6eqs
Human Sirt5 in complex with stalled peptidylimidate intermediate of inhibitory compound 29
Structural highlights
Function[SIR5_HUMAN] NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins. Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting. Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro.[1] [2] [3] [4] Publication Abstract from PubMedThe sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more "drug-like" properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for sirtuins. This is important information when applying inhibitors to probe mechanisms in biology. Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.,Rajabi N, Auth M, Troelsen KR, Pannek M, Bhatt D, Fontenas M, Hirshey MD, Steegborn C, Madsen AS, Olsen CA Angew Chem Int Ed Engl. 2017 Oct 17. doi: 10.1002/anie.201709050. PMID:29044784[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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