二硫化五亚甲基秋兰姆是Pin1的新型抑制剂。
Dipentamethylene thiuram monosulfide is a novel inhibitor of Pin1.
作者信息
Tatara Yota, Lin Yi-Chin, Bamba Yoshimasa, Mori Tadashi, Uchida Takafumi
机构信息
Molecular Enzymology, Department of Molecular and Cell Biology, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba, Sendai, Miyagi 981-8555, Japan.
出版信息
Biochem Biophys Res Commun. 2009 Jul 3;384(3):394-8. doi: 10.1016/j.bbrc.2009.04.144. Epub 2009 May 5.
Pin1 is involved in eukaryotic cell proliferation by changing the structure and function of phosphorylated proteins. PiB, the Pin1 specific inhibitor, blocks cancer cell proliferation. However, low solubility of PiB in DMSO has limited studies of its effectiveness. We screened for additional Pin1 inhibitors and identified the DMSO-soluble compound dipentamethylene thiuram monosulfide (DTM) that inhibits Pin1 activity with an EC50 value of 4.1 microM. Molecular modeling and enzyme kinetic analysis indicated that DTM competitively inhibits Pin1 activity, with a K(i) value of 0.05 microM. The K(D) value of DTM with Pin1 was determined to be 0.06 microM by SPR technology. Moreover, DTM specifically inhibited peptidyl-prolyl cis/trans isomerase activity in HeLa cells. FACS analysis showed that DTM induced G0 arrest of the HCT116 cells. Our results suggest that DTM has the potential to guide the development of novel antifungal and/or anticancer drugs.
Pin1通过改变磷酸化蛋白的结构和功能参与真核细胞增殖。Pin1特异性抑制剂PiB可阻断癌细胞增殖。然而，PiB在二甲基亚砜（DMSO）中的低溶解度限制了对其有效性的研究。我们筛选了其他Pin1抑制剂，并鉴定出可溶于DMSO的化合物二亚戊基二硫代氨基甲酸盐（DTM），其抑制Pin1活性的半数有效浓度（EC50）值为4.1微摩尔。分子建模和酶动力学分析表明，DTM竞争性抑制Pin1活性，抑制常数（K(i)）值为0.05微摩尔。通过表面等离子体共振（SPR）技术测定DTM与Pin1的解离常数（K(D)）值为0.06微摩尔。此外，DTM特异性抑制HeLa细胞中的肽基脯氨酰顺反异构酶活性。荧光激活细胞分选（FACS）分析表明，DTM诱导HCT116细胞停滞于G0期。我们的结果表明，DTM有潜力指导新型抗真菌和/或抗癌药物研发。
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