1BWC

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

Summary for 1BWC

• Entry DOI: 10.2210/pdb1bwc/pdb
• Descriptor: PROTEIN (GLUTATHIONE REDUCTASE), CHLORIDE ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: oxidoreductase, flavoenzyme, redox-active center
• Biological source: Homo sapiens (human)
• Cellular location: Isoform Mitochondrial: Mitochondrion. Isoform Cytoplasmic: Cytoplasm: P00390
• Total number of polymer chains: 1
• Total formula weight: 52619.52

Authors

Gallwitz, H.,Bonse, S.,Martinez-Cruz, A.,Schlichting, I.,Schumacher, K.,Krauth-Siegel, R.L. (deposition date: 1998-09-23, release date: 1999-07-20, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)