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Cited by 101Biochemical and Molecular ResearchAmino Acid Enzymes and MetabolismMetabolism and Genetic Disorders

Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs

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Haruki, Hirohito, Pedersen, Miriam Grønlund, Gorska, Katarzyna Irena, Pojer, Florence, Johnsson, Kai·2013·Science
DOI 10.1126/science.1232972
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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.

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  • Sulfasalazine targets the BH4 pathway by inhibiting SPR.

    “Intriguingly, sulfasalazine, a drug used for decades to treat autoimmune inflammatory bowel disease (IBD) and psoriatic arthritis (Gupta et al., 1990), is now recognized as targeting the BH4 pathway by inhibiting SPR (Haruki et al., 2013), in addition to other targets, such as NFκB (Wahl et al., 1998).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Haruki et al., 2013

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Authors
Haruki, H., Pedersen, M. G., Gorska, K. I., Pojer, F., & Johnsson, K.
Affiliations
École Polytechnique Fédérale de Lausanne (CH)
Corresponding author
Johnsson, Kai
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2013-05-24
Volume
340
Issue
6135
Pages
987-991
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1232972
OpenAlex
W2154693031
Cited by
101
References
84
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 7 · 2021: 5 · 2020: 12 · 2019: 17 · 2018: 2 · 2017: 7 · 2016: 7 · 2015: 4 · 2014: 12 · 2013: 2
FWCI
4.03
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Funders
  • National Science Foundation
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases
  • École Polytechnique Fédérale de Lausanne
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • National Center of Competence in Research Chemical Biology
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases
  • NHLBI Division of Intramural Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
sulfonamides, sulfamethoxazole, tetrahydrobiopterin biosynthesis, sepiapterin reductase, enzyme inhibition, off-target effects, adverse drug reactions, central nervous system toxicity, neurotransmitter synthesis, Pneumocystis carinii pneumonia, crystal structure
MeSH terms
Adult, Alcohol Oxidoreductases, Anti-Infective Agents, Biopterins, Cell Line, Central Nervous System, Fibroblasts, Humans, 5-Hydroxytryptophan, Levodopa, NADP, Nausea, Pneumonia, Pneumocystis, Protein Conformation, Structure-Activity Relationship, Sulfamethoxazole, Vomiting, Trimethoprim, Sulfamethoxazole Drug Combination, Crystallography, X-Ray

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