Sulfa Drugs Inhibit Sepiapterin Reduction and Chemical Redox Cycling by Sepiapterin Reductase

Abstract

Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), the 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 and bipyridinium herbicides (e.g., menadione, 9,10-phenanthrenequinone, and diquat); rapid reaction of the reduced radicals with molecular oxygen generates reactive oxygen species (ROS). Using recombinant human SPR, sulfonamide-and sulfonylurea-based sulfa drugs were found to be potent noncompetitive inhibitors of both sepiapterin reduction and redox cycling. The most potent inhibitors of sepiapterin reduction (IC 50 s 5 31-180 nM) were sulfasalazine, sulfathiazole, sulfapyridine, sulfamethoxazole, and chlorpropamide. Higher concentrations of the sulfa drugs (IC 50 s 5 0.37-19.4 mM) were required to inhibit redox cycling, presumably because of distinct mechanisms of sepiapterin reduction and redox cycling. In PC12 cells, which generate catecholamine and monoamine neurotransmitters via BH4-dependent amino acid hydroxylases, sulfa drugs inhibited both BH2/BH4 biosynthesis and redox cycling mediated by SPR. Inhibition of BH2/BH4 resulted in decreased production of dopamine and dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 5-hydroxytryptamine. Sulfathiazole (200 mM) markedly suppressed neurotransmitter production, an effect reversed by BH4. These data suggest that SPR and BH4-dependent enzymes, are "off-targets" of sulfa drugs, which may underlie their untoward effects. The ability of the sulfa drugs to inhibit redox cycling may ameliorate ROS-mediated toxicity generated by redox active drugs and chemicals, contributing to their anti-inflammatory activity.

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“…4E). The fact that SSA could negatively regulate H 2 O 2 formation [[59], [60], [61]] indicates that the opposing changes in ATP levels in the SSA and H 2 O 2 dataset is related to a similar H 2 O 2 regulated cellular mechanism in the two cases.…”

Humic analog AQDS can act as a selective inhibitor to enable anoxygenic photosynthetic bacteria to outcompete sulfate‐reducing bacteria under microaerobic conditions

“…Bacteria maintain a proton gradient (proton motive force) across the cell membrane that can be used to generate ATP and transport nutrients into the cells. Membrane depolarization could be one of the antibacterial mechanisms used by redox active drugs . To further investigate the possible mechanism behind the bacterial inhibition, DiBAC4(3), which is sensitive to changes in the membrane potential, was used to evaluate the effect of AQDS on SRB and APB monocultures.…”

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