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synthesis and biological evaluation of substituted indazolyl amide derivatives as s-adenosyl-L-homocysteine hydrolase inhibitors

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Chinese Chemical Letters 2016年第6期27卷 984-988页

作者： Xiang-Duan Tan Li-Guang Mao Wei Wu si-Yun Nian Guo-Ping Wang College of Pharmacy Guilin Medical University Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy The Ohio State University Zhangjiang Institute China State Institute of Pharmaceutical Industry shanghai Institute of Pharmaceutical Industry China State Institute of Pharmaceutical Industry

A series of novel amide derivatives bearing an indazole moiety were synthesized and evaluated for their in vitro s-adenosylL-homocysteine hydrolase（sAHase） inhibitory activity. Among these compounds, 8b,8m, 8r and 8w showed better or similar inhibitory effects compared to the positive control aristeromycin. These results provide a novel lead for the discovery of more potent non-adenosine analogs as sAHase inhibitors.

关键词： s-adenosylhomocysteine hydrolase sAHase inhibitors Amide derivatives Indazole synthesis

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Nuclear Targeting of Methyl-Recycling Enzymes in Arabidopsis thaliana Is Mediated by specific Protein Interactions

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Molecular Plant 2012年第1期5卷 231-248页

作者： sanghyun Lee Andrew C. Doxey Brendan J. McConkey Barbara A. Moffatt Department of Biology University of Waterloo Waterloo ON N2L 3G1 Canada Department of Developmental Biology Stanford University Stanford CA 94305 USA

Numerous transmethylation reactions are required for normal plant growth and development. s-adenosylhomocysteine hydrolase （sAHH） and adenosine kinase （ADK） act coordinately to recycle the by-product of these reactions, s-adenosylhomocysteine （sAH） that would otherwise competitively inhibit methyltransferase （MT） activities. Here, we report on investigations to understand how the sAH produced in the nucleus is metabolized by sAHH and ADK. Localization analyses using green fluorescent fusion proteins demonstrated that both enzymes are capable of localizing to the cytoplasm and the nucleus, although no obvious nuclear localization signal was found in their sequences. Deletion analysis revealed that a 41-amino-acid segment of sAHH （Glyls^-Lys19~） is required for nuclear targeting of this enzyme. This segment is surface exposed, shows unique sequence conservation patterns in plant sAHHs, and possesses additional features of protein-protein interaction motifs. ADK and sAHH interact in Arabidopsb via this segment and also interact with an mRNA cap MT. We propose that the targeting of this complex is directed by the nuclear localization signal of the MT; other MTs may similarly target sAHH/ADK to other subcellular compartments to ensure uninterrupted transmethylation.

关键词： Transmethylation subcellular localization s-adenosylhomocysteine hydrolase adenosine kinase nuclear targeting protein docking protein modeling protein motif analysis.

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s-Adenosyl homocysteine hydrolase may be involved in Dunaliella salina flagellar assembly and its overexpression induces apoptosis of esophageal squamous cell carcinoma

S-Adenosyl homocysteine hydrolase may be involved in Dunalie...

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生命的分子机器及其调控网络——2012年全国生物化学与...

作者： Qinghua Li Lihong Mao Ruili Wang Jie Li Lexun Xue Zhengzhou University

Background:As the only enzyme that catalyses the hydrolysis of s-adenosylhomocysteine,s-adenosylhomocysteine hydrolase (sAHH) is believed to play a critical role in the regula-tion of methylation reactions,and was screened to be one of the five new putative tumor suppressor by a genome-wide loss-of-function genetic screen in recent *** mod-ulating methylation is a very important biochemical mechanism that regulates gene ex-pression in many physiological ***:To investigate

关键词： s-adenosylhomocysteine hydrolase Dunaliella salina esophageal squamous cell carcinoma

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Effects of OGG1 methylation regulated byH19/sAHH/DNMT1 on the oxidative DNA damage and cell cycle arrest related to PAHs exposure

Effects of OGG1 methylation regulated byH19/SAHH/DNMT1 on th...

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中国毒理学会第九次全国毒理学大会

作者： LI Xue-jing FU Ye PAN Bao-long NIUYing-ying ZHANG Bin ZHAO Xinyu NIEJi-sheng WANG Rui-sheng YANG Jin Department of Occupational Health School of Public Health Shanxi Medical University General Hospital of Taiyuan Iron ＆ steel （Group） Co. Ltd.

OBJECTIVE To investigate the effects of OGG1 methylation regulated by H19/sAHH/DNMT1 on the oxidative DNA damage and cell cycle arrest related to PAHs exposure. METHODs We used high performance liquid chromatography mass spectrometry（HPLC-Ms） equipped to detect urine biomarkers of PAHs exposure, including 2-hydroxynaphthalene（2-NAP）, 2-hydroxyfluorene（2-FLU）, 9-hydroxyphenanthrene（9-PHE）, 1-hydroxypyrene（1-OHP）. The levels of sAM and sAH in plasma were detected by HPLC-ultraviolet, and the expression level of H19 was detected by RT-PCR. The protein expression levels of sAHH and DNMT1 were detected by Western blot. The content of 8-OHdG and DNMT1 activity were detected by *** interaction between H19 and sAHH was detected by RNA Binding ProteinImmunoprecipitation Assay. The interaction between sAHH and DNMT1 was detected by co-immunoprecipitation. The localization between H19, sAHH and DNMT1 was observed by lnc RNA fluorescence in situ hybridization（FIsH） combined with laser scanning confocal *** methylation level of OGG1 gene was detected by pyrosequencing, and the cell cycle was detected by flow cytometry. REsULTs After adjusting for covariates, urinary 1-hydroxypyrene（1-OHP） levels were positively associated with blood H19 RNA expression（OR: 1.51, 95% CI: 1.03-2.19）, while were negatively associated with plasma sAHH activity（OR: 0.63, 95% CI: 0.41-0.98）. H19 binding to sAHH exaggerate DNA methyltransferase 1（DNMT1） expressions and activity with BaP *** of H19 enhanced the interaction of sAHH and DNMT1 induced by BaP. Although BaPtreated cells H19 single knockdown expectedly decreased OGG1 methylation, reduced oxidative DNA damage and recovered s phase arrest with altering sAHH and DNMT1, while sAHH or DNMT1 single knockdown shows the opposite trend. And the H19/sAHH double knockdown restored OGG1 methylation, oxidative DNA damage and s phase to the control level while sAHH/DNMT1 double knockdown aggravated the alteration. CONCLUsI

关键词： Polycyclic aromatic hydrocarbons Oxidative DNA damage 8-oxoguanine DNA glycosylase 1 long non-coding RNA H19 s-adenosylhomocysteine hydrolase DNA methyltransferase

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