UnissResearch

Logo Universitàegli studi di Sassari
titoli, abstracts, parole chiave >>>
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 and Mastrobuoni, Guido and Sorrentino, Francesca and Dani, Barbara and Rigobello, Maria Pia and Bindoli, Alberto and Cinellu, Maria Agostina and Pieraccini, Giuseppe and 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, Vol. 2011 (2), p. 50-54. eISSN 2040-2511. Article.

Full text not available from this repository.

DOI: 10.1039/C0MD00181C

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
ID Code:7271
Status:Published
Refereed:Yes
Uncontrolled Keywords:Thioredoxin reductase, mass spectrometry, gold complexes, anticancer metallodrugs
Subjects:Area 03 - Scienze chimiche > CHIM/03 Chimica generale e inorganica
Divisions:001 Università di Sassari > 01 Dipartimenti > Chimica
Publisher:Royal Society of Chemistry
eISSN:2040-2511
Deposited On:21 Mar 2012 11:16

I documenti depositati in UnissResearch sono protetti dalle leggi che regolano il diritto d'autore

Repository Staff Only: item control page