Inhibition of adenylyl and guanylyl cyclase isoforms by the antiviral drug foscarnet

作     者：Kudlacek, O Mitterauer, T Nanoff, C Hohenegger, M Tang, WJ Freissmuth, M Kleuss, C 

作者机构：Univ Vienna Inst Pharmacol A-1090 Vienna Austria Univ Chicago Dept Neurobiol Pharmacol & Physiol Chicago IL 60637 USA Free Univ Berlin Inst Pharmacol D-14195 Berlin Germany 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：2001年第276卷第5期

页      面：3010-3016页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

主　　题：腺苷酸环化酶/拮抗剂和抑制剂 抗肿瘤联合化疗方案 抗病毒药/药理学 细胞 培养的 仓鼠亚科 环AMP/代谢 环GMP/代谢 环磷酰胺 二聚作用 二磷酸盐类/化学 二磷酸盐类/代谢 二磷酸盐类/药理学 多柔比星 酶抑制剂/药理学 膦甲酸/药理学 GTP结合蛋白质α亚单位 Gs/代谢 鸟苷酸环化酶/拮抗剂和抑制剂 同工酶类/拮抗剂和抑制剂 膜蛋白质类/代谢 长春新碱 动物 人类 

摘      要：The pyrophosphate (PPi) analog foscarnet inhibits viral DNA-polymerases and is used to treat cytomegalovirus and human immunodeficiency vius infections. Nucleotide cyclases and DNA-polymerases catalyze analogous reactions, i.e. a phosphodiester bond formation, and have similar topologies in their active sites. Inhibition by foscarnet of adenylyl cyclase isoforms was therefore tested with (i) purified catalytic domains C1 and C2 of types I and VII (IC1 and VIIC1) and of type II (IIC2) and (ii) membrane-bound holoenzymes (from mammalian tissues and types I, II, and V heterologously expressed in Sf9 cell membranes). Foscarnet was more potent than PPi in suppressing forskolin-stimulated catalysis by both, IC1/IIC2 and VIIC1/IIC2. Stimulation of VIIC1/IIC2 by G alpha (s) relieved the inhibition by foscarnet but not that by PPi, The IC50 of foscarnet on membrane-bound adenylyl cyclases also depended on their mode of regulation. These findings predict that receptor-dependent cAMP formation is sensitive to inhibition by foscarnet in some, but not all, cells. This was verified with two cell lines;foscarnet blocked cAMP accumulation after A(2A)-adenosine receptor stimulation in PC12 but not in HEK-A(2A) cells. Foscarnet also inhibited soluble and, to a lesser extent, particulate guanylyl cylase, Thus, foscarnet interferes with the generation of cyclic nucleotides, an effect which may give rise to clinical side effects. The extent of inhibition varies with the enzyme isoform and with the regulatory input.