Dopamine Covalently Modifies DNA in a Tyrosinase-Enhanced Manner

Abstract

Parkinson’s Disease (PD) is characterized by the chronic and progressive loss of dopaminergic neurons of the nigrostriatal pathway. An important theory suggests that the dopamine neurotransmitter can itself play a role in the degeneration.1–7 One hypothesis is that dopamine (DA), which is synthesized from the essential amino acid tyrosine, can be converted to a reactive quinone metabolite (Figure 1). This oxidation of the catecholamine can either occur spontaneously or be accelerated by the enzyme tyrosinase. The attractive aspect of this hypothesis is that tyrosinase is a known component of the DA neurons which are at risk in PD. The dopamine quinone product is destructive to macromolecules for two reasons. First, it is a highly reactive molecule which is capable of covalently modifying nucleophiles such as sulfhydryls and amino groups. In fact, dopamine quinone is known to covalently modify both DNA and proteins.3,6–8 Second, through a series of oxidation reactions, dopamine quinone can contribute to the production of hydrogen peroxide, Superoxide radical, and the hydroxyl radical. These very reactive chemical entities can in turn generate extensive macromolecular damage. In the present experiments, we investigated the role of tyrosinase in DA-mediated DNA damage. The central hypothesis is that tyrosinase catalyzes the formation of dopamine quinone and therefore enhances the covalent modification of DNA by DA.