Differential Reactivity of Metal Binding Domains of Copper ATPases towards Cisplatin and Colocalization of Copper and Platinum. Issue 36 (30th May 2018)

• Record Type: Journal Article
• Authors: Fang, Tiantian; Tian, Yao; Yuan, Siming; Sheng, Yaping; Arnesano, Fabio; Natile, Giovanni; Liu, Yangzhong
• Is Part Of: Chemistry. Volume 24:Issue 36(2018)
• Page Start: 8999
• Page End: 9003
• Publication Date: 2018-05-30
• Subjects: cisplatin -- copper-ATPase -- mechanism -- metallodrugs; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201801894
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The Menkes (MNK) and Wilson (WLN) disease proteins are two P‐type ATPases responsible for active Cu efflux. These ATPases are also associated with resistance to cisplatin. In this work, different metal‐binding domains (MBDs) of ATPases (9 out of 12 domains) were compared based on their reactivity towards cisplatin. The reaction rates of the MBDs can be largely different; the reaction of MNK6 is about six times faster than that of WLN2. Copper coordination favors the platination of the MBDs to different extents. The rate of platination was generally greater for holo‐MBDs than for apo‐MBDS (particularly in the case of WLN4 and WLN2); however, it was negligibly affected in the case of MNK6. Interestingly, the platinum binding weakens the Cu I coordination, but does not expel the copper ion from MBDs. The latter results nicely explain the inhibitory effect of Cu upon the cisplatin translocation promoted by Cu‐ATPases and can help in understanding how copper levels can modulate the sensitivity of cancer cells to platinum chemotherapy. Abstract : The various metal‐binding domains (MBDs) of Cu‐ATPases show different reactivity towards cisplatin. Copper coordination favors the platination of the MBDs to different extents. Platinum binding weakens the Cu I coordination, but does not expel the copper ion from the MBD, which can explain the inhibitory effect of Cu I upon the translocation of cisplatin promoted by Cu‐ATPases.