Affiliation:
1. Department of Medicinal Chemistry Virginia Commonwealth University Richmond VA USA
2. Department of Pharmaceutical Sciences Albany College of Pharmacy and Health Sciences Colchester VT USA
3. Institute for Structural Biology, Drug Discovery and Development Virginia Commonwealth University Richmond VA USA
Abstract
Human sirtuins play important roles in various cellular events including DNA repair, gene silencing, mitochondrial biogenesis, insulin secretion and apoptosis. They regulate a wide array of protein and enzyme targets through their NAD+‐dependent deacetylase activities. Sirtuins are also thought to mediate the beneficial effects of low‐calorie intake to extend longevity in diverse organisms from yeast to mammals. Small molecules mimicking calorie restriction to stimulate sirtuin activity are attractive therapeutics against age‐related disorders such as cardiovascular diseases, diabetes and neurodegeneration. Little is known about one of the mitochondrial sirtuins, SIRT5. SIRT5 has emerged as a critical player in maintaining cardiac health and neuronal viability upon stress and functions as a tumour suppressor in a context‐specific manner. Much has been debated about whether SIRT5 has evolved away from being a deacetylase because of its weak catalytic activity, especially in the in vitro testing. We have, for the first time, identified a SIRT5‐selective allosteric activator, nicotinamide riboside (NR). It can increase SIRT5 catalytic efficiency with different synthetic peptide substrates. The mechanism of action was further explored using a combination of molecular biology and biochemical strategies. Based on the existing structural biology information, the NR binding site was also mapped out. These activators are powerful chemical probes for the elucidation of cellular regulations and biological functions of SIRT5. The knowledge gained in this study can be used to guide the design and synthesis of more potent, isotype‐selective SIRT5 activators and to develop them into therapeutics for metabolic disorders and age‐related diseases.
Funder
National Center for Advancing Translational Sciences
National Institute of General Medical Sciences
Subject
Cell Biology,Molecular Biology,Biochemistry
Cited by
2 articles.
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