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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Abstract

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
Volume286
Issue number44
DOIs
Publication statusPublished - Nov 4 2011

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Clotrimazole
Adenosine Triphosphatases
Chemical activation
Derivatives
Thapsigargin
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Enzyme Activation
Inhibitory Concentration 50
Charge transfer
Stabilization
Adenosine Triphosphate
Rabbits
4-aminoquinoline
Enzymes
Experiments
7-chloro-4-aminoquinoline

ASJC Scopus subject areas

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

Cite this

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

In: Journal of Biological Chemistry, Vol. 286, No. 44, 04.11.2011, p. 38383-38389.

Research output: Contribution to journalArticle

Bartolommei, G, Tadini-Buoninsegni, F, Moncelli, MR, Gemma, S, Camodeca, C, Butini, S, Campiani, G, Lewis, D & Inesi, G 2011, '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', Journal of Biological Chemistry, vol. 286, no. 44, pp. 38383-38389. https://doi.org/10.1074/jbc.M111.287276
Bartolommei, Gianluca ; Tadini-Buoninsegni, Francesco ; Moncelli, Maria Rosa ; Gemma, Sandra ; Camodeca, Caterina ; Butini, Stefania ; Campiani, Giuseppe ; Lewis, David ; Inesi, Giuseppe. / 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. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 44. pp. 38383-38389.
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abstract = "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.",
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T1 - 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

AU - Bartolommei, Gianluca

AU - Tadini-Buoninsegni, Francesco

AU - Moncelli, Maria Rosa

AU - Gemma, Sandra

AU - Camodeca, Caterina

AU - Butini, Stefania

AU - Campiani, Giuseppe

AU - Lewis, David

AU - Inesi, Giuseppe

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N2 - 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.

AB - 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.

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