The Ca 2+-ATpase (SERCA1) is inhibited by 4-aminoquinoline derivatives through interference with catalytic activation by Ca 2+, whereas the ATPase E 2 state remains functional

Gianluca Bartolommei, Francesco Tadini-Buoninsegni, Maria Rosa Moncelli, Sandra Gemma, Caterina Camodeca, Stefania Butini, Giuseppe Campiani, David Lewis, Giuseppe Inesi

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Several clotrimazole (CLT) and 4-aminoquinoline derivatives were synthesized and found to exhibit in vitro antiplasmodial activity with IC50 ranging from nM to μM values. We report here that some of these compounds produce inhibition of rabbit sarcoplasmic reticulum Ca 2+-ATPase (SERCA1) with IC 50 values in the μM range. The highest affinity for the Ca 2+-ATPase was observed with NF1442 (N-((3-chlorophenyl)(4- ((4-(7-chloroquinolin- 4-yl)piperazin-1-yl)methyl)phenyl)methyl)-7-chloro- 4-aminoquinoline) and NF1058 (N-((3-chlorophenyl)(4-(pyrrolidin- 1-ylmethyl)phenyl)methyl)-7-chloro-4-aminoquinoline), yielding IC 50 values of 1.3 and 8.0 μM as demonstrated by measurements of steady state ATPase activity as well as single cycle charge transfer. Characterization of sequential reactions comprising the ATPase catalytic and transport cycle then demonstrated that NF1058, and similarly CLT, interferes with the mechanism of Ca 2+ binding and Ca 2+-dependent enzyme activation (E 2 to E 1·Ca 2 transition) required for formation of phosphorylated intermediate by ATP utilization. On the other hand, Ca 2+ ndependent phosphoenzyme formation by utilization of P i (i.e. reverse of the hydrolytic reaction in the absence of Ca 2+) was not inhibited by NF1058 or CLT. Comparative experiments showed that the high affinity inhibitor thapsigargin interferes not only with Ca 2+ binding and phosphoenzyme formation with ATPbut also with phosphoenzyme formation by utilization of P i even though this reaction does not require Ca 2+. It is concluded that NF1058 and CLT inhibit SERCA by stabilization of an E 2 state that, as opposed to that obtained with thapsigargin, retains the functional ability to form E 2-P by reacting with P i.

Original languageEnglish
Pages (from-to)38383-38389
Number of pages7
JournalJournal of Biological Chemistry
Issue number44
Publication statusPublished - Nov 4 2011

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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