Radeke H S, Digits C A, Casaubon R L, Snapper M L
Eugene F Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467-3860, USA.
Chem Biol. 1999 Sep;6(9):639-47. doi: 10.1016/s1074-5521(99)80115-x.
The marine sponge metabolite (-)-ilimaquinone has antimicrobial, anti-HIV, anti-inflammatory and antimitotic activities, inhibits the cytotoxicity of ricin and diptheria toxin, and selectively fragments the Golgi apparatus. The range of activities demonstrated by this natural product provides a unique opportunity for studying these cellular processes.
Affinity chromatography experiments show that (-)-ilimaquinone interacts with enzymes of the activated methyl cycle: S-adenosylmethionine synthetase, S-adenosylhomocysteinase and methyl transferases. Known inhibitors of these enzymes were found to block vesicle-mediated secretion in a manner similar to (-)-ilimaquinone. Moreover, the antisecretory effects of (-)-ilimaquinone and inhibitors of methylation chemistry, but not brefeldin A, could be reversed in the presence of the cellular methylating agent S-adenosylmethionine. Of the enzymes examined in the activated methyl cycle, S-adenosylhomocysteinase was specifically inhibited by (-)-ilimaquinone. Consistent with these observations, (-)-ilimaquinone was shown to obstruct new methylation events in adrenocorticotrophic hormone (ACTH)-secreting pituitary cells.
(-)-ilimaquinone inhibits cellular methylations through its interactions with S-adenosylhomocysteinase. Furthermore, these studies indicate that the inhibition of secretion by ilimaquinone is the result of the natural product's antimethylation activity. It is likely that the ability to fragment the Golgi apparatus, as well as other activities, are also related to ilimaquinone's influence on methylation chemistry.
海洋海绵代谢产物（-）-伊立莫醌具有抗菌、抗艾滋病毒、抗炎和抗有丝分裂活性，可抑制蓖麻毒素和白喉毒素的细胞毒性，并选择性地使高尔基体断裂。这种天然产物所展示的一系列活性为研究这些细胞过程提供了独特的机会。
亲和层析实验表明，（-）-伊立莫醌与活性甲基循环的酶相互作用：S-腺苷甲硫氨酸合成酶、S-腺苷同型半胱氨酸酶和甲基转移酶。发现这些酶的已知抑制剂以类似于（-）-伊立莫醌的方式阻断囊泡介导的分泌。此外，在细胞甲基化剂S-腺苷甲硫氨酸存在的情况下，（-）-伊立莫醌和甲基化化学抑制剂（而非布雷菲德菌素A）的抗分泌作用可被逆转。在活性甲基循环中检测的酶中，（-）-伊立莫醌特异性抑制S-腺苷同型半胱氨酸酶。与这些观察结果一致，（-）-伊立莫醌被证明会阻碍分泌促肾上腺皮质激素（ACTH）的垂体细胞中的新甲基化事件。
（-）-伊立莫醌通过与S-腺苷同型半胱氨酸酶相互作用抑制细胞甲基化。此外，这些研究表明伊立莫醌对分泌的抑制是该天然产物抗甲基化活性的结果。伊立莫醌使高尔基体断裂的能力以及其他活性可能也与它对甲基化化学的影响有关。
