Oxidase copper-containing amine

Several lupin alkaloids have been derived from the unsaturated quinalozidine 433, that was obtained in the treatment of amine 431 with ortho-quinone 432. This quinone behaves as a model of topaquinone, the cofactor of copper-containing amine oxidases. The cyclization step involved a nucleophilic attack of the piperidine nitrogen of 431 onto a side-chain aldehyde function that is unmasked by the oxidative deamination. Quinolizine 433, when treated with dehydropiperidine, gave the oxime ether 434 that, on ozonolysis followed by reduction, afforded sparteine 10, presumably via the bis(iminium) system 435 (Scheme 102) <1996JOC5581>. 

Molecular Biology of the Copper-Containing Amine Oxidase... 

MOLECULAR BIOLOGY OF THE COPPER-CONTAINING AMINE OXIDASE FAMILY... 

Copper-containing amine oxidases (non-blue copper proteins) catalyze the oxidative deamination of primary amines to the corresponding aldehydes with the release of ammonia and concomitant reduction of oxygen to hydrogen peroxide. They typically use a quinone redox cofactor [topaquinone (TPQ)], which is bound covalently in the active site, and are thought to form a Cu(I)-TPQ semi-quinone radical intermediate during the redox reaction [13]. 

Amine oxidase catalyses the oxidative deamination of amines to the corresponding aldehyde, hydrogen peroxide and ammonia. The copper containing amine oxidase from pig plasma (PPAO) is one of the better characterised in this class of enzyme. The homogeneously pure enzyme has a molecular weight of 190,000 composed of two subunits with equal molecular weight. The present evidence suggests that copper is essential for catalytic activity and therefore much effort has been made to determine the structure of copper sites... 

In contrast to the substantial work with MAO, relatively little research has been reported on the mechanism of inhibition of copper-containing amine oxidases and SSAO by cyclopropylamines. Bovine plasma amine oxidase, equine plasma amine oxidase, Escherichia coii amine oxidase, and Arthrobacter globiformis amine oxidase were inhibited by frans-2-phenylcyclopropylamine (8a) and the mode of inhibition was shown by spectral and crystal structure analyses to be competitive and reversible [36,37,129],... 

E.M. Shepard, FI. Fleather, G.A. Juda, D.M. Dooley, Inhibition of six copper-containing amine oxidases by the antidepressant drug tranylcypromine, Biochim. Biophys. Acta 1647 (2003) 252-259. 

A detailed study of the inhibition of MAOs by fluorophenyl cyclopropyl amines shows that the presence of fluorine has very important effects on this inhibition. While some of the regioisomers are inhibitors of the CAO (copper-containing amine oxidase), some other ones, such as 2-fluoro-l-arylcylopro-pyl amines, are excellent selective and irreversible inhibitors of MAO A. In this latter case, the nonfluorinated parent compound is a poor inhibitor of MAO B (Figure 7.55). ° " ... 

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). 

Topaquinone (TPQ), the oxidized form of 2,4,5-trihydroxyphenylalanine (TOPA), is the cofactor of copper-containing amine oxidases. The following model compounds have been prepared in order to understand the catalytic function of TPQ the jV-pivaloyl derivative of 6-hydroxydopamine in aqueous acetonitrile [38] topaquinone hydantoin and a series of 2-hydroxy-5-alkyl-l,4-benzoquinones in anhydrous acetonitrile (o- as well as />-quinones) [39] 2-hydroxy-5-methy 1-1,4-benzoquinone in aqueous system [40] and 2,5-dihydroxy-1,4-benzoquinone [41]. Reaction of model compounds with 3-pyrrolines revealed why copper-quinopro-tein amine oxidases cannot oxidize a secondary N [42], The studies clearly showed that certain model compounds do not require the presence of Cu for benzylamine oxidation whereas TPQ does [38,40] the aminotransferase mechanism proceeds via the -quinone form [39] the 470 nm band can be ascribed to a 71-71 transition of TPQ in />-quinonic form with the C-4 hydroxyl ionized but hydrogen bonded to some residue [40] hydrazines attack at the C-5 carbonyl, forming an adduct in the azo form [41], Electrochemical characterization has been carried out for free TPQ [43],... 

