Tanaka K, Matsutani S, Kanda A, Kato T, Yoshida T
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
J Antibiot (Tokyo). 1994 Jun;47(6):631-8. doi: 10.7164/antibiotics.47.631.
Evidence accumulated to date suggests that extracellular group II phospholipase A2 (PLA2-II) is involved in the pathogenesis of inflammatory disease. During screening for PLA2 inhibitors, we found a novel PLA2 inhibitor named thielocin B3 in the culture broth of an ascomycetes. Thielocin B3 strongly inhibited human PLA2-II (IC50 = 0.076 microM) in a reversible and noncompetitive manner (Ki = 0.098 microM), whereas it inhibited human group I PLA2 only weakly (IC50 = 18 microM). It also quenched the tryptophan fluorescence of Naja mocambique venom PLA2; almost 100% quenching being attained at a thielocin B3/enzyme molar ratio of 1.0. Its inhibitory activity toward human PLA2-II and Naja mocambique PLA2 was markedly decreased by methylation of its two carboxyl groups, while the quenching observed for Naja mocambique PLA2 was not altered. These results suggest that the two carboxyl groups do not participate in the binding of thielocin B3 to the enzyme, but play a crucial role in the PLA2 inhibition. Furthermore, in the rat carrageenan-induced pleurisy model, thielocin B3 significantly reduced both exudate volume and PLA2 activity in the exudate when coinjected with carrageenan.
迄今积累的证据表明，细胞外II型磷脂酶A2（PLA2-II）参与炎症性疾病的发病机制。在筛选PLA2抑制剂的过程中，我们在一种子囊菌的培养液中发现了一种名为硫链丝菌素B3的新型PLA2抑制剂。硫链丝菌素B3以可逆和非竞争性方式强烈抑制人PLA2-II（IC50 = 0.076 microM）（Ki = 0.098 microM），而对人I型PLA2的抑制作用较弱（IC50 = 18 microM）。它还能淬灭莫桑比克眼镜蛇毒PLA2的色氨酸荧光；在硫链丝菌素B3/酶摩尔比为1.0时，几乎可达到100%淬灭。其两个羧基甲基化后，对人PLA2-II和莫桑比克眼镜蛇PLA2的抑制活性显著降低，而对莫桑比克眼镜蛇PLA2观察到的淬灭作用未改变。这些结果表明，两个羧基不参与硫链丝菌素B3与酶的结合，但在PLA2抑制中起关键作用。此外，在大鼠角叉菜胶诱导的胸膜炎模型中，与角叉菜胶共同注射时，硫链丝菌素B3显著降低了渗出液体积和渗出液中的PLA2活性。
