Crosslinking Glutathionylation Mediated by O2-Arylated (Bis)diazeniumdiolate "Double JS-K"

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CHEM-5

* FARE Award Winner

Authors

• RJ Holland
• AE Maciag
• V Kumar
• JE Saavedra
• RK Prud'homme
• H Chakrapani
• LK Keefer

Abstract

Attachment of glutathione (GSH) to cysteine residues in proteins (S-glutathionylation ) is an easily reversible post-translational modification that can profoundly alter protein structure and function. Often serving in a protective role, e.g., by temporarily saving protein thiols from irreversible oxidation and inactivation, glutathionylation is normally identified and semi-quantitatively assessed using anti-GSH antibodies thought to be specific for recognition of the S-glutathionylation modification. Here we describe an alternate mechanism of protein glutathionylation in which the sulfur atoms of the GSH and the protein’s thiol group are covalently bound via a crosslinking agent, rather than through a disulfide bond. The modification is recognized by the anti-GSH antibody as if it were authentic S-glutathionylation, requiring mass spectrometry to distinguish between them. The cross-linking pathway likely plays an important role in mediating the action of Double JS-K and related bis-diazeniumdiolates as anti-cancer agents.

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