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  • Accumulating studies revealed a decline of TET expression in


    Accumulating studies revealed a decline of TET1 expression in various cancers including breast, liver, colon, skin, prostate cancers [[36], [37], [38]]. Contrast to these studies, our previous research shows that TET1 is overexpressed in EC and improves the efficacy of chemotherapy in EC, coincide with current result [16]. To explain the Oxaliplatin results between our research and other studies we assume that TET1 target on different downstream genes in different cancers. For example, in prostate cancer TET1 maintains metalloproteinase family proteins 2 and 3, which are tissue inhibitor. Therefore, TET1 exhibit anti-cancer activity in prostate and breast cancer. While in our research, TET1 target in GLOI, which is known for supporting cancer cell proliferation, as a result, TET1 acts as cancer proliferation inducer in EC [36].
    Conflict of interest
    Acknowledgements The authors thank Prof. Zhao Shimin (Fudan University, Shanghai, China) for providing the plasmids pcDNA3.0-TET1-flag. We also thank Prof. Shi Yujiang (Harvard University, Cambridge, MA) for providing pPB-TET1 plasmid. This work was supported by grants from the National Natural Science Foundation of China (grants 81672562, 81872111, 81370074), the project of Outstanding Medical Doctor, the cross project of Medical and Engineering (YG2016MS27), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20181714), the Shanghai Municipal Public Health Bureau (grant XYQ2013119), and the “Chenxing Project” from Shanghai Jiao Tong University to Z.Z.
    Introduction Many enzyme substrates are chiral molecules and most enzymes catalyze reactions asymmetrically. In other words, most enzymes can only convert one enantiomer of a chiral substrate. For example, lipase B from Candida antarctica favors the R enantiomer of 1-phenylethanol [1]. However, there are enzymes with a different type of stereospecificity. Glyoxalase I (GlxI) is a paradigm of this behavior. GlxI takes both enantiomers of its chiral substrate, but converts them to a single enantiomer of the product. The enzyme is a part of glyoxalase system, which is composed of two enzymes (glyoxalase I and glyoxalase II) that catalyze the conversion of methylglyoxal (MG) to D-lactate. The system performs a critical two-step detoxification of cytotoxic MG. MG is produced naturally as a byproduct of normal biochemistry, but it is highly toxic due to its chemical reactions with proteins, nucleic acids, and other cellular components. GlxI, the subject of the present study, catalyzes the first step of the reaction, the conversion of the hemithioacetal of MG and glutathione (H-SG) to S-d-lactoylglutathione. The second detoxification step, in which the lactoylglutathione is split into glutathione and D-lactate, is carried out by glyoxalase II (Scheme 1). It has been observed that GlxI is unusually active in various cancer cells and that MG is especially toxic to cancer cells [2]. Thus, the inhibition of GlxI could be a fruitful way to control tumors. An essential prerequisite to rational design of competitive inhibitors is detailed information about the active-site structure and reaction mechanism. Human GlxI is a homodimer of 43kDa, containing 183 amino acid residues per monomer. The enzyme has been crystallized with several inhibitors, like S-benzylglutathione (B-SG) [3] and S-[(p-nitrobenzyl)oxycarbonyl]glutathione (NBC-SG) [4]. However, the most interesting structure for the study of the catalytic mechanism is the complex with S-[N-hydroxy-N-(p-iodophenyl)carbamoyl] glutathione (HIC-SG) [4]. This inhibitor mimics the enediolate intermediate that has been suggested to be formed in the first step of the catalytic reaction [4], [5], [6], [7]. According to the crystal structures, the active site of the enzyme consists of a shell of residues around a Zn2+ ion. In the resting human enzyme, His-126, Gln-33, Glu-99, Glu-172 and two water molecules are coordinated to the Zn2+ ion. When the inhibitor binds to the enzyme, it coordinates to the metal ion, displacing the two water molecules and Glu-172, giving a penta-coordinated site.