4J7U

Crystal structure of human sepiapterin reductase in complex with sulfathiazole

Summary for 4J7U

• Entry DOI: 10.2210/pdb4j7u/pdb
• Related: 4HWK 4J7X
• Descriptor: Sepiapterin reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-amino-N-(1,3-thiazol-2-yl)benzenesulfonamide, ... (7 entities in total)
• Functional Keywords: reductase, oxidoreductase-antibiotic complex, oxidoreductase/antibiotic
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P35270
• Total number of polymer chains: 4
• Total formula weight: 130340.05

Authors

Groenlund Pedersen, M.,Pojer, F.,Johnsson, K. (deposition date: 2013-02-14, release date: 2013-06-05, Last modification date: 2023-09-20)

Primary citation

Haruki, H.,Pedersen, M.G.,Gorska, K.I.,Pojer, F.,Johnsson, K.
Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs.
Science, 340:987-991, 2013

PubMed 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.

PubMed: 23704574
DOI: 10.1126/science.1232972

Experimental method

X-RAY DIFFRACTION (2.44 Å)