アルデヒドテルペノイドによるホスホリパーゼA₂不活性化機構

抄録

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.