Nicotinamide riboside activates SIRT5 deacetylation

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.

Axonal Protection by Oral Nicotinamide Riboside Treatment with Upregulated AMPK Phosphorylation in a Rat Glaucomatous Degeneration Model

“…In other neurons, NR upregulated the expression of key proteins of lipid droplet dynamics, PLIN1 and CIDEC, in the cochlea [ 39 ]. It is interesting to note a very recent study showing that NR was identified as a SIRT5-selective activator [ 40 ]. Thus, further studies will be necessary to fully understand the molecular mechanism implicated in NR neuroprotection.…”

Sirtuins as Players in the Signal Transduction of Citrus Flavonoids

“…SIRT5 is mainly localized into the mitochondrial matrix, playing a key role in the detoxification of ROS and in the regulation of protein substrates in fatty acid metabolism [174]. In this regard, recent studies revealed that SIRT5 is involved in metabolic diseases, particularly in hepatic steatosis [175], in cancer, and in SARS-CoV-2 infection [176].…”

“…SIRT5 consists of two domains; the larger one is a typ NAD + binding site containing six parallel beta-strands (β1-3 and β7-9) forming a cen sheet surrounded by several alpha-helices (α1, α2, α7, α10-13), while the smaller on characterized by structural zinc ions and five α-helices (α3-5, α8-9) and three antipara β-sheets (β4-6) [173] (Figure 8). SIRT5 is mainly localized into the mitochondrial matrix, playing a key role in detoxification of ROS and in the regulation of protein substrates in fatty acid metabol [174]. In this regard, recent studies revealed that SIRT5 is involved in metabolic disea particularly in hepatic steatosis [175], in cancer, and in SARS-CoV-2 infection [1 Emerging evidence supports the capability of QUE to modulate SIRT5 express promoting the mitigation of several illnesses.…”