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Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase pi
Lin, Yu1,2; Huang, Yongdong3; Zheng, Wei1,2; Wang, Fuyi1,2; Habtemariam, Abraha4; Luo, Qun1,2; Li, Xianchan1,2; Wu, Kui1,2; Sadler, Peter J.4; Xiong, Shaoxiang1,2
2013-11-01
Source PublicationJOURNAL OF INORGANIC BIOCHEMISTRY
Volume128Issue:0Pages:77-84
AbstractThe organometallic ruthenium(II) anticancer complexes [(eta(6)-arene)Ru(en)Cl](+) (arene = p-cymene (1), biphenyl (2) or 9,10-dihydrophenanthrene (3); en = ethylenediamine), exhibit in vitro and in vivo anticancer activities. In the present work, we show that they inhibit human glutathione-S-transferase pi (GST pi) with IC50 values of 59.4 +/- 13, 63.2 +/- 0.4 and 37.2 +/- 1.1 mu M, respectively. Mass spectrometry revealed that complex 1 binds to the S-donors of Cys15, Cys48 within the G-site and Cys102 at the interface of the GST pi dimer, while complex 2 binds to Cys48 and Met92 at the dimer interface and complex 3 to Cys15, Cys48 and Met92. Moreover, the binding of complex 1 to Cys15 and Cys102, complex 2 to Cys48 and complex 3 to Cys15 induces the irreversible oxidation of the coordinated thiolates to sulfenates. Molecular modeling studies indicate that the coordination of the {(arene)Ru(en)}(2+) fragment to Cys48 blocks the hydrophilic G-site sterically, perhaps preventing substrate from proper positioning and accounting for the reduction in enzymatic activity of ruthenated GST pi. The binding of the ruthenium arene complexes to Cys102 or Met92 disrupts the dimer interface which is an essential structural feature for the proper functioning of GMT, perhaps also contributing to the inhibition of GST pi. (C) 2013 Elsevier Inc. All rights reserved.
KeywordOrganometallic Ruthenium Complex Anticancer Glutathione-s-transferase Enzyme Inhibition Mass Spectrometry
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine ; Physical Sciences
Indexed BySCI
Language英语
WOS KeywordTANDEM MASS-SPECTROMETRY ; STABLE SULFENIC ACID ; DNA-BINDING PROTEINS ; ARENE COMPLEXES ; 3-DIMENSIONAL STRUCTURE ; LIQUID-CHROMATOGRAPHY ; CISPLATIN BINDING ; SUBUNIT INTERFACE ; DRUG-RESISTANCE ; ETHACRYNIC-ACID
WOS Research AreaBiochemistry & Molecular Biology ; Chemistry
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Inorganic & Nuclear
WOS IDWOS:000326060800009
Citation statistics
Cited Times:25[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/13357
Collection研究所(批量导入)
Affiliation1.Beijing Natl Lab Mol Sci, Beijing 100190, Peoples R China
2.Chinese Acad Sci, Inst Chem, CAS Key Lab Analyt Chem Living Biosyst, Beijing 100864, Peoples R China
3.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing 100190, Peoples R China
4.Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England
Recommended Citation
GB/T 7714
Lin, Yu,Huang, Yongdong,Zheng, Wei,et al. Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase pi[J]. JOURNAL OF INORGANIC BIOCHEMISTRY,2013,128(0):77-84.
APA Lin, Yu.,Huang, Yongdong.,Zheng, Wei.,Wang, Fuyi.,Habtemariam, Abraha.,...&Xiong, Shaoxiang.(2013).Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase pi.JOURNAL OF INORGANIC BIOCHEMISTRY,128(0),77-84.
MLA Lin, Yu,et al."Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase pi".JOURNAL OF INORGANIC BIOCHEMISTRY 128.0(2013):77-84.
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