A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation.

Can e-commerce reduce urban CO emissions? Evidence from National E-commerce Demonstration Cities policy in China.

The existing studies ignore the potential impact of e-commerce on CO emissions. Based on panel data of 284 cities at the prefecture level and above in China from 2003 to 2019, we regard National E-commerce Demonstration Cities (NEDC) policy as a quasi-natural experiment and empirically examine the impact and mechanism of NEDC policy on urban CO emissions by using multi-period difference-in-difference (DID) model and mediating effect model. The results show that, under the premise of satisfying parallel trends, the NEDC policy significantly reduces urban CO emissions.

GRAMD1/ASTER-mediated cholesterol transport promotes Smoothened cholesterylation at the endoplasmic reticulum.

Hedgehog (Hh) signaling pathway plays a pivotal role in embryonic development. Hh binding to Patched1 (PTCH1) derepresses Smoothened (SMO), thereby activating the downstream signal transduction. Covalent SMO modification by cholesterol in its cysteine-rich domain (CRD) is essential for SMO function.

Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion.

High cholesterol is a major risk factor for cardiovascular disease. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease.

Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate.

Hedgehog (Hh) is a morphogen that binds to its receptor Patched 1 and activates Smoothened (SMO), thereby governing embryonic development and postnatal tissue homeostasis. Cholesterol can bind and covalently conjugate to the luminal cysteine-rich domain (CRD) of human SMO at the D95 residue (D99 in mouse). The reaction mechanism and biological function of SMO cholesterylation have not been elucidated.

The 3-beta-hydroxysteroid-Delta(8), Delta(7)-isomerase EBP inhibits cholesterylation of Smoothened.

Hedgehog (Hh) pathway plays a central role in vertebrate embryonic development and carcinogenesis. The G-protein coupled receptor-like protein Smoothened (SMO) is one of the major members in Hh pathway. Covalent modification of cholesterol on the 95th asparagine (D95) of human SMO, which is regulated by Hh and PTCH1, is critical for SMO activation.

Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling.

Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond.

Rhodium(III)-catalyzed C-H/C-C activation sequence: vinylcyclopropanes as versatile synthons in direct C-H allylation reactions.

Succession of C-H activation and C-C activation was achieved by using a single rhodium(III) catalyst. Vinylcyclopropanes were used as versatile coupling partners. Mechanistic studies suggest that the olefin insertion step is rate-determining and a facile β-carbon elimination is involved, which represents a novel ring opening mode of vinylcyclopropanes.