A pyrrolidine-based specific inhibitor of cytosolic phospholipase A(2)alpha blocks arachidonic acid release in a variety of mammalian cells.
We analyzed a recently reported (K. Seno, T. Okuno, K. Nishi, Y. Murakami, F. Watanabe, T. Matsuur, M. Wada, Y. Fujii, M. Yamada, T. Ogawa, T. Okada, H. Hashizume, M. Kii, S.-H. Hara, S. Hagishita, S. Nakamoto, J. Med. Chem. 43 (2000)) pyrrolidine-based inhibitor, pyrrolidine-1, against the human group IV cytosolic phospholipase A(2) alpha-isoform (cPLA(2)alpha). Pyrrolidine-1 inhibits cPLA(2)alpha by 50% when present at approx. 0.002 mole fraction in the interface in a number of in vitro assays. It is much less potent on the cPLA(2)gamma isoform, calcium-independent group VI PLA(2) and groups IIA, X, and V secreted PLA(2)s. Pyrrolidine-1 blocked all of the arachidonic acid released in Ca(2+) ionophore-stimulated CHO cells stably transfected with cPLA(2)alpha, in zymosan- and okadaic acid-stimulated mouse peritoneal macrophages, and in ATP- and Ca(2+) ionophore-stimulated MDCK cells.
Ghomashchi
F
F
Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195, USA.
Stewart
A
A
Hefner
Y
Y
Ramanadham
S
S
Turk
J
J
Leslie
C C
CC
Gelb
M H
MH
D000818:Animals; D016718:Arachidonic Acid / Q000032:analysis / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D054513:Group IV Phospholipases A2; D006801:Humans; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D010743:Phospholipids / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D008563:Membrane Lipids; D010743:Phospholipids; D011759:Pyrrolidines; D016718:Arachidonic Acid; D010741:Phospholipases A; D054513:Group IV Phospholipases A2