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Thioredoxin reductase, an emerging target for anticancer metallodrugs. Enzyme inhibition by cytotoxic gold(III) compounds studied with combined mass spectrometry and biochemical assays

Gabbiani, Chiara, Mastrobuoni, Guido, Sorrentino, Francesca, Dani, Barbara, Rigobello, Maria Pia, Bindoli, Alberto, Cinellu, Maria Agostina, Pieraccini, Giuseppe, Messori, Luigi and Casini, Angela 2011. Thioredoxin reductase, an emerging target for anticancer metallodrugs. Enzyme inhibition by cytotoxic gold(III) compounds studied with combined mass spectrometry and biochemical assays. MedChemComm 2 (1) , pp. 50-54. 10.1039/C0MD00181C

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Abstract

The seleno-enzyme thioredoxin reductase (TrxR) is a putative target for cytotoxic gold complexes. We investigated the mechanism of TrxR inhibition by a group of structurally diverse gold(III) compounds; the antiarthritic gold(I) drugs auranofin and aurothiomalate were also studied for comparison purposes. The tested compounds – either gold(III) or gold(I) – were found to produce potent enzyme inhibition only after pre-reduction of the enzyme with NADPH, indicating that TrxR inhibition is the result of protein structure modifications occurring upon cofactor binding. MALDI-ToF MS experiments on the intact enzyme provided evidence for extensive enzyme metallation, while experiments on trypsinized gold(III)-protein adducts identified a specific protein fragment – namely 236IGEHMEEHGIK246 – bearing an attached gold(I) ion. Independent mechanistic information on the system was derived from BIAM assays capable of monitoring selective metal binding to cysteine and/or selenocysteine residues. While the effects produced by auranofin could be essentially ascribed to gold(I) coordination to the active site selenol, the effects caused by the various gold(III) compounds were better interpreted in terms of oxidative protein damage.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Royal Society of Chemistry
ISSN: 2040-2503
Date of Acceptance: 14 November 2010
Last Modified: 04 Jun 2017 08:30
URI: http://orca.cf.ac.uk/id/eprint/79333

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