Tyrosinase copper complexes

The reaction of binuclear copper complexes with oxygen as models for tyrosinase activity was also markedly accelerated by applying pressure (106408 ). Tyrosinase is a dinuclear copper protein which catalyses the hydroxylation of phenols. This reaction was first successfully modeled by Karlin and co-workers (109), who found that an intramolecular hydroxylation occurred when the binuclear Cu(I) complex of XYL-H was treated with oxygen (Scheme 5). 

Copper-catalyzed oxidations of phenols by dioxygen have attracted considerable interest owing to their relevance to enzymic tyrosinases (which transform phenols into o-quinones equation 24) and laccases (which dimerize or polymerize diphenols),67 and owing to their importance for the synthesis of specialty polymers [poly(phenylene oxides)]599 and fine chemicals (p-benzoquinones, muconic acid). A wide variety of oxidative transformations of phenols can be accomplished in the presence of copper complexes, depending on the reaction conditions, the phenol substituents and the copper catalyst.56... 

Oxidative coupling polymerization provides great utility for the synthesis of high-performance polymers. Oxidative polymerization is also observed in vivo as important biosynthetic processes that, when catalyzed by metalloenzymes, proceed smoothly under an air atmosphere at room temperature. For example, lignin, which composes 30% of wood tissue, is produced by the oxidative polymerization of coniferyl alcohol catalyzed by laccase, an enzyme containing a copper complex as a reactive center. Tyrosine is an a-amino acid and is oxidatively polymerized by tyrosinase (Cu enzyme) to melanin, the black pigment in animals. These reactions proceed efficiently at room temperature in the presence of 02 by means of catalysis by metalloenzymes. Oxidative polymerization is observed in vivo as an important biosynthetic process that proceeds efficiently by oxidases. 

Kinetically slow steps in the formation of melanin from DOPA are the formation of dopaquinone from DOPA (step 1, kD), the reaction of dopachrome to dihydroxyindole (step 2), and the polymerization to form melanin (step 3, kM). Step 1 and step 2 proceed with about the same rate in the oxidative coupling polymerization catalyzed by tyrosinase. However, step 1 becomes remarkably slow when a macromolecule-metal complex is used as a catalyst. The copper complex in poly(l-vinylimidazole-co-vinylpyrrolidone) has been found [38] to act as an excellent catalyst and to exhibit the highest activity for melanin formation. The ratio of the rate constants ( m/ d) is approximately 3 (tyrosinase... 

Our own work in the area of aerobic oxidations was inspired by the exquisite research performed on the structure and reactivity of the binuclear copper proteins (7), hemocyanin and tyrosinase, and by the seminal contribution of Riviere and Jallabert (8). These two authors have shown that the simple copper complex CuCl - Phen (Phen = 1,10-phenanthroline) promoted the aerobic oxidation of benzylic alcohols to the corresponding aromatic aldehydes and ketones (Fig. 2). 

B. Reaction Aspects of p,-Peroxo Dinuclear Copper Complexes Relevant to Tyrosinase Catalysis... 

Related to copper-containing enzymes such as laccase and tyrosinase, recent studies have been conducted on the structural characterization of the reactive species generated from molecular oxygen and copper complexes. A continuous effort has also been directed toward the efficient utilization of such oxygen-copper complexes as oxidants, in industrial processes, which will hopefully replace metal compounds such as chromate, manganate and others. 

There are three reasonable combinations of metal oxidation states for oxidized Type 3 copper that are consistent with spectral and redox data (1) Cu(I) Cu(I) with some other group, e.g., disulfide, functioning as a two-electron acceptor (2) Cu(I)-Cu(III) where Cu(III) is low spin and (3) an antiferromagnetically coupled Cu(II)-Cu(II) dimer. Magnetic susceptibility studies on Rhus vernicifera laccase have established that the two Type 3 copper atoms in this enzyme are present as an antiferromagnetically coupled Cu(II) dimer (4). The Type 3 copper atoms of hemocyanin and tyrosinase appear to be similarly coupled and separated by 3-5 A (5,6,7). Further structural information on the Type 3 copper chromophore is scanty neither the identity of the ligands nor the geometry of the site has been ascertained. There is likewise a paucity of literature on binuclear copper complexes that exhibit structural features expected for Type 3 copper. 

Many chemists have been fascinated by metalloenzyme-catalyzed oxygenation of various organic substrates with molecular oxygen. The phenolase activity of tyrosinase is one such reaction. Thus, great efforts have so far been made to develop oxygenation reactions of phenols by molecular oxygen catalyzed by various copper complexes. However, little information is available about the mechanistic details of such catalytic oxidation reactions. 

Fig. 4. Ligands used for biomimetic copper complexes of tyrosinase and catechol oxidase.

Based on the information on the binuclear copper complex and on the results of how different anions and organic ligands interact with the site, pathways of hydroxylation and oxidation reaction mechanisms of tyrosinase were proposed as shown in Figure 11.6 [18]. The proposed mechanism of action for N. crassa PPO appears to fit the data for most PPOs. The proposed mechanisms for hydroxylation and dehydrogenation reactions with phenols probably occur by separate pathways but are linked by a common deoxy PPO intermediate (deoxy in Figure 11.6). Proposed intermediates in the o-diphenol oxidation pathway are shown in Figure 11.6a. 

X-ray analysis of both copper(I) (e.g. 9) and copper(II) complexes, independent synthesis, and ammonolysis to the free ligands 35 and 36, confirmed the hydroxylation pathway.42 02-binding and hydroxylation in complex 10 were shown to be sensitive to electronic effects of the para-substituent (X = OMe, Me, C02Me, N02>. Tyrosinase, which contains a dinuclear copper active site strongly resembling the hemocyanine active site, binds O2 reversibly and activates O2 for arene hydroxylation (stoichiometry Cu O2 = 2 These are key features observed in the dinuclear copper complexes shown in... 

Ortho-hydroxylations by copper complexes mimicking tyrosinase action take place probably via intervention of p-peroxocopper(III) species. 

Tyrosinase-catalyzed transformations of catechols and o-benzoquinones were modeled by copper complexes which mimic both the spectroscopic characteristics [44-48] and the chemical behavior [49,50] of the biological systems. Tyrosinases have so-called copper type 3 centers, which are strongly antiferromagnetically coupled. The multicopper concept has emerged as an important feature in the modeling approach. 

Copper(II) complexes with phenoxo ligands have attracted great interest, in order to develop basic coordination chemistry for their possible use as models for tyrosinase activity (dimeric complexes) and fungal enzyme galactose oxidase (GO) (monomeric complexes). The latter enzyme catalyzes the two-electron oxidation of primary alcohols with dioxygen to yield aldehyde and... 

Encapsulated Cu—chlorophthalocyanines oxidize hexane at C-l using 02 and at C-2 using H202 as oxidants. The dimeric structure of copper acetate is intact when it is incorporated into the zeolite. This is a regioselective aromatic hydroxylation catalyst, which mimics the specificity of the monooxygenase enzyme tyrosinase.82,89 Zeolite NaY catalysts made with a tetranuclear Cu(II) complex were synthesized and characterized.90... 

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