Copper amine oxidases mechanisms

M. Mure, S.A. Mills, J.P. Klinman, Catalytic mechanism of the topa quinone containing copper amine oxidases. Biochemistry 41 (2002) 9269-9278. 

Mechanisms. Studies of model reactions473-476 and of electronic, Raman,456 477 478 ESR,479/480 and NMR spectra and kinetics481 have contributed to an understanding of these enzymes.459 461 464 482 483 For these copper amine oxidases the experimental evidence suggests an aminotransferase mechanism.450 453 474 4743 d Tire structure of the E.coli oxidase shows that a single copper ion is bound by three histidine imidazoles and is located adjacent to the TPQ (Eq. 15-53). Asp 383 is a conserved residue that may be the catalytic base in Eq. 15-53.474b A similar mechanism can be invoked for LTQ and TTQ. 

Medda, R., Padiglia, A., Pedersen, J. Z., Rotilio, G., Finazzi Agro, and Floris, G, 1995, The reaction mechanism of copper amine oxidase detection of intermediates by the use of substrates and inhibitors, Biochem. 34 16375-16381. 

Mukherjee A. Smirnov V. V. Land M. P. Brown D. E. Shepard E. M. Dooley D. M. Roth J. P. Inner-sphere mechanism for molecular oxygen reduction catalyzed by copper amine oxidases. J. Am. Chem. Soc. 2008, 130, 9459-9473. 

Lee, Y., and Sayre, L. M., 1995, Model studies on the quinone-containing copper amine oxidases unambiguous demonstration of a transamination mechanism, J. Amer. Chem. Soc. 117 11823nll828. 

DuBois JL, Klinman JP. Mechanism of post-translational quinone formation in copper amine oxidases and its relationship to the catalytic turnover. Arch. Biochem. Biophys. 2005 433 255-265. 

Fig. (3). Mechanism of the substrate oxidation by copper amine oxidases [29]. The scheme shows the roles of copper, topa quinone cofactor and proton abstracting base (Asp) in the catalytic cycle. The oxidized enzyme (a) reacts with an amine substrate giving a Schiff base formation at C-5 of the TPQ (b-c), followed by proton abstraction (d). After hydrolysis and release of the aldehyde, an aminoresorcinol species is formed (e), and the reduced cofactor is reoxidized by molecular oxygen via Cu(I)-semiquinone intermediate (/).

Mechanism based inactivators of copper amine oxidases... 

The most recent crystallographic study discloses the structure of the methylamine oxidase from the yeast Hansenula polymorpha [31], which shows an integrated network of water molecules providing electron transfer from topa quinone to copper and other important features such as the channel for oxygen entry and hydrogen peroxide release. The role of the active site aspartate base (Asp319) in the aminotransferase mechanism of the copper amine oxidase from H. polymorpha has been probed by site-directed mutagenesis [141]. It has been demonstrated by several... 

Copper amine oxidase (CAO) enzymes carry out the aerobic oxidation of primary amines to aldehydes (Scheme 14.8a). While copper is present in the active site, substrate oxidation proceeds by an organocatalytic pathway involving an o-quinone cofactor via a transamination mechanism (Scheme 14.8b). 

Figure 1.51 Mechanism of deamination by copper amine oxidases.

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],... 

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],... 

From the sequence of reactions found it follows that copper-quinoprotein amine oxidases catalyze an aminotransferase reaction. A different reaction sequence occurs with flavoprotein amine oxidases (EC 1.4.3.4), where formation of NH3 is not dependent on the presence of 02. However, since reductive trapping of amines in the first half-reaction [86] showed attachment of substrate but not of tritium, the mechanism is also different from the aminotransferase reaction that... 

Cu has a bifunctional role in copper-quinoprotein amine oxidases, catalyzing the formation of TPQ from the specific tyrosy l residue in the precursor protein and playing a role in the catalytic mechanism, most probably with 02 reacting with Cu(I) in the oxidative part of the cycle. The recent discovery of LTQ suggests that other combinations of quinone cofactors may be found in the future. 

Welford R. W. D. Lam A. Mirica L. M. Klinman J. P. Partial conversion of Hansenula polymorpha amine oxidase into a plant amine oxidase implications for copper chemistry and mechanism. Biochemistry 2007, 46, 10817-10827. 

Copper is an essential element to most life forms. In humans it is the third most abundant trace element only iron and zinc are present in higher quantity. Utilization of copper usually involves a protein active site which catalyzes a critical oxidation reaction, e.g., cytochrome oxidase, amine oxidases, superoxide dismutase, ferroxidases, dopamine-/ -hydrox-ylase, and tyrosinase. Accordingly, animals exhibit unique homeostatic mechanisms for the absorption, distribution, utilization, and excretion of copper (J). Moreover, at least two potentially lethal inherited diseases of copper metabolism are known Wilson s Disease and Menkes s Kinky Hair Syndrome (I). 

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