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  • Ginsenoside Re lysine mixture had increased anticancer effec


    Ginsenoside Re-lysine mixture had increased anticancer effects upon heat processing by regulating Bcl-2 and Bax (Yamabe et al., 2013). Ginsenoside Re (20mg/kg) inhibited NF-κB activation by inhibiting LPS binding to TLR4 on macrophages in TNBS-treated mice (Lee, Hyam, Jang, Han, & Kim, 2012). The chemistry, metabolism, and pharmacokinetics of ginsenoside Re were shown in Peng et al. (2012). Ginsenoside Re only decreased the chymotrypsin-like activity of 26S proteasome by 10% (Chang et al., 2008). Fifty micrometres ginsenoside Re inhibited 40% of the E1 activity. Therefore, ginsenosides Re and Rg1 are in a novel class of ubiquitin E1 inhibitors within functional foods application or herbal medicine. Ginsenoside Rb1 can protect NSC 14613 synthesis from UV radiation-induced apoptosis by inducing DNA repair (Cai, Jin, Luo, Lin, & Gao, 2009). Treating HepG2 cells with ginsenoside Rd significantly inhibited metastasis, most likely by blocking MMP activation and MAPK signaling pathways involved in cancer cell migration (Yoon, Choi, Cha, & Lee, 2012). Ginsenoside Rd, Re, Rb1, and Rg1 (100μg/mL) decreased MDR1 protein levels in MCF-7/ADR cells. Ginsenoside Rd most potently inhibited MDR1 protein expression without cytotoxicity (Pokharel, Kim, Han, Oh, & Kang, 2010). In our previous study, ginsenosides Rb1 and Rd inhibited 30% and 52.9% of the chymotrypsin-like activity but did not increase caspase-like and tryptic-like activities in the 26S proteasome (Chang et al., 2008). In this study, we demonstrated that ginsenosides Rb1, Rb2, Rc, and Rd increased E1 activity (Fig. 3). Fifty micrometres ginsenosides Rb1 and Rd increased E1 activity by 2.2- and 1.74-fold. The roles of ginsenoside in E1 and 26S proteasome inhibition are shown in Table 2. The nitro substitute on the furan ring may be important for PYR-41 inhibition of the E1 enzyme (Yang et al., 2007). The macrocycle core and aliphatic tail of Largazole are responsible for inhibiting E1 activity (Ungermannova et al., 2012b). Ginsenosides Re and Rg1 are similar in terms of their biological structure–activity relationships (SAR) (Fig. 3). Unlike in PYR-41 and Largazole, the 3-OH and 6-O-Glu position of ginsenosides Re and Rg1 might play an important role in the ubiquitin E1 activity inhibitory effect in vitro. The substitution of 6-O-Glu in ginsenoside Rg1 has a more inhibitory effect when compared to the substitution of the O-Glc2-Rha position on ginsenoside Re. These results suggest that the biological structure–activity relationship is important for determining E1 activity. Previous in vitro studies show that the 3-O-Glc2-Glu position of the ginsenoside may be the functional group that inhibits the chymotrypsin-like activity of 26S proteasomes (Chang et al., 2008). Ginsenosides Re and Rg1 did not inhibit caspase-like and trypsin-like activities in the 26S proteasome. Although ginsenosides Re and Rg1 without the 3-O-Glc2-Glu position might be the explanation, the 3-OH and 6-O-Glu position of ginsenosides Re and Rg1 might be important functional groups for the inhibition of ubiquitin E1 activity. Nevertheless, there are more sugar moieties (glycons) in ginsenoside Re than ginsenoside Rg1. That is why ginsenoside Rg1 has a higher inhibitory effect on E1 activity than ginsenoside Re. Therefore, ginsenoside Rg1 is the only one that significantly inhibits both the 26S proteasome chymotrypsin-like activity and E1 activity. These results have shown that ginsenoside Rb2 and Rc cause no inhibition of E1 and 26S proteasome activities. As in previous report, the cycle of mRFP-Ub–E1 formation is approximately 5–20min (Fig. 2B). There is observable time-dependent increase in E1 ubiquitination from 0 to 15min in the control group (Fig. 4A). mRFP-Ub–E1 formation decreased by inhibition of ginsenoside Re during 15min in vitro (Fig. 4B). Therefore, ginsenoside Re is not inhibited mRFP-Ub–E1 formation in a time-dependent manner. However, 50μM of ginsenoside Rg1 decreased E1 activity in a constant manner. Fifty micrometres ginsenosides Re and Rg1 regulated E1 activity to 1.35- and 0.36-fold at 30min.