Topaquinone cofactors

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]. 

These homodimeric enzymes, that are present in both prokaryotic and eukaryotic organisms, contain one Cu ion and one redox-active cofactor topaquinone (TPQ) per monomer [5, 6]. They catalyze the oxidative deamination of primary amines [7-9]. The Cu(ll) ion is coordinated by three histidine residues and three water molecules (Fig. 11.1). The TPQ cofactor is not far from the Cu ion. The process can be divided into an initial reductive reaction followed by an oxidative step, based on the redox state of TPQ the Cu ion is thought to be involved in the formation of the TPQ semiquinone through reduction of Cu(II) to Cu(I). An alternative hypothesis has been recently proposed where the copper ion stays as Cu(II) and the one-electron reduction of O2 is carried out by a modified amino-resorcinol TPQ cofactor. The Cu(II) would provide electrostatic stabilization to the superoxide anion intermediate [10-12]. The reduction of molecular oxygen would result in weakly Cu-bormd hydroperoxide which is subsequently displaced by a water molecule, gets protonated and it is eliminated as hydrogen peroxide. 

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>. 

This enzyme [EC 1.4.99.3], also known as amine dehydrogenase and primary-amine dehydrogenase, catalyzes the reaction of R-CH2-NH2 with water and an acceptor to produce R-CHO, ammonia, and the reduced acceptor. Tryptophan tryptophylquinone (TTQ) is the cofactor for this enzyme. See Resonance Raman Spectroscopy Topaquinone... 

Topaquinone (TPQ). Both bacteria and eukaryotes contain amine oxidases that utilize bound copper ions and 02 as electron acceptors and form an aldehyde, NH3, and H202. The presence of an organic cofactor was suggested by the absorption spectra which was variously attributed to pyridoxal phosphate or PQQ. However, isolation from the active site of bovine serum... 

Lysine tyrosylquinone (LTQ). Another copper amine oxidase, lysyl oxidase, which oxidizes side chains of lysine in collagen and elastin (Eq. 8-8) contains a cofactor that has been identified as having a lysyl group of a different segment of the protein in place of the - OH in the 2 position of topaquinone.465 Lysyl oxidase plays an essential role in the crosslinking of collagen and elastin. 

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],... 

Duine, J. A., 1991, Quinoproteinsoenzymes containing the quinonoid cofactor p>rroloquino-line quinone, topaquinone or tryptophan-tryptophan quinone. Eur. J. Biochem. 

Dooley, D. M., 1999, Structure and biogenesis of topaquinone and related cofactors, J. Biol. Inorg. Chem. 4 1911. 

The copper metalloenzymes are involved in oxygen-using reactions. These enzymes include cytochrome c oxidase (respiratory chain), lysyl oxidase (collagen synthesis), and dopamine [3-hydroxylase (neurotransmitter synthesis). Lysyl oxidase is a small protein with a molecular weight of 32 kDa. This enzyme contains an unusual modification, namely cross-linking between two different parts of its polypeptide chain. The cross-linked region consists of a structure called lysine tyrosylquinone (Klinman, 1996). Two amino acids are involved in this cross-linked structure, and these are Lys 314 and Tyr 349. Lysine tyrosylquinone is used as a cofactor and is necessary for the catalytic activity of the enzyme. Other copper metalloenzymes contain a related cofactor, namely 2,4,5-tiihydrox5q5henylalanine (topaquinone, TPQ). Serum amino oxidase is a copper metalloenzyme that contains TPQ. TPQ consists of a modified residue of phenylalanine. The copper in the active site of the enzyme occurs immediately adjacent to the TPQ cofactor. 

Redox proteins that include quinone cofactor units play important roles in biological ET processes. Some of the quinoproteins include the quinone cofactor in a non-covalently linked configuration, such as the pyrroloquinoline quinone, PQQ, dependent enzymes, whereas other quinoproteins include the quinone cofactor covalently-linked to the protein, for example topaquinone (2,4,6-trihydroxyphenylalanine quinone, TPQ) dependent enzymes. A number of quinoproteins include in addition to the quinone cofactor an ET cofactor unit in another protein subunit. These cofactors may be metal ions or a cytochrome-type heme cofactor such as D-fructose dehydrogenase that is a heme containing PQQ-dependent enzyme. ... 

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]. 

Figure 7 Currently preferred mechanism for biogenesis of the topaquinone cofactor in copper-containing amine oxidase. ...

Oxidative Deamination Reactions. The enzymes amine oxidases (AOs) catalyze the oxidative deamination of a wide range of biogenic amines. There are two classes of AOs copper AOs and flavin-containing AOs. Copper-containing AOs catalyze the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone (TPQ) (2,4,5-trihydroxyphenylalanine) as cofactor (Figure 1.50). 

A carbonyl-containing cofactor has been long known to exist in amine oxidases, identified by Klinman and co-workers as topaquinone (TPQ). This cofactor derives from a protein tyrosine precursor and it is thought that a copper(II) ion is required for its generation to TPQ. A mechanism for the... 

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