It is safe to predict that there will be major effort in understanding the biological roles of copper-containing amine oxidases and the relationship to flavin-containing amine oxidases. The diversity of amine oxidases in all forms of life and their involvement in key cellular processes in plants and mammals underline the importance of this objective. 

McCracken, J., Peisach, J., Cote, C. E., McGuirl, M. A., and Dooley, D. M., 1992, Pulsed EPR studies of the semiquinone state of copper-containing amine oxidases, J. Amer. Chem. Soc. 114 3715n3720. 

Mclntire, W. S., and Hartmann, C., 1993, Copper-containing amine oxidases in Principles and Applications of Quinoproteins, Editor Davison, V., Marcel Dekker publisher 97fi 171. 

Schwartz, B., Green, E. L., Sanders-Loehr, J., and Klinman, J. P., 1998, The relationship between conserved consensus site residues and die productive conformation for TPQ cofactor in a copper-containing amine oxidase from yeast. Biochemistry 37 16591nl6600. 

Wilce, M. C. J-, Dooley, D. M., Freeman, H. C., Guss, J. M., Matsunami, H., Mclntire, W. S., Ruggiero, C. E., Tanizawa, K., and Yamaguchi, H., 1997, Crystal shnctiwes of die copper-containing amine oxidase from Arthrobacter globiformis in the holo and apo forms. Biochemistry, 36 16116fil6133. 

Copper-containing amine oxidases [E.C. 1.4.3.6] are one of the most widely distributed classes of Type 2 copper enzymes. They have been highly purified from bacteria. 

An example [27] is provided by the recent determination of the rate of intramolecular electron transfer in a copper-containing amine oxidase, Cu -topaNH2/ Cu -topasQ, Eq. 26, where topa represents 3-(2,4,5-trihydroxyphenyl)-l-alanine. 

The broad group of copper-containing amine oxidases, which contain diamine oxidase (DAO) and semicar-bazide-sensitive amine oxidases (SSAO). 

The enantioselective oxidation of amphetamine SS by copper containing amine oxidases from Escherichia coli and Klebsiella oxytoca was reported in 2000 by Had salihoglu et al. [34] Moderate E values of 1S were obtained, opening up the possibility for future applications of amine oxidase catalyzed resolutions of substi tuted amphetamines (Figure 14.2S). 

Other oxidoreductases that can play a major or less important role in drug metabolism are hemoglobin, monoamine oxidases (EC 1.4.3.4 MAO-A and MAO-B), which are essentially mitochondrial enzymes, the cytosolic molybdenum hydroxylases (xanthine oxidase, EC 1.1.3.22 xanthine dehydrogenase, EC 1.1.1.204 and aldehyde oxidase, EC 1.2.3.1), d the broad group of copper-containing amine oxidases (EC 1.4.3.6) (36-39). 

Bovine serum amine oxidase (BSAO) is a copper-containing amine oxidase which utilizes a covalently bound 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor in the two-electron oxidation of a broad spectrum of primary amines [99]. The oxidation is thought to proceed via the formation of an iminium complex between the oxidized form of the cofactor and the primary amine (1 in Scheme 10.4). The substrate imine undergoes deprotonation to form product imine, which, after hydrolysis, releases aldehyde product and reduced cofactor [100]. Proton transfer is either partially or largely rate-limiting for the oxidation of benzylamines, as evidenced by a large deuterium isotope effect at the methylene adjacent to the amino group [36, 101, 102]. 

The copper-containing amine oxidases (copper amine oxidases, diamine oxidases) possess either a topaquinone or a 6-hydroxydopamine cofactor (Fig. 16.7-15), generally integrated in the oxidase primary structure. Tyrosine residues of the enzyme backbone in the active site are discussed as precursors for the prosthetic group[37]. 

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