Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes

“…However, the occurrence of glycogen has been reported in cancer cells from diverse tissue origins that normally do not store glycogen (42)(43)(44). To test the functional role of this metabolic pathway on erastin-induced ferroptosis, we treated cells with either of two GP inhibitors, CP-91149 (45) or GP inhibitor (46), and monitored the effects on erastin sensitivity. These inhibitors did not rescue cells from erastin lethality (Fig.…”

Section: Phkg2 Regulates Ferroptosis Through Modulation Of Available mentioning

confidence: 99%

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

Yang

Kim

Gaschler

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

1,406

1,134

View full text Add to dashboard Cite

Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown. We report here the mechanism of lipid peroxidation during ferroptosis, which involves phosphorylase kinase G2 (PHKG2) regulation of iron availability to lipoxygenase enzymes, which in turn drive ferroptosis through peroxidation of polyunsaturated fatty acids (PUFAs) at the bis-allylic position; indeed, pretreating cells with PUFAs containing the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) prevented PUFA oxidation and blocked ferroptosis. We further found that ferroptosis inducers inhibit GPX4 by covalently targeting the active site selenocysteine, leading to accumulation of PUFA hydroperoxides. In summary, we found that PUFA oxidation by lipoxygenases via a PHKG2-dependent iron pool is necessary for ferroptosis and that the covalent inhibition of the catalytic selenocysteine in Gpx4 prevents elimination of PUFA hydroperoxides; these findings suggest new strategies for controlling ferroptosis in diverse contexts.

show abstract

“…N-Ethylmaleimide (NEM), FSK, and IBMX were obtained from Sigma. The glycogen phosphorylase inhibitor (Klabunde et al 2005) was purchased from EMD Biosciences.…”

Section: Reagentsmentioning

confidence: 99%

A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease

Cheng

Zhang²,

Gentry³

et al. 2007

Genes Dev.

View full text Add to dashboard Cite

Cori's disease is a glycogen storage disorder characterized by a deficiency in the glycogen debranching enzyme, amylo-1,6-glucosidase,4-␣-glucanotransferase (AGL). Here, we demonstrate that the G1448R genetic variant of AGL is unable to bind to glycogen and displays decreased stability that is rescued by proteasomal inhibition. AGL G1448R is more highly ubiquitinated than its wild-type counterpart and forms aggresomes upon proteasome impairment. Furthermore, the E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL. Malin is known to be mutated in Lafora disease, an autosomal recessive disorder clinically characterized by the accumulation of polyglucosan bodies resembling poorly branched glycogen. Transfection studies in HepG2 cells demonstrate that AGL is cytoplasmic whereas Malin is predominately nuclear. However, after depletion of glycogen stores for 4 h, ∼90% of transfected cells exhibit partial nuclear staining for AGL. Furthermore, stimulation of cells with agents that elevate cAMP increases Malin levels and Malin/AGL complex formation. Refeeding mice for 2 h after an overnight fast causes a reduction in hepatic AGL levels by 48%. Taken together, these results indicate that binding to glycogen crucially regulates the stability of AGL and, further, that its ubiquitination may play an important role in the pathophysiology of both Lafora and Cori's disease.

show abstract

Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes

Cited by 61 publications

References 33 publications

Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease

Contact Info

Product

Resources

About