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  • br Significance Ubl post translational modifications are

    2020-11-14


    Significance Ubl post-translational modifications are potential targets for developing novel therapeutics for life-threatening diseases, such as c-Myc- and KRas-driven cancers that lack targeted therapy. However, only a few drugs are available to target these modifications. This lack of drugs highlights our knowledge deficiency in regulating Ubl aphidicolin receptor by small molecules. Here, we identified an allosteric, covalent inhibitor chemotype that inhibits the SUMO-activating enzyme (E1) by targeting an unexpected buried site. Because the only previously known mechanism to inhibit E1 enzymes is through targeting the ATP-binding site, identification of an allosteric inhibitory mechanism of the activating enzymes could spur innovative drug discovery efforts targeting Ubl modifications. This finding also raises the possibility of allosteric E1 regulation by small-molecule metabolites.
    STAR★Methods
    Acknowledgments We thank the City of Hope core facilities, including the Animal Model Core, Bioinformatic Core, NMR Core, Flow Cytometry Core, and Florescence Microscopy Core for excellent technical support, and NIH grants R01GM086171, R01GM102538, and R01CA212119, R01CA216987, and R03DA026556 (to Y.C.) for funding, and R44CA189499 (to S.X.O.). E.S. is a fellowship recipient of the California Institute of Regenerative Medicine. The Conrad Prebys Center for Chemical Genomics wishes to acknowledge the NIH Roadmap Grant U54 HG005033 for providing funds to during its participation as a comprehensive screening center of the Molecular Libraries Probe Production Centers Network (MLPCN). We thank Dr. Sumeet Salaniwal for assistance in preparing Table 1. Dr. Gregory P. Roth, who led the medicinal chemistry studies described here, passed away. Gregory is remembered for his many scientific contributions including those described here.
    Introduction Issues of ecological effects caused by various types of emerging organic contaminants (EOCs) have become long-term environmental concerns. Different types of EOCs include pharmaceuticals and personal care products (PPCPs), surfactants and endocrine disruptors, etc. (Pal et al., 2010; Jurado et al., 2012). They have been detected in effluents from municipal sewage treatment plants (Petrovic et al., 2003; Boleda et al., 2009; Wolf et al., 2012). The production and utilization of PPCPs in China is higher than some developed countries due to fast economic development and great population. Many kinds of EOCs display pseudo-persistent exposure characteristics (Amariei et al., 2017; Li, 2014). Of these Pentachlorophenol (PCP) and Bisphenol A (BPA) are particularly relevant compounds. BPA is a common chemical that has been widely used in the fabrication of epoxy- and polyester-styrene resins. Studies have testified that BPA was potentially toxic to embryos, which could cause genetic defects, and BPA can also be converted to DNA binding metabolites in vitro. Although the half-life of BPA released into the water environment was short, it can still contaminate the water environment due to its mass production and using. As shown in Table 1, the BPA in the water environment became stable after being combined with suspended particles and migrated to the sediments, which resulted in higher BPA content in the sediments than in water bodies. Research shown that the BPA content in sediments was 0.11 to 13,420 μg/kg. PCP has been used as an industrial antiseptic and biocide since the 1960s. Due to its proven carcinogenicity and toxicity, as well as the existence of a large number of known PCP-contaminated sites, PCP has been designated as a priority toxic pollutant by the United States Environmental Protection Agency (EPA) under the guidance of the Clean Water Act in 1972. PCP was prevalent in water bodies in China, and the concentration of PCP in surface water of Yangtze River Basin was much higher than that in other watersheds, and the maximum concentration reached 594 ng/L shown in Table 2 (Gao et al., 2008).