6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2. 2018

Shang-Ju Chuang, and Shu-Chun Cheng, and Hui-Chi Tang, and Chiao-Yin Sun, and Chi-Yuan Chou
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, 112, Taiwan.

Ubiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells' survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2. Enzyme-kinetic and X-ray crystallographic data suggest that 6-thioguanine displays a noncompetitive and slow-binding inhibitory mechanism against USP2. Our study provides a clear rationale for the clinical evaluation of 6-thioguanine for USP2-upregulated cancers.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D010450 Endopeptidases A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS. Endopeptidase,Peptide Peptidohydrolases
D011499 Protein Processing, Post-Translational Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility. Amino Acid Modification, Post-Translational,Post-Translational Modification,Post-Translational Protein Modification,Posttranslational Modification,Protein Modification, Post-Translational,Amino Acid Modification, Posttranslational,Post-Translational Amino Acid Modification,Post-Translational Modifications,Post-Translational Protein Processing,Posttranslational Amino Acid Modification,Posttranslational Modifications,Posttranslational Protein Processing,Protein Processing, Post Translational,Protein Processing, Posttranslational,Amino Acid Modification, Post Translational,Modification, Post-Translational,Modification, Post-Translational Protein,Modification, Posttranslational,Modifications, Post-Translational,Modifications, Post-Translational Protein,Modifications, Posttranslational,Post Translational Amino Acid Modification,Post Translational Modification,Post Translational Modifications,Post Translational Protein Modification,Post Translational Protein Processing,Post-Translational Protein Modifications,Processing, Post-Translational Protein,Processing, Posttranslational Protein,Protein Modification, Post Translational,Protein Modifications, Post-Translational
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072017 Deubiquitinating Enzymes Enzymes that remove UBIQUITIN from a protein substrate, including POLYUBIQUITIN, or from other molecules. Deubiquitinase,Deubiquitinating Enzyme,Deubiquitinases,Enzyme, Deubiquitinating,Enzymes, Deubiquitinating
D013866 Thioguanine An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. 6-Thioguanine,2-Amino-6-Purinethiol,Lanvis,Tabloid,Thioguanin-GSK,Thioguanine Anhydrous,Thioguanine Hemihydrate,Thioguanine Monosodium Salt,Thioguanine Tabloid,Tioguanina Wellcome,Tioguanine,2 Amino 6 Purinethiol,6 Thioguanine,Anhydrous, Thioguanine,Thioguanin GSK,ThioguaninGSK
D043222 Ubiquitin Thiolesterase A thioester hydrolase which acts on esters formed between thiols such as DITHIOTHREITOL or GLUTATHIONE and the C-terminal glycine residue of UBIQUITIN. Neuron Cytoplasmic Protein 9.5,PARK5 Protein,Parkinson Disease 5 Protein,UCHL1 Protein,Ubiquitin C-Terminal Esterase,Ubiquitin C-Terminal Hydrolase,Ubiquitin Carboxy-Terminal Esterase,Ubiquitin Carboxy-Terminal Hydrolase,Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1,Uch-L1 Protein,C-Terminal Esterase, Ubiquitin,C-Terminal Hydrolase, Ubiquitin,Carboxy-Terminal Esterase, Ubiquitin,Carboxy-Terminal Hydrolase, Ubiquitin,Esterase, Ubiquitin C-Terminal,Esterase, Ubiquitin Carboxy-Terminal,Hydrolase, Ubiquitin C-Terminal,Hydrolase, Ubiquitin Carboxy-Terminal,Thiolesterase, Ubiquitin,Ubiquitin C Terminal Esterase,Ubiquitin C Terminal Hydrolase,Ubiquitin Carboxy Terminal Esterase,Ubiquitin Carboxy Terminal Hydrolase,Ubiquitin Carboxyl Terminal Hydrolase Isozyme L1,Uch L1 Protein
D054875 Ubiquitination The act of ligating UBIQUITINS to PROTEINS to form ubiquitin-protein ligase complexes to label proteins for transport to the PROTEASOME ENDOPEPTIDASE COMPLEX where proteolysis occurs. Ubiquitylation
D018360 Crystallography, X-Ray The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) X-Ray Crystallography,Crystallography, X Ray,Crystallography, Xray,X Ray Crystallography,Xray Crystallography,Crystallographies, X Ray,X Ray Crystallographies

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