1BWC

STRUCTURE OF HUMAN GLUTATHIONE REDUCTASE COMPLEXED with AJOENE INHIBITOR AND SUBVERSIVE SUBSTRATE

1BWC の概要

• エントリーDOI: 10.2210/pdb1bwc/pdb
• 分子名称: PROTEIN (GLUTATHIONE REDUCTASE), CHLORIDE ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, flavoenzyme, redox-active center
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform Mitochondrial: Mitochondrion. Isoform Cytoplasmic: Cytoplasm: P00390
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52619.52

構造登録者

Gallwitz, H.,Bonse, S.,Martinez-Cruz, A.,Schlichting, I.,Schumacher, K.,Krauth-Siegel, R.L. (登録日: 1998-09-23, 公開日: 1999-07-20, 最終更新日: 2024-10-16)

主引用文献

Gallwitz, H.,Bonse, S.,Martinez-Cruz, A.,Schlichting, I.,Schumacher, K.,Krauth-Siegel, R.L.
Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies.
J.Med.Chem., 42:364-372, 1999

PubMed Abstract: Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), a garlic-derived natural compound, is a covalent inhibitor as well as a substrate of human glutathione reductase (GR) and Trypanosoma cruzi trypanothione reductase (TR). The 2.1-A resolution crystal structure of GR inhibited by (E)-ajoene revealed a mixed disulfide between the active site Cys58 and the CH2=CH-CH2-SO-CH2-CH=CH-S moiety of ajoene. The modified enzyme has a markedly increased oxidase activity when compared to free GR. GR reduces (Z)-ajoene with a kcat/Km of 6.8 x 10(3) M-1 s-1 yielding 4,5,9-trithiadodeca-1, 6,11-triene (deoxyajoene) and 4,8,9,13-tetrathiahexadeca-1,6,10, 15-tetraene as stable reaction products. The reaction leads also to the formation of single-electron reduced products and concomitantly superoxide anion radicals as shown by coupling the reaction to the reduction of cytochrome c. The interactions between the flavoenzymes and ajoene are expected to increase the oxidative stress of the respective cell. The antiparasitic and cytostatic actions of ajoene may at least in part be due to the multiple effects on key enzymes of the antioxidant thiol metabolism.

PubMed: 9986706
DOI: 10.1021/jm980471k

実験手法

X-RAY DIFFRACTION (2.1 Å)