Significance Soluble adenylyl cyclase (sAC) generates the ubiquitous signaling molecule cAMP in response to bicarbonate. In physiological systems, bicarbonate is in nearly instantaneous equilibrium with carbon dioxide and pH; therefore, sAC, and its evolutionarily related cyclases, serve as nature’s carbon dioxide/bicarbonate/pH sensors. In particular, bicarbonate regulation of mammalian sAC mediates numerous cellular processes, from sperm activation to pH homeostasis and mitochondrial ATP synthesis. We solved crystal structures of sAC’s catalytic domains in complex with substrate, products, and regulators. The structures reveal insights into sAC catalysis, how bicarbonate binds to and activates sAC, and how sAC can be inhibited by a drug. Our results reveal mechanisms that will facilitate the development of drugs targeting this signaling system.
Medicinal Chemistry C. A. Olsen and co-workers describe the identification of inhibitors of sirtuin 5 hydrolase with high potencies through an extensive structure–activity relationship study in their Communication on page 14836 ff.
Abstract Sirtuin 6 (SIRT6) is a member of the NAD + -dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death.
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