The polymerization of melanin: a poorly understood phenomenon with egregious biological implications.
Several hypotheses have explicitly implicated the role of an altered redox status of melanin in the aetiology of melanoma and macular degeneration. The balance between the intrinsic anti-oxidant and pro-oxidant properties of melanin is lost, resulting in an altered redox phenotype. We propose that such an alteration of the redox status of melanin may arise, in part, due to suboptimal conditions for the effective polymerization of melanin precursors. We suggest that a decrease in the degree of polymerization or molecular weight of the melanin polymer may cause an alteration of the redox status of the polymer towards a more pro-oxidant state. A higher propensity of smaller oligomers to complex metals, coupled with an upregulation of metallothionein expression, results in increased production of free radicals including the superoxide anion. This, in association with an increase in the rate of tyrosinase degradation, a decrease in the rate of tyrosinase activation, alterations to template protein structure or alterations in the kinetics of the oxidation of tyrosine via the Raper-Mason pathway, may result in an overcoming of the cellular anti-oxidant pool, an increased susceptibility to oxidative stress and alterations to the reaction kinetics of melanogenesis, thus setting up a cycle of increasing oxidative stress and proliferation leading to the leakage of melanin monomers outside the organelle, thereby causing cytotoxicity and necrosis.
Sarangarajan
Rangaprasad
R
Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, USA.
Apte
Shireesh P
SP
D000818:Animals; D001704:Biopolymers / Q000378:metabolism*; D005609:Free Radicals; D006801:Humans; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism; D010084:Oxidation-Reduction
D001704:Biopolymers; D005609:Free Radicals; D008543:Melanins