30 マノアライドによるホスホリパーゼA_2不活性化機構の解明にむけて(ポスター発表の部)

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Manoalide isolated from the marine sponge significantly reduces chemically induced inflammation in vivo and irreversibly inhibits phospholipase A_2 (PLA2) directly. PLA_2 is an enzyme hydrolyzing the ester linkage at C-2 position of phospholipid, and is found in several neurotoxic venoms, pancreas of animals, and various cells. We have studied independently to elucidate the mechanism of inhibition of PLA_2 by synthesized manoalide and its analogues. PLA_2 used in our study was isolated from bovine pancreas, and the activity was measured toward the mixed micell of di-dodecanoylphosphatidylcholine with sodium cholate. Our study is focused the following three points. 1. Development of simple analogue for manoalide which possesses the equal ability to inhibit PLA_2 comparing to that of dl-manoalide. 2. Elucidation of the necessary functional groups in manoalide to inhibit PLA_2. 3. Understanding the inhibition mechanism of PLA_2 by manoalide; 1)identification and characterization of the amino acid residues which are modified by manoalide selectively, and 2)understanding the mechanism of the reaction of manoalide with those amino acids residues. We have found that compound 1a is an excellent analogue of manoalide and the two aldehyde groups of manoalide is essentially necessary for the inhibition of PLA_2. Furthermore, it was strongly suggested that analogue 1a reacted selectively with Lys^<53> and Lys^<56> in bovine pancreatic PLA_2, and resulted that the hydrolytic ability of bovine pancreatic PLA_2 toward the mixed micell of phosphatidylcholine with sodium cholate was inhibited. These results suggest that Lys^<53> and Lys^<56> are probably concerned with the binding of mixed micell forming from phospholids and anionic surface-active agents.
天然有機化合物討論会の論文
1991-09-07

30 マノアライドによるホスホリパーゼA_2不活性化機構の解明にむけて(ポスター発表の部)

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