Inhibition of Sepiapterin Mediated Formation of Dihydrobiopterin and Chemical Redox Cycling by Sulfa Drugs

Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), a precursor for tetrahydrobiopterin (BH4), a cofactor critical for nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism. SPR also mediates chemical redox cycling, catalyzing one electron reduction of redox active chemicals including quinones; rapid reaction of these radicals with molecular oxygen generates reactive oxygen species (ROS). Using recombinant human SPR, sulfonamide and sulfonylurea based sulfa drugs were found to be potent non-competitive inibitors of both sepiapterin reduction and redox cycling. The most active inhibitors of sepiapterin reduction (IC50's = 31-180 nM) were sulfasalazine, sulfathiazole, sulfapyridine, sulfamethoxazole and chlorpropamide. Higher concentrations of the sulfa drugs (IC50's = 0.37-19.4 µM) were required to inhibit redox cycling. In PC12 cells, which generate catecholamine and monoamine neurotransmitters via BH4-dependent amino acid hydroxylases, su...