Structural Insights into the Iodothyronine Deiodinase 2 Catalytic Core and Deiodinase Catalysis and Dimerization.

Iodothyronine deiodinases (Dio) are selenocysteine-containing membrane enzymes that activate and inactivate the thyroid hormones (TH) through reductive iodide eliminations. The three deiodinase isoforms are homodimers sharing highly conserved amino acid sequences, but they differ in their regioselectivities for the deiodination reaction and regulatory features. We have now solved a crystal structure of the mouse deiodinase 2 (Dio2) catalytic domain.

Elucidating the Unconventional Binding Mode of a DNA-Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development.

Sirtuin 6 (Sirt6), an NAD-dependent deacylase, has emerged as a promising target for aging-related diseases and cancer. Advancing the medicinal chemistry of Sirt6 modulators is crucial for the development of chemical probes aimed at unraveling the intricate biological functions of Sirt6 and unlocking its therapeutic potential. A proprietary DNA-encoded library yielded Sirt6 inhibitor 2-Pr, displaying remarkable inhibitory activity and isoform-selectivity, and featuring a chemical structure distinct from reported Sirt6 modulators.

Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity.

Sirtuins are NAD-dependent protein lysine deacylases implicated in aging-related diseases. Mammalian Sirtuin 4 (Sirt4) is located in mitochondria and a potential therapeutic target for cancer and metabolic diseases, but no potent and selective Sirt4 inhibitors have been reported. Here, we describe the identification of potent Sirt4-specific small-molecule inhibitors.

SIRT6 Protects Against Lipopolysaccharide-Induced Inflammation in Human Pulmonary Lung Microvascular Endothelial Cells.

Inflammatory response in the pulmonary endothelium drives the pathogenesis of acute lung injury and sepsis. Sirtuin 6 (SIRT6), a member of class III NAD+-dependent deacetylases belonging to the sirtuin family, regulates senescence, metabolism, and inflammation and extends lifespan in mice and model organisms. However, the role of SIRT6 in pulmonary endothelial inflammation is unknown.