610308-75-3Relevant academic research and scientific papers
Design, synthesis, and evaluation of water-soluble phospholipid analogues as inhibitors of phospholipase C from Bacillus cereus
Franklin, Christopher L.,Li, Hui,Martin, Stephen F.
, p. 7298 - 7307 (2007/10/03)
The rate of hydrolysis of natural phospholipids by the phosphatidyleholine-preferring phospholipase C from Bacillus cereus (PLC Bc) follows the order phosphatidylcholine > phosphatidylethanolamine ? phosphatidyl-L-serine. To probe the structural basis for this substrate specificity, a series of water-soluble, nonhydrolyzable substrate analogues were needed so their complexes with the enzyme could be studied via X-ray crystallography and isothermal titration calorimetry (ITC). Accordingly the water-soluble dithiophospholipids 2-10 having choline, ethanolamine, and L-serine headgroups were synthesized, and the inhibitory activity of each was determined in an assay using 1,2-dihexanoyl-sn-glycero-3-phosphocholine (C6PC) as the monomeric substrate. The 1,2-dibutanoyl dithiophosphocholine 2 was a weak inhibitor, whereas the related 1,2-dipentanoyl dithiophospho-choline 3 and the ethylene glycol dithiophosphocholines 4 and 5 were moderate inhibitors. The 1,2-ω -hydroxydiacyl dithiophosphocholines 6 and 7 were potent inhibitors, while the related compound 8, which had shorter acyl side chains, was a weak inhibitor. The dithiophosphoethanolamine 9 was a modest inhibitor, whereas the dithiophospho-L-serine 10 was a somewhat weaker inhibitor. Overall, the phospholipid analogues had increasing Ki values according to the order 2 ? 10 3 4 ≈ 5 ≈ 8 9 ? 6 ? 7 and increasing solubility according to the sequence 5 ≈ 7 4 ≈ 6 ≈ 9 3 10 8 2.
