1999 年 57 巻 10 号 p. 876-887
Recently, it has been reported that some unsaturated aldehyde terpenoids inhibit phospholipase A2 (PLA2), which catalyzes hydrolysis of the ester linkage at the sn-2 position of glycerophospholipids. Since the release of arachidonic acid from glycerophospholipids is the rate-limiting step in the production of eicosanoid mediators of inflammation, the inhibitory mechanism of PLA2 by these aldehyde terpenoids has been of biochemical and medicinal interest.
It is known at present that the three aldehyde terpenoids, scalaradial, manoalide, and (E) -3methoxycarbonyl-2, 4, 6-trienal compound A strongly inactivate PLA2. As the inhibitory mechanism of PLA2 by manoalide, our group has found that the irreversible modification of Lys 56 in the interfacial recognition site of bovine PLA2 by manoalide is responsible for the inactivation of this enzyme. Although the real reaction mechanism between manoalide and the lysine residues of PLA2 has not been elucidated, our model studies on the reactions between manoalide analogs and mono- and diamines strongly suggested that manoalide reacted with the two close lysine residues to give polymerized compounds. In the case of the (E) -3-methoxycarbonyl-2, 4, 6-trienal compound A, it would inhibit the hydrolytic activity of bovine pancreatic PLA2 by the formation of the dihydropyridine derivatives resulting from the reaction with lysine residues of PLA2via 6π-electrocyclization of the intermediary Schiff bases. Moreover, scalaradial also irreversibly reacts with lysine residues to inactivate PLA2, and the production of the pyrrole derivative has been proposed by Cimino and coworkers based on the model reaction with methylamine.
Thus, it would be concluded that the irreversible formation of the product by the reaction with the lysine residue in the interfacial recognition site of PLA2 is essential for sufficient inactivation of PLA2 by unsaturated aldehyde terpenoids such as manoalide, scalaradial, and the (E) -3-methoxycarbonyl2, 4, 6-trienal compounds.