SYNTHESIS OF CHIRAL LIPIDS. APPLICATIONS TO THE SPECIFICITIES OF LIPOLYTIC ENZYMES.
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PublisherThe University of Arizona.
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AbstractIn this study, synthetic routes to certain short acyl chain phospholipids were developed. Their inhibitory or substrate properties for phospholipase A₂ were then examined. An improved method for the acylation of glycerophosphocholine is described using a mixed fatty acid - trifluoroacetic acid anhydride. This partial synthetic route is particularly suitable for obtaining short acyl chain phosphatidylcholines. A new pathway for constructing the unnatural sn-1-phosphatidylcholines is also described, starting from L-arabinose. This is converted first to a key intermediate, 2,3-O-isopropylidene-sn-glycerol, which is then phosphorylated and transformed into sn-glycero-1-phosphocholine. This can be acylated as above to give sn-1-phosphatidylcholines. Routes to the short chain phosphatidylethanolamines were investigated and discussed. A procedure, using phospholipase D, was used to convert L-diC₆ PC into L-diC₆ PE in a transphosphatidylation reaction. Failed attempts to obtain shorter chain homologs by this and other methods are also detailed. The kinetics of inhibition of the phospholipase A₂ hydrolysis of L-diC₆ PC by the D-isomer are also reported for the monomeric concentration range. It was found that the D- enantiomer did not behave as a pure competitive inhibitor, and that an enzyme-substrate-inhibitor complex can exist. The implications of these results with regard to PLA₂ hydrolysis of mixed micelles is discussed. The PLA₂ substrate properties of both the anionic and zwitterionic diC₆ PE's were also studied. It was established that the anionic diC₆ PE is either a very poor substrate relative to the zwitterionic diC₆ PE, or acts as a competitive inhibitor towards its hydrolysis. Similarly, the rates of base-catalyzed acyl ester hydrolysis are about 18 times greater for the zwitterionic than for the anionic diC₆ PE. The importance of a protonated amino group in both these hydrolyses studies is noted. In addition, certain physical properties of diC₆ PE, such as its critical micelle concentration and carbon-13 NMR spectrum, are also given.