title: Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs.
abstract: 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.
authors.affiliation: EPFL, Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Centre of Competence in Research in Chemical Biology, 1015 Lausanne, Switzerland.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Haruki
authors.forename: Miriam Grønlund
authors.initials: MG
authors.lastname: Pedersen
authors.forename: Katarzyna Irena
authors.initials: KI
authors.lastname: Gorska
authors.forename: Florence
authors.initials: F
authors.lastname: Pojer
authors.forename: Kai
authors.initials: K
authors.lastname: Johnsson
mesh_terms: D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects; D018360:Crystallography, X-Ray; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000096:biosynthesis; D009249:NADP / Q000737:chemistry; D009325:Nausea / Q000139:chemically induced; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013420:Sulfamethoxazole / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000890:Anti-Infective Agents; D001708:Biopterins; D007980:Levodopa; D009249:NADP; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D006916:5-Hydroxytryptophan; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; C003402:sapropterin; D013420:Sulfamethoxazole