Human Sirtuins: An Overview of an Emerging Drug Target in Age-Related Diseases and Cancer

Alessandra      Donadini; Camillo      Rosano; Lamberto      Felli; Marco      Ponassi

Abstract

Sir2-like proteins (Sirtuins) are a class of enzymes conserved throughout the kingdoms of life. In fact, from Archaea to Mammals, these (class III) NAD⁺-dependent deacetylases catalyse the removal of the acetyl moiety from a substrate protein. Sirtuins show a conserved central catalytic domain with two more variable amino- and carboxy-terminal flanking regions. Amino acid comparison of these central conserved catalytic core sequences allows us to divide Sirtuins into five different classes (I, II, III, IV and U). These proteins differ in their subcellular localization (i.e. in Eukaryotes they can be found in the nucleus, cytoplasm or mitochondria). In humans there are seven Sirtuins (SIRT1-7) that are implicated in various physiological processes including aging and age-related disorders such as neoplasms, cardiovascular, metabolic and neurodegenerative diseases, and inflammation. Nowadays, the estimated life expectancy is definitely longer than in the past thus, we may consider all aging-related problems as having a strong social impact. Consequently, Sirtuins are emerging, particularly from a pharmacological point of view, as new and valuable drug targets.

Keywords: Aging, caloric restriction, cancer, deacetylase, drug targets, NAD+, X-ray crystallography.

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