Enzymes diamine oxidase

An alternative pathway of histamine metabolism involves oxidative deamination by the enzyme diamine oxidase (histaminase) to form 5-imidazoleacetic acid. Diamine oxidase is present in both tissues and blood and plays a particular role in metabolizing the large concentrations of histamine that may be present in food. An additional metabolite, A-acetyl histamine (a conjugate of acetic acid and histamine), can be produced if histamine is ingested orally. This product may result from metabolism of histamine by gastrointestinal tract bacteria. Because of its rapid breakdown after oral administration, histamine produces few systemic effects when given by this route. 

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. 

Lerke et al (1983) developed a rapid screening method to detect histamine in fish. The qualitative procedure uses a two-step sequential enzyme system. In the first step, the enzyme diamine oxidase catalyzes the breakdown of histamine with production of hydrogen peroxide. Detection of hydrogen peroxide is then performed by the formation of crystal violet from the leuco base in the presence of peroxidase at 596 nm. The method could be used to detect histamine in raw or heat-processed fish. Later, Lopez-Sabater et al (1993) modified the procedure to achieve histamine quantification. Further modification of the Lerke method by Rodriguez-... 

In a different approach, three enzyme-based amperometric biosensors for biogenic amines were apphed for meat spoilage monitoring.The enzyme diamine oxidase (EC 1.4.3.6) was used to mmiitor the total biogenic amine content (cadav-erine, histamine, tyramine, hyptamine, phenylethylamine and spermidine) while Monoamine oxidase A (EC 1.4.3.4) was used for determination of tyramine. 

Histamine is synthesized from the amino acid histidine via the action of the specific enzyme histidine decarboxylase and can be metabolized by histamine-TV-methyl transferase or diamine oxidase. Interesting, in its role as a neurotransmitter the actions of histamine are terminated by metabolism rather than re-uptake into the pre-synaptic nerve terminals. 

Hydrogen peroxide is present in normal aqueous (approximately 30 /imol/1) whilst mean concentrations of around 70 tmol/l have been reported in aqueous from patients with cataracts, supporting a role for oxidative damage in the formation of cataracts (Spector and Garner, 1981). Diamine oxidase is one of the few enzymes to have been detected in bovine aqueous humour (albeit in trace quantities). It has been su ested that the hydrogen peroxide present in aqueous may be the product of the oxidative deamination of diamine substrates. This hypothesis is still unproven, since diamine oxidase substrates have not been identified in aqueous humour. 

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... 

Nau WM, Ghale G, Hennig A et al (2009) Substrate-selective supramolecular tandem assays monitoring enzyme inhibition of arginase and diamine oxidase by fluorescent dye displacement from calixarene and cucurbituril macrocycles. J Am Chem Soc 131 11558-11570... 

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 oxidase, a soluble enzyme found in liver and other tissues, is mainly involved in the metabolism of endogenous compounds such as the aliphatic diamine putrescine (chap. 7, Fig. 40). 

Diamine oxidase (DAO) activity could be determined by first reacting cadaverine with an enzyme to produce A1-piperidine, which then was reacted with 2-aminobenzaldehyde and finally chromium(VI) oxide to form 6,7,8,9-tetrahydro-ll//-pyrido[2,l-b]quinazolin-ll-one (7). The latter was determined on an HPLC apparatus (Scheme 5) (84MI4). 

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 crude enzyme preparation was found to catalyse the conversion of cadaverine (16) mainly into 17-oxosparteine (27) in the presence of pyruvic acid. The pyruvic acid served as a receptor for the amino-groups of (16) in a transamination reaction, having manifestly a close relationship to alkaloid formation.11 Diamine oxidase activity might have been expected to account for the... 

A -Piperideine (17) has been shown to be a precursor of quinolizidine alkaloids in whole plants (cf. Vol. 8, p. 3). However, neither it nor its self-condensation products could be detected as products in the enzymic reaction. [This conclusion is not completely unambiguous, albeit reasonably safe, because the products of the reaction of diamine oxidase, the first of which is (17), were simply compared with those of the alkaloid synthase reaction by g.l.c., and the products of the two reactions were found to be different].11 It seems likely at this stage that (17) is not normally implicated in quinolizidine biosynthesis but can be substituted for an enzyme-generated intermediate via its open form (32) (see Scheme 5). Since no intermediates earlier than (27) could be detected, it is suggested that biosynthesis in vitro and in vivo proceeds by a series of enzyme-linked intermediates (see Scheme 5), none of which is desorbed from the enzyme or enzyme-complex until (27) is liberated. However, in some plants, biosynthesis must stop with the liberation of a compound (31), having the lupinine skeleton... 

Quinolizidine Alkaloids.—Important new information (cf. Vol. 11, p. 4) has been obtained on the biosynthesis of quinolizidine alkaloids such as lupanine (27) in experiments with enzyme preparations from Lupinus polyphyllus cell suspension cultures26 and with chloroplasts.27 These alkaloids are formed from three molecules of lysine by way of cadaverine (25),1,2 and the enzymic evidence26,27 is that conversion of cadaverine into these alkaloids occurs without release of intermediates until 17-oxosparteine (26) is generated the enzyme is a transaminase and not a diamine oxidase. 

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. 

The most specific metabolizing enzyme is imidazole N-methyl-transferase ( histamine acetylase ), which can be inhibited in vivo by amodiaquine, chloroquine and metoprine. Histamine is also metabolized by hlstaminase , and this enzyme can be inhibited by aminoguanidine, metronidazole and pentamidine (see diamine oxidase inhibitors). Metabolites in the urine can be measured to give some index of histamine turnover. 

ANTIFUNGAL, ANTIMICROBIAL and ANTIINFLAMMATORY activity, and to be a powerful cytotoxic agent (functioning by DNA intercalation and uncoupling of oxidative phosphorylation). It is an ENZYME INHIBITOR (alanine aminotransferase and human plasma diamine oxidase). It shows antiplaque activity, and has been used in toothpastes and oral rinses. Causes temporary change in intraocular pressure. Sanomigran pizotifen. 

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. 

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