Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • The roles of ginsenoside in E and S

    2019-07-02

    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 NSC 687852 weight of mRFP-Ub–E1 formation is approximately 5–20min (Fig. 2B). There is observable time-dependent increase in E1 ubiquitination from 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. The inhibition of mRFP-Ub–E1 formation by ginsenosides Re was not in time-dependent in vitro (Fig. 4B). Fifty micrometres ginsenoside Rg1 decreased E1 activity to 0.24- to 0.36-fold over 30min. This finding suggests that ginsenoside Rg1 may irreversibly inhibit mRFP-Ub–E1 formation or NSC 687852 weight a tight-binding substrate. This observation will help us to further investigate the E1 mechanism using ginsenoside Rg1. To address whether ginsenosides Re and Rg1 directly inhibited mRFP-Ub substrate without E1, the reaction mixture was separated by 8% SDS–PAGE under nondenaturing conditions. An electropherogram revealed significant differences between the control and E1-untreated samples. There were no differences between mRFP-Ub-only and mRFP-Ub with inhibitor ginsenosides Re or Rg1 (Supplemental Fig. 1). Therefore, ginsenosides Re and Rg1 cannot directly interact to inhibit mRFP-Ub. We proposed a model for the ginsenoside Rb1, Rb2, Rc, Rd, Re, and Rg1 inhibition of the ubiquitin–proteasome pathway (Fig. 5). Ginsenosides Re and Rg1 induced protein accumulation by blocking the first step of ubiquitination, which is ubiquitin-E1 activation. Ginsenosides Rb1 and Rd inhibited the chymotrypsin-like activity of the 26S proteasome but increased E1 activity, resulting in the accumulation of ubiquitinated proteins. Ginsenosides Rb2 and Rc did not inhibit the chymotrypsin-like activity of the 26S proteasome; moreover, sticky ends increased E1 activity, and therefore, ginsenosides Rb2 and Rc could lead to more protein degradation.
    Declaration of conflicting interests