FEBS Letters | |
Derivatives of thapsigargin as probes of its binding site on endoplasmic reticulum Ca2+ ATPase | |
Poulsen, Jens-Christian J.2  Andersen, Annette1  Christensen, Søren Brøgger1  Treiman, Marek2  | |
[1] PharmaBiotec, Department of Organic Chemistry, The Royal Danish School of Pharmacy, University of Copenhagen, Copenhagen, Denmark;Department of Medical Physiology, Biotechnology Center for Signal Peptide Research, University of Copenhagen, Panun Institute, Blegdamsvej 3C, DK-2200 N Copenhagen, Denmark | |
关键词: Thapsigargin; Ca2+ ATPase; Endoplasmic reticulum; Ca2+ store; | |
DOI : 10.1016/0014-5793(93)80416-R | |
学科分类:生物化学/生物物理 | |
来源: John Wiley & Sons Ltd. | |
【 摘 要 】
The naturally occurring sesquiterpene lactone thapsigargin is a potent and selective inhibitor of SERCA ATPases, a family of Ca2+-pumping ATPases present in the endoplasmic reticulum of all mammalian cells. We have studied some of the molecular features of thapsigargin responsible for its inhibitory action towards these Ca2+ ATPases. A series of thapsigargin analogues were synthesised and their inhibitory potencies determined using the uptake of 45Ca2+ in bovine cerebellar microsomes as a sensitive marker of Ca2+ ATPase activity. An attenuation of the inhibitory potency relative to the parent compound was found ranging from slight to over 3 orders of magnitude. The inhibitory activity showed a very strong configuration dependence, a major contribution from the ester groups at C3 and C10, and an apparently minor contribution from the lactone ring substituents. The data are consistent with thapsigargin fitting to a sterically discriminating cleft involving the hydrophobic transmembrane region of the ATPase, and is compatible with available kinetic evidence of thapsigargin-mediated inhibition.
【 授权许可】
Unknown
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