Oxidation of 4-alkylphenols and catechols by tyrosinase: ortho-substituents alter the mechanism of quinoid formation.
Numerous phenols and catechols are known to be substrates for tyrosinase. While the catalytic mechanism of phenol oxidation by tyrosinase has been well studied, little work has been done to determine the influence of substituents on the reaction. In the present investigation, we explored the effects of changing substituents at the 2 and 6 position on the mechanism of tyrosinase-catalyzed oxidation of 4-allyl and 4-propylphenols and catechols. We have previously demonstrated that tyrosinase initially oxidizes hydroxychavicol (4-allyl-catechol) to an o-quinone (3,5-cyclohexadien-1,2-dione) which because of the relatively acidic protons in the benzyl position, readily isomerizes to the tautomeric p-quinone methide (4-allylidene-2,5-cyclohexadien-1-one, QM) (Bolton et al., 1994). We have confirmed through GSH trapping studies that oxidation of 4-allylphenol by tyrosinase yields the same o-quinone GSH conjugates as hydroxychavicol. In contrast, the presence of additional ortho substituents dramatically alters the mechanism of tyrosinase-catalyzed oxidation of 4-alkylphenols. For example, eugenol (4-allyl-2-methoxyphenol), which possesses 1 ortho-methoxy substituents, is not oxidized to a o-quinone or a QM. However, when both ortho o-quinones or QMs which may be selectively toxic to the malignant melanocyte. Although mammalian tyrosinase is much more substrate specific compared to the mushroom tyrosinase used in this study [42], it should be possible to identify compounds which are substrates for the mammalian form but are otherwise oxidatively stable. In order to develop such target compounds an improved understanding of substituent effects on tyrosinase-catalyzed oxidation of catechols and phenols is necessary. This should for the development of strategies for therapeutic compounds that are selectively toxic toward melanoma.
Krol
E S
ES
Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago 60612-7231, USA.
Bolton
J L
JL
D001487:Basidiomycota / Q000201:enzymology; D002396:Catechols / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005054:Eugenol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D010084:Oxidation-Reduction; D010636:Phenols / Q000737:chemistry / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D002396:Catechols; D010636:Phenols; D011809:Quinones; C079313:4-propylcatechol; D005054:Eugenol; D014442:Monophenol Monooxygenase; D005978:Glutathione