fig. 3a). In the reductive half-reaction the D-amino acid substrate is converted to the imino acid product via hydride transfer (21). During the oxidative half-reaction, the imino acid is released and hydrolyzed. Mammalian and yeast DAAO share the same catalytic mechanism, but they differ in kinetic mechanism, catalytic efficiency, substrate specificity, and protein stability. The dimeric structures of the mammalian enzymes show a head-to-head mode of monomer-monomer interaction, which is different from the head-to-tail mode of dimerization observed in Rhodotorula gracilis DAAO (20). Benzoate is a potent competitive inhibitor of mammalian DAAO. Binding of this ligand strengthens the apoenzyme-flavin interaction and increases the conformational stability of the porcine enzyme. 

A reasonable mechanism would be an oxidative deamination following an overall mechanism similar to that in Figure 35.9, with release of ammonia. 

Disposition - It is possible that one mechanism for the disposition of the endogenously produced amine is by diffusion, which could be followed by re-uptake by nerve endings (or by other material in tissues) as has been shown with norepinephrine. But as yet there is no evidence for such a cycle for HT, although, as noted above, brain and its particulate fractions have the capacity for uptake. A main catabolic pathway for HT is oxidative deamination by monoamine oxidase to form 5-hy-droxyindoleacetaldehyde, most of which is converted to 5-hydroxyindole-acetic acid (HIAA) by aldehyde dehydrogenase and NAD S, 56 relatively small portion is reduced to 5-hydroxytryptophol by alcohol dehydrogenase and NADH " Monoamine oxidase, which, like... 

Studies on monoamine inactivation mechanisms in insects have yielded equivocal results with N-acetylation (6-9), oxidative deamination (10,11) and -sulphate or 6-alanyl conjugation (12,13) proposed as possible routes of monoamine catabolism however, the weight of evidence favours N-acetylation as the principal mechanism of monoamine breakdown Sodium-sensitive and sodium-insensitive uptake mechanisms for OA have also been described in the cockroach central nervous system (14). 

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