Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL
نویسندگان
چکیده
The function of monoacylglycerol lipase (MGL), a key actor in the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2AG), is tightly controlled by the cell's redox state: oxidative signals such as hydrogen peroxide suppress MGL activity in a reversible manner through sulfenylation of the peroxidatic cysteines, C201 and C208. Here, using as a starting point the crystal structures of human MGL (hMGL), we present evidence from molecular dynamics and metadynamics simulations along with high-resolution mass spectrometry studies indicating that sulfenylation of C201 and C208 alters the conformational equilibrium of the membrane-associated lid domain of MGL to favour closed conformations of the enzyme that do not permit the entry of substrate into the active site.
منابع مشابه
In Vitro Inhibition of Human Sperm Creatine Kinase by Nicotine, Cotinine and Cadmium, as a Mechanism in Smoker Men Infertility
Background Nicotine, cotinine and cadmium are harmful components of cigarettes that have an effect on human reproductive function. Although the effects of cigarette smoke on male reproductive function is characterized in several articles its mechanism of action is still unknown. In the present study, we investigate the effect of nicotine, cotinine and cadmium on human sperm creatine kinase acti...
متن کاملComputational Study of the Mechanism, Reaction Rate and Thermochemistry of Atmospheric Oxidation of Methylamine with Singlet Oxygen
The reaction of CH₃NH₂ with O₂ on the singlet potential energy surfaces (PES) was carried out using the B3LYP, CCSD(T) and G3B3 theoretical approaches along with 6-311++G(3df,3pd) basis set. The suggested mechanism for the title reaction consists of one pre-reactive complex. From the pre-reactive complex, nine types of products, CH2NH+H2O2, CH3NH+OOH,...
متن کاملDiabetes and Oxidative Stress: The Mechanism and Action
Abstract Diabetes mellitus is one of the major metabolic disorders. Diabetes is recognized for severe complications including diabetic nephropathy, neuropathy and retinopathy. Long-lasting effect of hyperglycemia results in increased oxidative stress. Oxidative stress results from an imbalance between radical-generating and radical scavenging systems. Increased oxidative stress has been shown ...
متن کاملInteraction Study of 1, 3 Substituted Isatin Derivatives with Anti Inflammatory Properties with Cyclooxygenase 1 and 2 Enzymes by Molecular Docking Method
Introduction: Inflammation as the body's defense response is accompanied with various diseases. Prostaglandins are major mediators of inflammation produced by the cyclooxygenase enzymes. So inhibitors of these enzymes can be effective in treating inflammation. There are reports of inhibition of these enzymes by isatin derivatives to control inflammation. Isatin is a heterocyclic compound whose...
متن کاملThe effect of podophyllotoxin as an inducer of apoptosis using molecular docking method
Background and aim: Podophyllotoxin is used as one of the main treatments for genital warts. It is a precursor of etoposide and teniposide, which is used in the treatment of various cancers. Despite a large number of cancer studies, the exact mechanism of podophyllotoxin remains unknown. Chemotherapy drugs reduce cancer cells by inducing apoptosis. The regulation of the apoptotic pathway has be...
متن کامل