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Ramsden C.A.,Keele University | Riley P.A.,Totteridge Institute for Advanced Studies
Bioorganic and Medicinal Chemistry | Year: 2014

Tyrosinase is an enzyme widely distributed in the biosphere. It is one of a group of proteins with a strongly conserved bicopper active centre able to bind molecular oxygen. Tyrosinase manifests two catalytic properties; monooxygenase and oxidase activity. These actions reflect the oxidation states of the active centre. Tyrosinase has four possible oxidation states and the details of their interaction are shown to give rise to the unusual kinetic behaviour of the enzyme. The resting state of the enzyme is met-tyrosinase [Cu(II)2] and activation, associated with a 'lag period', involves reduction to deoxy-tyrosinase [Cu(I)2] which is capable of binding dioxygen to form oxy-tyrosinase [Cu(II)2·O2]. Initially the conversion of met- to deoxy-tyrosinase is brought about by a catechol that is indirectly formed from an ortho-quinone product of tyrosinase action. The primary function of the enzyme is monooxygenation of phenols to ortho-quinones by oxy-tyrosinase. Inactivation of the enzyme results from monooxygenase processing of catechols which can lead to reductive elimination of one of the active-site copper ions and conversion of oxy-tyrosinase to the inactive deact-tyrosinase [Cu(II)Cu(0)]. This review describes the tyrosinase pathways and the role of each oxidation state in the enzyme's oxidative transformations of phenols and catechols. © 2014 Published by Elsevier Ltd. Source


Riley P.A.,Totteridge Institute for Advanced Studies
Melanoma Research | Year: 2014

In summary, there fore, it is posited that carcinogenesis results from somatic mutations affecting the mechanisms of epigenetic inheritance. In consequence, there is a ramification of clones expressing anomalous sets of genes characteristic of earlier developmental states or of other tissues. Among the abnormal biological properties expressed is migratory behaviour characteristic of embryological cells and this is the crucial feature of the malignant phenotype © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Ramsden C.A.,Keele University | Riley P.A.,Totteridge Institute for Advanced Studies
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Contradictory reports on the behaviour of hydroquinone as a tyrosinase substrate are reconciled in terms of the ability of the initially formed ortho-quinone to tautomerise to the thermodynamically more stable para-quinone isomer. Oxidation of phenols by native tyrosinase requires activation by in situ formation of a catechol formed via an enzyme generated ortho-quinone. In the special case of hydroquinone, catechol formation is precluded by rapid tautomerisation of the ortho-quinone precursor to catechol formation. © 2014 Elsevier Ltd. All rights reserved. Source


Ramsden C.A.,Keele University | Riley P.A.,Totteridge Institute for Advanced Studies
Arkivoc | Year: 2010

Tyrosinase oxidation of catechols to ortho-quinones is accompanied by suicide inactivation of the enzyme. The rates of these competing processes vary and depend on the nature of ring substituents. For a series of 4-substituted catechols the relationships between structure and reaction rates have been examined using multiple regression. Significant but different structure-rate relationships were found for each process. The oxidation rate (k1) is greatest for short hydrophobic substituents; there is an optimum substituent hydrophobicity (π ̃ 0.7) for the rate of inactivation (k2). © ARKAT USA, Inc. Source


Stratford M.R.L.,University of Oxford | Ramsden C.A.,Keele University | Riley P.A.,Totteridge Institute for Advanced Studies
Bioorganic and Medicinal Chemistry | Year: 2012

In vitro studies, using combined spectrophotometry and oximetry together with hplc/ms examination of the products of tyrosinase action demonstrate that hydroquinone is not a primary substrate for the enzyme but is vicariously oxidised by a redox exchange mechanism in the presence of either catechol, l-3,4-dihydroxyphenylalanine or 4-ethylphenol. Secondary addition products formed in the presence of hydroquinone are shown to stimulate, rather than inhibit, the kinetics of substrate oxidation. © 2012 Elsevier Ltd. All rights reserved. Source

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