4HWK

Crystal structure of human sepiapterin reductase in complex with sulfapyridine

4HWK の概要

• エントリーDOI: 10.2210/pdb4hwk/pdb
• 分子名称: Sepiapterin reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: reductase, oxidoreductase-antibiotic complex, oxidoreductase/antibiotic
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P35270
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 130852.36

構造登録者

Groenlund Pedersen, M.,Pojer, F.,Johnsson, K. (登録日: 2012-11-08, 公開日: 2013-06-05, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.4 Å)