Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2 - PubMed (original) (raw)
. 1993 Jun 15;32(23):5935-40.
doi: 10.1021/bi00074a003.
Affiliations
- PMID: 8018213
- DOI: 10.1021/bi00074a003
Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2
I P Street et al. Biochemistry. 1993.
Abstract
A trifluoromethyl ketone analogue of arachidonic acid in which the COOH group is replaced with COCF3 (AACOCF3) was prepared and found to be a tight- and slow-binding inhibitor of the 85-kDa cytosolic human phospholipase A2 (cPLA2). Enzyme inhibition was observed when AACOCF3 was tested in assays using either phospholipid vesicles or phospholipid/Triton X-100 mixed micelles. The fact that the inhibition developed over several minutes in both assays establishes that AACOCF3 inhibits by direct binding to the enzyme rather than by decreasing the fraction of enzyme bound to the substrate interface. From the measured values of the inhibitor association and dissociation rate constants, an upper limit of the equilibrium dissociation constant for the Ca(2+).AACOCF3.PLA2 complex of 5 x 10(-5) mole fraction was obtained. Thus, detectable inhibition of cPLA2 by AACOCF3 occurs when this compound is present in the assay at a level of one inhibitor per several thousand substrates. Arachidonic acid analogues in which the COOH group is replaced by COCH3, CH(OH)CF3, CHO, or CONH2 did not detectably inhibit the cPLA2. The arachidonyl ketones AACOCF2CF3 and AACOCF2Cl were found by 19F NMR to be less hydrated than AACOCF3 in phospholipid/Triton X-100 mixed micelles, and compared to AACOCF3 these compounds are also weaker inhibitors of cPLA2. In keeping with the fact that cPLA2 displays substrate specificity for arachidonyl-containing phospholipids, the arachidic acid analogue C19H39COCF3 is a considerably less potent inhibitor compared to AACOCF3.(ABSTRACT TRUNCATED AT 250 WORDS)
Similar articles
- Arachidonyl trifluoromethyl ketone, a potent inhibitor of 85-kDa phospholipase A2, blocks production of arachidonate and 12-hydroxyeicosatetraenoic acid by calcium ionophore-challenged platelets.
Riendeau D, Guay J, Weech PK, Laliberté F, Yergey J, Li C, Desmarais S, Perrier H, Liu S, Nicoll-Griffith D, et al. Riendeau D, et al. J Biol Chem. 1994 Jun 3;269(22):15619-24. J Biol Chem. 1994. PMID: 8195210 - NMR structural studies of the tight complex between a trifluoromethyl ketone inhibitor and the 85-kDa human phospholipase A2.
Trimble LA, Street IP, Perrier H, Tremblay NM, Weech PK, Bernstein MA. Trimble LA, et al. Biochemistry. 1993 Nov 30;32(47):12560-5. doi: 10.1021/bi00210a002. Biochemistry. 1993. PMID: 8251473 - Cytosolic phospholipase A2 inhibition attenuates ischemia-reperfusion injury in an isolated rat lung model.
Bellido-Reyes YA, Akamatsu H, Kojima K, Arai H, Tanaka H, Sunamori M. Bellido-Reyes YA, et al. Transplantation. 2006 Jun 27;81(12):1700-7. doi: 10.1097/01.tp.0000226065.82066.21. Transplantation. 2006. PMID: 16794537 - Inhibition of collagen-induced platelet activation by arachidonyl trifluoromethyl ketone.
McNicol A, Nickolaychuk BR. McNicol A, et al. Biochem Pharmacol. 1995 Nov 27;50(11):1795-802. doi: 10.1016/0006-2952(95)02048-9. Biochem Pharmacol. 1995. PMID: 8615857 - Distinguishing phospholipase A2 types in biological samples by employing group-specific assays in the presence of inhibitors.
Lucas KK, Dennis EA. Lucas KK, et al. Prostaglandins Other Lipid Mediat. 2005 Sep;77(1-4):235-48. doi: 10.1016/j.prostaglandins.2005.02.004. Prostaglandins Other Lipid Mediat. 2005. PMID: 16099408 Review.
Cited by
- Synthesis, activity and metabolic stability of propan-2-one substituted tetrazolylalkanoic acids as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase.
Ekodo Voundi M, Hanekamp W, Lehr M. Ekodo Voundi M, et al. RSC Med Chem. 2023 Aug 10;14(10):2079-2088. doi: 10.1039/d3md00224a. eCollection 2023 Oct 18. RSC Med Chem. 2023. PMID: 37859716 Free PMC article. - Functions and mechanisms of cytosolic phospholipase A2 in central nervous system trauma.
Zhang HJ, Chen YT, Hu XL, Cai WT, Wang XY, Ni WF, Zhou KL. Zhang HJ, et al. Neural Regen Res. 2023 Feb;18(2):258-266. doi: 10.4103/1673-5374.346460. Neural Regen Res. 2023. PMID: 35900400 Free PMC article. Review. - Dynamic Role of Phospholipases A2 in Health and Diseases in the Central Nervous System.
Sun GY, Geng X, Teng T, Yang B, Appenteng MK, Greenlief CM, Lee JC. Sun GY, et al. Cells. 2021 Oct 30;10(11):2963. doi: 10.3390/cells10112963. Cells. 2021. PMID: 34831185 Free PMC article. Review. - The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies.
Ramer R, Wittig F, Hinz B. Ramer R, et al. Cancers (Basel). 2021 Nov 15;13(22):5701. doi: 10.3390/cancers13225701. Cancers (Basel). 2021. PMID: 34830856 Free PMC article. Review. - Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma.
Cioce M, Canino C, Pass H, Blandino G, Strano S, Fazio VM. Cioce M, et al. J Exp Clin Cancer Res. 2021 Nov 2;40(1):344. doi: 10.1186/s13046-021-02118-y. J Exp Clin Cancer Res. 2021. PMID: 34727953 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources
Miscellaneous