Koglin Markus, Stasch Johannes-Peter, Behrends Sönke
Institut für Experimentelle und Klinische Pharmakologie, Universität Hamburg, Martinistrasse 52, Hamburg, D-20246, Germany.
Biochem Biophys Res Commun. 2002 Apr 12;292(4):1057-62. doi: 10.1006/bbrc.2002.6764.
Soluble guanylyl cyclase is an important target for endogenous nitric oxide and the guanylyl cyclase modulator, YC-1. Recently BAY 41-2272 was identified as a similar but more potent and more specific substance. While YC-1 also acts as non-specific phosphodiesterase inhibitor, BAY 41-2272 is devoid of an effect on phosphodiesterases. BAY 41-2272 has so far only been tested on the alpha(1)/beta(1) heterodimeric isoform of soluble guanylyl cyclase and its binding site has been mapped to a region in the alpha(1) subunit amino-terminal sequence. Although this region is poorly conserved in the alpha(2) subunit, we show in the current study that the alpha(2)/beta(1) heterodimeric enzyme isoform is activated by BAY 41-2272. Deletion analysis of the alpha(2) subunit and co-expression with the beta(1) subunit in the baculovirus/Sf9 system is consistent with the amino-terminal amino acids 104 to 401 of the alpha(2) subunit as binding site for BAY 41-2272.
可溶性鸟苷酸环化酶是内源性一氧化氮和鸟苷酸环化酶调节剂YC-1的重要靶点。最近，BAY 41-2272被鉴定为一种类似但更有效且更具特异性的物质。虽然YC-1也作为非特异性磷酸二酯酶抑制剂起作用，但BAY 41-2272对磷酸二酯酶没有影响。到目前为止，BAY 41-2272仅在可溶性鸟苷酸环化酶的α(1)/β(1)异源二聚体同工型上进行了测试，其结合位点已定位到α(1)亚基氨基末端序列的一个区域。尽管该区域在α(2)亚基中保守性较差，但我们在当前研究中表明，α(2)/β(1)异源二聚体酶同工型被BAY 41-2272激活。在杆状病毒/Sf9系统中对α(2)亚基进行缺失分析并与β(1)亚基共表达，结果表明α(2)亚基的氨基末端氨基酸104至401作为BAY 41-2272的结合位点。
