Monoamine-diamine oxidases

Metabolism. MetaboHsm of histamine occurs via two principal enzymatic pathways (Fig. 1). Most (50 to 70%) histamine is metabolized to /V-methylhistamine by A/-methyltransferase, and some is metabolized further by monoamine oxidase to /V-methy1imidazo1eacetic acid and excreted in the urine. The remaining 30 to 40% of histamine is metabolized to imidazoleacetic acid by diamine oxidase, also called histaminase. Only 2 to 3% of histamine is excreted unchanged in the urine. 

Biosynthesis is performed in one step by the enzyme L-histidine decarboxylase (HDC, E.C. 4.1.1.22). Histamine metabolism occurs mainly by two pathways. Oxidation is carried out by diamine oxidase (DAO, E.C. 1.4.3.6), leading to imidazole acetic acid (IAA), whereas methyla-tion is effected by histamine N-methyltransferase (HMT, E.C. 2.1.1.8), producing fe/e-methylhistamine (t-MH). IAA can exist as a riboside or ribotide conjugate. t-MH is further metabolized by monoamine oxidase (MAO)-B, producing fe/e-methylimidazole acetic acid (t-MIAA). Note that histamine is a substrate for DAO but not for MAO. Aldehyde intermediates, formed by the oxidation of both histamine and t-MH, are thought to be quickly oxidized to acids under normal circumstances. In the vertebrate CNS, histamine is almost exclusively methylated... 

FIGURE 14-3 Synthesis and metabolism of histamine. Solid lines indicate the pathways for histamine formation and catabolism in brain. Dashed lines show additional pathways that can occur outside the nervous system. HDC, histidine decarboxylase HMT, histamine methyltransferase DAO, diamine oxidase MAO, monoamine oxidase. Aldehyde intermediates, shown in brackets, have been hypothesized but not isolated. 

Let us for a moment consider the enzymes responsible for oxidation, the oxidases. Some are very specific as to the type of substrate which they will oxidize others are relatively nonspecific, such as the mixed function oxidases while some have a limited functional specificity such as monoamine oxidase, diamine oxidase and xanthine oxidase. Notice that the specific name for each enzyme will related in some way to its substrate. 

Amine oxidation. As well as the microsomal enzymes involved in the oxidation of amines, there are a number of other amine oxidase enzymes, which have a different subcellular distribution. The most important are the monoamine oxidases and the diamine oxidases. The monoamine oxidases are located in the mitochondria within the cell and are found in the liver and also other organs such as the heart and central nervous system and in vascular tissue. They are a group of flavoprotein enzymes with overlapping substrate specificities. Although primarily of importance in the metabolism of endogenous compounds such as 5-hydroxy try pt-amine, they may be involved in the metabolism of foreign compounds. 

Diamine Oxidases. Diamine oxidases are enzymes that also oxidize amines to aldehydes. The preferred substates are aliphatic diamines in which the chain length is four (putrescine) or five (cadaverine) carbon atoms. Diamines with carbon chains longer than nine will not serve as substrates but can be oxidized by monoamine oxidases. Secondary and tertiary amines are not metabolized. Diamine oxidases are typically soluble pyridoxal phosphate-containing proteins that also contain copper. They have been found in a number of tissues, including liver, intestine, kidney, and placenta. 

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). 

The standard reaction mixture contained 0.1 M glycine (pH 9.5), 5 mM dithiothreitol, 250 fiM TV1 -acetylspermidine, and 250 to 400 fig of protein in a final volume of 250 fiL. The reaction mixtures also contained 0.56 mM aminoguanidine and 0.04 mM pargyline to inhibit diamine oxidase and monoamine oxidase, respectively. The reaction was initiated by adding enzyme and stopped by the addition of 50 fiL of 50% trichloroacetic acid. After filtration, 25 to 100 fiL aliquots were injected. The reaction was linear with time and protein up to 60 to 500 fig of protein. 

Amine concentrations can be determined by using either diamine oxidase or monoamine oxidase in which the amine is oxidized to an aldehyde, hydrogen peroxide, and ammonia with uptake of oxygen (Equation 17). 

Butylamines are well absorbed from the gut and respiratory tract. Butylamines are expected to be readily metabolized, and the metabolic pathway is similar to that of other lower amines. Amines may be metabolized by monoamine oxidase and diamine oxidase (histaminase). 

DIAMINE OXIDASE INHIBITORS act on the non-selective enzyme diamine oxidase (histaminase), which has as substrate such diverse substances as histamine, cadaverine and putrescine. As with the monoamine-oxidase enzyme, an intermediate complex is formed to yield the aldehyde, and this is then oxidized. The enzyme has been studied in relation to histamine metabolism, and is found to be released in certain circumstances from eosinophils and other tissues, and can be used as a marker in thyroid and ovarian carcinoma. Blood levels are raised in pregnancy, and heparin raises these levels. Amounts of the enzyme are high in the intestinal mucosa, liver and kidney of most species, A preparation of the enzyme itself (Torantil ) was once available for use in therapeutics for conditions in which a deficiency of histamine was implicated. 

The FAD-requiring enzymes in mammalian systems include the D- and L-amino acid oxidases, mono- and diamine oxidases, glucose oxidase, succinate dehydrogenase, a-glycerophosphate dehydrogenase, and glutathione reductase. FMN is a cofactor for renal L-amino acid oxidase, NADH reductase, and a-hydroxy acid oxidase. In succinate dehydrogenase, FAD is linked to a histidyl residue in liver mitochondrial monoamine oxidase, to a cysteinyl residue. In other cases, the attachment is nonco-valent but the dissociation constant is very low. 

