Tetrahydrobiopterin Biosynthesis as an Off-Target of Sulfa Drugs

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Science  24 May 2013:
Vol. 340, Issue 6135, pp. 987-991
DOI: 10.1126/science.1232972

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Going Off-Target

Sulfamethoxazole is a widely used sulfa-drug often used at high doses in the treatment of Pneumocytis pneumonia (PCP) in immunocompromised individuals. Haruki et al. (p. 987) show that sulfamethoxazole and certain other sulfa drugs inhibit the enzyme septiapterin reductase that catalyzes the final step in the biosynthesis of tetrahydrobiopterin (BH4). BH4 is a cofactor in the biosynthesis of neurotransmitters such as serotonin and dopamine. In cell culture, sulfamethoxazole lowered neurotransmitter levels through depletion of BH4, which may explain central nervous system side effects associated with PCP treatment.


The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system–related side effects, particularly in high-dose sulfamethoxazole therapy of Pneumocystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use.

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