Nakane M, Murad F
Pharmaceutical Products Division Abbott Laboratories, Abbott Park, Illinois 60064.
Adv Pharmacol. 1994;26:7-18. doi: 10.1016/s1054-3589(08)60048-4.
The cloning of particulate and soluble guanylyl cyclases is summarized in Table I. With respect to transmembrane signal transduction systems, guanylyl and adenylyl cyclases can be grouped together with some protein tyrosine kinases and protein tyrosine phosphatases to form a diverse protein family with various structural and functional similarities (Garbers, 1989, 1991, 1992; Koesling et al., 1991; Chinkers and Garbers, 1991; Fig. 1). Particulate guanylyl cyclase contains a single transmembrane domain, and the peptide-binding portion (ligand receptor) is on the exterior surface and the catalytic region on the interior, similar to the protein tyrosine kinase/receptor and the protein tyrosine phosphatase/receptor families (Yarden et al., 1986; Charbonneau et al., 1988; Tonks et al., 1988). Protein tyrosine kinases and phosphatases are also activated by ligand binding to the extracellular domain, which in turn results in phosphorylation or dephosphorylation. On the other hand, soluble guanylyl cyclase exists as a heterodimer with two putative catalytic domains, and both subunits are essential for enzyme activity and activation by nitric oxide. It is thus particularly interesting that adenylyl cyclase also contains two catalytic domains, which are both necessary for catalytic activity (Tang et al., 1991). It is possible that particulate guanylyl cyclase may also dimerize on hormonal stimulation and two catalytic domains from two monomers form a functional catalytic center capable of forming cyclic GMP. The catalytic core of GC-A expressed in bacteria was shown to form a homodimer with positively cooperative kinetics (Thorpe et al., 1991). The physiological significance of the existence of multiple forms of soluble guanylyl cyclase subunits remains unclear. Future studies should reveal the differences in tissue distribution and activation by nitrovasodilators in various heterodimers of soluble guanylyl cyclase.
颗粒型和可溶性鸟苷酸环化酶的克隆情况总结于表I。关于跨膜信号转导系统，鸟苷酸环化酶和腺苷酸环化酶可与一些蛋白酪氨酸激酶和蛋白酪氨酸磷酸酶归为一类，形成一个具有各种结构和功能相似性的多样蛋白家族（加伯斯，1989年、1991年、1992年；克斯林等人，1991年；钦克斯和加伯斯，1991年；图1）。颗粒型鸟苷酸环化酶含有一个单一跨膜结构域，肽结合部分（配体受体）位于外表面，催化区域位于内部，类似于蛋白酪氨酸激酶/受体和蛋白酪氨酸磷酸酶/受体家族（亚登等人，1986年；沙博诺等人，1988年；汤克斯等人，1988年）。蛋白酪氨酸激酶和磷酸酶也通过配体与细胞外结构域结合而被激活，进而导致磷酸化或去磷酸化。另一方面，可溶性鸟苷酸环化酶以具有两个推定催化结构域的异二聚体形式存在，两个亚基对于酶活性和一氧化氮激活均至关重要。因此特别有趣的是，腺苷酸环化酶也含有两个催化结构域，这两个结构域对于催化活性都是必需的（唐等人，1991年）。颗粒型鸟苷酸环化酶在激素刺激下也可能二聚化，来自两个单体的两个催化结构域形成一个能够形成环磷酸鸟苷的功能性催化中心。在细菌中表达的GC - A的催化核心显示形成具有正协同动力学的同二聚体（索普等人，1991年）。可溶性鸟苷酸环化酶亚基多种形式存在的生理意义仍不清楚。未来的研究应揭示可溶性鸟苷酸环化酶各种异二聚体在组织分布和硝基血管扩张剂激活方面的差异。
