Totteridge Institute for Advanced Studies

London, United Kingdom

Totteridge Institute for Advanced Studies

London, United Kingdom

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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.


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.


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.


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.


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.


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: 2013

The inactivation of tyrosinase by resorcinol (1,3-dihydroxybenzene) and seventeen simple derivatives has been investigated using combined spectrophotometry and oximetry together with hplc/ms examination of the oxidation products. The results are consistent with a Quintox mechanism, analogous to that proposed for catechol inactivation of tyrosinase, in which the resorcinol substrate is oxidised via the monooxygenase route leading to a hydroxy intermediate that undergoes deprotonation and results in irreversible elimination of Cu(0) from the active site. Hplc/ms evidence for formation of the resorcinol monooxygenase product (3-hydroxy-ortho-quinone) is presented and the relationship between the ring position of simple resorcinol substituents (H, Me, F, Cl) and tyrosinase inactivation is rationalised. © 2012 Elsevier Ltd. All rights reserved.


Riley P.A.,Totteridge Institute for Advanced Studies
Biological Journal of the Linnean Society | Year: 2013

Industrial melanism, a phenomenon observed in some moths and especially in the case of the peppered moth (Biston betularia), has received much attention as an example of Darwinian evolution in action. The rapid rise in the proportion of the darker melanic form of the adult moth coincided with the advent of atmospheric pollution resulting from industrialization, and was ascribed to the improved camouflage of the melanotic insects against a background blackened by soot, which conferred a selective advantage in the avoidance of predation by birds. The topic of the increase in melanization during the initial period of industrial expansion and the reversal of the process after the introduction of the Clean Air Act has received much attention. Although there is sound experimental evidence to support selective avian predation as a major mechanism to account for the changes in the relative frequency of melanics, it is not clear that this is the only selective factor involved in industrial melanism. It is possible that other processes may have made a contribution to the preponderance of melanic variants. In the present study, the hypothesis is advanced that melanization may have conferred a selective advantage by protecting the insects from the toxic effects of metals by virtue of the strong metal chelating action of melanin. © 2013 The Linnean Society of London.


Riley P.A.,Totteridge Institute for Advanced Studies
Journal of Analytical Oncology | Year: 2016

It has been shown that cancer incidence is not only a function of the size of the population at risk but is strongly associated with the turnover rate of the tissue concerned. There is a strong negative correlation between melanoma incidence and the degree of skin pigmentation, and yet the melanocyte density is the same for all races. The proposal advanced in this communication is that the probability of undergoing malignant change is critically dependent on the melanocyte turnover and that this is regulated by the pigmentation process. In melanocytes, the division rate is influenced by the process of pigment donation, probably by a mechanism whereby the continual cytoplasmic loss due to cytocrine transfer of melanosomes (termed the 'Amputation Cycle') inhibits replication. Consequently the turnover of melanocyte stem cells in heavily pigmented epidermis will be diminished, and this is held to account for the strong negative correlation between the degree of skin pigmentation and melanoma incidence. © 2016 Lifescience Global.


PubMed | University of Oxford and Totteridge Institute for Advanced Studies
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2015

Oxidation of 4-methylcatechol previously exposed to aqueous calcium chloride was shown by ion chromatography to be associated with release of calcium ions. The catechol was oxidised to the corresponding orthoquinone by the use of tyrosinase from Agaricus bisporus. The oxidative release of calcium from the catechol is ascribed to the diminution of the available hydroxyl functions able to act as chelating groups. Our results suggest that the redox status of melanin may regulate calcium binding and influence calcium levels in pigmented cells.


PubMed | Keele University and Totteridge Institute for Advanced Studies
Type: Journal Article | Journal: Bioorganic & 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.

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