NDLI: Profiling patterns of glutathione reductase inhibition by the natural product illudin S and its acylfulvene analogues

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Molecular BioSystems Vol - 5 Issue - 8

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Molecular BioSystems Vol - 5 Issue - 5

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Profiling patterns of glutathione reductase inhibition by the natural product illudin S and its acylfulvene analogues

Content Provider	Royal Society of Chemistry (RSC)
Author	Sturla, Shana J. Liu, Xiaodan
Copyright Year	2009
Abstract	Acylfulvenes (AFs) are a class of antitumor agents with favorable cytotoxic selectivity profiles compared to their natural product precursor, illudin S. Like many alkylating agents, illudin S and AFs readily react with thiol-containing small molecules such as cysteine, glutathione and cysteine-containing peptides; reduced cellular glutathione levels can affect illudin S toxicity. Glutathione reductase (GR) is a critical cellular antioxidant enzyme that regulates the intracellular ratio of reduced–oxidized glutathione. In this study, we found that acylfulvene analogues are GRinhibitors, and evaluated aspects of the drug–enzyme interactions as compared with the structurally related natural productilludin S and the known irreversible GRinhibitor, carmustine. Acylfulvene analogues exhibited concentration-dependent GR inhibitory activity with micromolar IC50s; however, up to 2 mM illudin S did not inhibit GR activity. The absence of NADPH attenuates GR inhibition by AFs and the presence of glutathione disulfide (GSSG), the natural GR substrate, which binds to the enzyme active site, has a minimal effect in protecting GR from AFs. Furthermore, each compound can induce GR conformation changes independent of the presence of NADPH or GSSG. These results, together with gel-filtration analysis results and mass spectrometry data, indicate AF is a reversible inhibitor and HMAF an irreversible inhibitor that can form a bis-adduct with GR by reacting with active site cysteines. Finally in a cell-based assay, illudin S and HMAF were found to inhibit GR activity, but this inhibition was not associated with the reduction of GR levels in the cell. A model accounting for differences in mechanisms of GR inhibition by the series of compounds is discussed.
Starting Page	1013
Ending Page	1024
Page Count	12
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	5
Issue Number	9
Journal	Molecular BioSystems
DOI	10.1039/b904720d
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	NADPH Cysteine Glutathione disulfide Enzyme Carmustine Active site Illudin Chemical structure Natural product Enzyme inhibitor Cytotoxicity Antioxidant Glutathione reductase Nicotinamide adenine dinucleotide phosphate IC50 Mass spectrometry Glutathione
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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