Hich shows that the key Glu294 does not move in the course of active website closure. This locating supports the proposal that steric strain, introduced by active web-site closure, is employed to overcome kinetic and thermodynamic barriers to acylglutamyl anhydride formation. The internal oxyanion hole residue Asn347 seems to become an essential buttress for Glu294. A crystal structure in the N347A mutant revealed unanticipated roles in positioning and tuning the reactivity of Glu294, making use of steric, electrostatic, and possibly stereoelectronic effects. Degradation of an AcCoA analog by unidentified microbial enzymes produced an activated acetyl donor and acetate, which suggests that ester analogs of AcCoA (e.g., 5a) could be employed to make a stabilized acetylglutamyl anhydride on AarC. Deletion of a thiol-carboxylate contact amongst CoA and AarC GluSUPPLEMENTARY MATERIALThe Supplementary Material for this short article may be discovered on the web at: journal.frontiersin.org/article/10.3389/fchem. 2016.
AutophAgic punctuM AutophAgic punctuMAutophagy ten:5, 930sirtuininhibitor32; May possibly 2014; sirtuininhibitor2014 Landes BioscienceDimethyl -ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathyEquipe 11 labelis par la Ligue Nationale contre le Cancer; INSERM U1138; Centre de Recherche des Cordeliers; Paris, France; 2Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy; Villejuif, France; 3UniversitsirtuininhibitorParis Descartes/Paris 5; Paris, France; 4Department of Internal Medicine (Cardiology); University of Texas Southwestern Medical Center; Dallas, TX USA; 5Institute of Molecular Biosciences; University of Graz; Graz, Austria; 6P e de Biologie; H ital Europ n Georges Pompidou; Paris, FranceIKeywords: acetyl-coenzyme A, dilated cardiopathy, macroautophagySubmitted: 01/21/2014 Revised: 02/11/2014 Accepted: 02/14/2014 dx.Protease Inhibitor Cocktail manufacturer doi.org/10.4161/auto.28235 Correspondence to: Guido Kroemer: E mail: [email protected]; Frank Madeo; E-mail: [email protected] Punctum to: Mari G, Pietrocola F, Eisenberg T, Kong Y, Malik SA, Andryushkova A, Schroeder S, Pendl T, Harger A, Niso-Santano M, et al. Regulation of autophagy by cytosolic acetyl-coenzyme a. Mol Cell 2014; 53:710sirtuininhibitor5; PMID:24560926; dx.doi.org/10.1016/j.molcel.2014.01.t has been a longstanding problem to recognize distinct and efficient pharmacological modulators of autophagy. Lately, we discovered that depletion of acetyl-coenzyme A (AcCoA) induced autophagic flux, whilst manipulations made to raise cytosolic AcCoA efficiently inhibited autophagy. Therefore, the cell permeant ester dimethyl -ketoglutarate (DMKG) enhanced the cytosolic concentration of -ketoglutarate, which was converted into AcCoA via a pathway relying on either on the two isocitrate dehydrogenase isoforms (IDH1 or IDH2), as well as on ACLY (ATP citrate lyase).CNTF, Human DMKG inhibited autophagy in an IDH1-, IDH2- and ACLY-dependent style in vitro, in cultured human cells.PMID:26780211 Additionally, DMKG efficiently prevented autophagy induced by starvation in vivo, in mice. Autophagy plays a maladaptive function inside the dilated cardiomyopathy induced by stress overload, meaning that genetic inhibition of autophagy by heterozygous knockout of Becn1 suppresses the pathological remodeling of heart muscle responding to hemodynamic anxiety. Repeated administration of DMKG prevents autophagy in heart muscle responding to thoracic aortic constriction (TAC) and simultaneously abolishes all pathological and functional correlates of dila.
