Download MendeleyChemical Probing of the Human Sirtuin 5 Active Site Reveals its Substrate Acyl Specificity and Peptide-Based Inhibitors.
Roessler, C., Nowak, T., Pannek, M., Gertz, M., Nguyen, G.T., Scharfe, M., Born, I., Sippl, W., Steegborn, C., Schutkowski, M.(2014) Angew Chem Int Ed Engl 53: 10728
- PubMed: 25111069
- DOI: https://doi.org/10.1002/anie.201402679
- Primary Citation of Related Structures:
4UTN, 4UTR, 4UTV, 4UTX, 4UTZ, 4UU7, 4UU8, 4UUA, 4UUB - PubMed Abstract:
Sirtuins are NAD(+)-dependent deacetylases acting as sensors in metabolic pathways and stress response. In mammals there are seven isoforms. The mitochondrial sirtuin?5 is a weak deacetylase but a very efficient demalonylase and desuccinylase; however, its substrate acyl specificity has not been systematically analyzed. Herein, we investigated a carbamoyl phosphate synthetase?1 derived peptide substrate and modified the lysine side chain systematically to determine the acyl specificity of Sirt5. From that point we designed six potent peptide-based inhibitors that interact with the NAD(+) binding pocket. To characterize the interaction details causing the different substrate and inhibition properties we report several X-ray crystal structures of Sirt5 complexed with these peptides. Our results reveal the Sirt5 acyl selectivity and its molecular basis and enable the design of inhibitors for Sirt5.
Organizational Affiliation:
Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Strasse 3, 06120 Halle/Saale (Germany).