In the presence of suitable nucleophiles (such as benzoyl acetic acid) the primary imines can be spontaneously further modified in situ. A convenient approach to obtain phenacyl-derivatives, building blocks in the synthesis of certain alkaloids, was reported 38. In some cases, diamine oxidases exhibit activities complementary to monoamine oxidases. For example vanillylamine is far more efficiently converted into vanillin by a diamine oxidase from Aspergillus niger than by the monoamine oxidase from E. coIi[1 L... 

Hui, J. Y., and Taylor, S. L. (1985). Inhibition of in vivo histamine metabolism in rats by foodborne and pharmacologic inhibitors of diamine oxidase, histamine iV-methyltransfer-ase and monoamine oxidase. Toxicol. Appl. Pharmacol. 81, 241-249. 

Histamine is formed from the amino acid histidine and is stored in high concentrations in vesicles in mast cells. Histamine is metabolized by the enzymes monoamine oxidase and diamine oxidase. Excess production of histamine in the body (by. for example, systemic mastocytosis) can be detected by measurement of imidazoleacetic acid (its major metabolite) in tbe urine. Because it is released from mast cells in response to IgE-mediated (immediate) allergic reactions, this autacoid plays an important pathophysiologic role in seasonal rhinitis (hay fever), urticaria, and angioneurotic e ma. Histamine also plays an important physiologic role in the control of acid secretion in the stomach and as a neurotransmitter. 

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. 

Once released, histamine is rapidly metabolized in vivo (based on products from radiolabeled histamine administered intradermally) to nearly inactive metabolites by two major pathways N-methylation, and oxidation (Fig. 37.3). Methylation (S-adenosylmethionine), which is catalyzed by the intracellular enzyme N-methyltransferase, yields an inactive metabolite. A portion of the N-methylated metabolite is oxidized sequentially via monoamine oxidase and then via aldehyde oxidase to the corresponding N-methylimidazole acetic acid. Histamine also is oxidized to imidazole acetic acid by diamine oxidase (histaminase). A small amount of this acid intermediate is converted to the corresponding ribotide, an unusual metabolite (5). 

Primary amines often are converted to the corresponding aldehydes by oxidation (Fig. 27.4). These aldehydes then may participate in additional reactions such as the formation of Schiff bases. The enzymes that catalyze these reactions are known as monoamine oxidases and diamine oxidases. Monoamine oxidases act on monoamines, whereas diamine... 

Fig. 27.4. Phenylalanine ammonia lyase and tyrosine ammonia lyase monoamine and diamine oxidases (Geissman and Grout, 1969).

Monoamine oxidase Diamine oxidase Epoxide Hydratase... 

Acetylcholine is formed from choline (which is also an important constituent of phospholipids) and acetyl CoA under the catalytic influence of choline acetyl-ase. It is hydrolised by acetylcholinesterase or choline esterase. Two important steps in the formation of noradrenaline from tyr dopa decarboxylase and dopamine hydroxylase. Adrenaline is formed from noradrenaline by phenyl ethanolamine A -methyltransferase. Both noradrenaline and adrenaline are metabolised by catechol 0-methyl transferase or monoamine oxidase. Some later steps in their metabolism involve aldehyde dehydrogenase and alcohol dehydrogenase (aldehyde reductase), After hydroxylation to its 5-hydroxy derivative, tryptophan is converted by 5-hydroxytryptophan decarboxylase to 5-hydroxytryptamine (serotonin). The major routes of serotonin metabolism involve either monoamine oxidase or hydroxyindole 0-methyltransferase. Histamine is synthesised from histidine by histidine decarboxylase, and is metabolised by either diamine oxidase or histamine Af-methyltransferase. Gamma aminobutyric acid is formed by glutamate decarboxylase and metabolised by... 

Beta-glucuronidase Aryl acylamidase Monoamine oxidase Diamine oxidase Azobenzene reductase Nitro reductase... 

Enzymes catalysing reductions are also found in liver microsomes, e.g. azo-benzene reductase and nitroreductase. Oxidation reactions, which are not due to cytochrome P-450 are catalysed by hexahydrobenzoate dehydrogenase, alcohol dehydrogenase, aldehyde dehydrogenase, xanthine oxidase, and aldehyde oxidase. Several amines are oxidised by monoamine oxidase or diamine oxidase. 

The oxidative deamination of histamine, in the course of which imidazol-acetic acid is formed, is catalysed by diamine-oxidase and also by monoamine-oxidase. By means of a specific histamine-A -methyltransferase, histamine is transformed into 1,4-methylhistamine, which is further... 

The animal diamine oxidase is inhibited by cyanide and other carbonyl reagents. In contrast to liver monoamine oxidase, diamine oxidase is not sensitive to p-chloromercuribenzoate or other SH reagents. Iso-nicotinoyl hydrazide is a potent inhibitor of diamine oxidase. The chemical basis for the inhibitions are not known. It has been suggested that the bacterial enzymes contain flavins, but there is no evidence for any cofactors in the animal enzymes. Again in contrast to monoamine oxidase, diamine oxidase is inhibited by excess substrate. This is interpreted as showing combination of the enzyme with separate substrate molecules at the two adsorbing sites in this situation there is no effective reaction, as the catalysis appears to require combination of the substrate at two points. 

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