Molecule of the Month: Sirtuins

While studying a rather obscure gene regulatory protein, called Sir2, researchers made a startling discovery. If they engineered yeast cells to produce much higher than normal levels of Sir2, the cells lived 30% longer. This observation ignited interest in the protein, to discover what it does and how it might affect aging in yeast, and perhaps in our own cells. Researchers soon discovered that Sir2 is an enzyme that removes acetyl groups from histones, allowing them to form tighter regions of chromatin that silences genes. Similar proteins are found in nearly all living organisms, and have been collectively named “sirtuins.”

Our cells build seven different sirtuins (termed SIRT1-SIRT7). They perform a variety of functions. Some perform the canonical function of modifying histones and regulating transcription. Others target proteins in the cytoplasm and mitochondria, and are implicated in regulating a wide array of processes such as metabolism and neurodegeneration. Some specialize in removing acetyl groups, while others remove larger modifications such as attached lipids, or create new modifications. Continued study of these molecules has revealed additional strong connections to aging in many organisms.

Sirtuins perform an unusual reaction using a familiar cofactor. They take NAD, a cofactor that is normally involved in electron transport, and remove its signature nicotinamide ring. Then, they extract the acetyl group from their target protein and attach it to the remaining fragment of NAD. Structures of sirtuins, such as the structure of Sir2 in PDB entry 4iao, have a distinctive structure. They have two domains that grip NAD and position the acetylated lysine next to it, catalyzing the transfer reaction. Some sirtuins also have additional domains that interact with other regulatory proteins, such as Sir4 included in this structure.

Discovery of the connections between sirtuins and aging launched an extensive search for compounds that can enhance the action of sirtuins. Resveratrol, a natural compound found in grape skins and other fruit, was one of the first candidates, and was widely (and probably over-enthusiastically) promoted in the popular media. The structure of resveratrol with SIRT1 (PDB entry 5btr) shows that it may act allosterically, helping to close down the domains of the protein and promote its action. Thousands of other compounds have since been tested. For instance, the compound in PDB entry 5mf6 is a selective activator of SIRT6, and shows a similar allosteric mechanism.