The oxidation of 3-hydroxyanthranilic acid by Cu,Zn superoxide dismutase: Mechanism and possible consequences

Cu,Zn SOD, but not Mn SOD, catalyzes the oxidation of 3-hydroxyanthranilic acid (3-HA) under aerobic conditions. In the absence of O-2, the Cu(II) of the enzyme is reduced by 3-HA. One plausible mechanism involves the reducti on of the active site Cu(II) to Cu(I), which is then reoxidized by the O-2( -) generated by autoxidation of the anthranilyl or other radicals on the pa thway to cinnabarinate, We may call this the superoxide reductase, or SOR, mechanism. Another possibility invokes direct reoxidation of the active sit e Cu(I) by the anthranilyl, or other organic radicals, or by the peroxyl ra dicals generated by addition of O-2 to these organic radicals. Such oxidati ons catalyzed by Cu,Zn SOD could account for the deleterious effects of the mutant Cu,Zn SODs associated with familial amyotrophic lateral sclerosis a nd of the overproduction or overadministration of wild-type Cu,Zn SOD. (C) 2001 Academic Press.