Sirtuins in neurodegenerative diseases: a biological-chemical perspective

Abstract

Sirtuins, commonly known as NAD(+)-dependent class III histone deacetylase enzymes, have been extensively studied to evaluate their potential role in different disease states. Based on the published literature, sirtuins have been implicated in providing a myriad of intrinsic and extrinsic biological effects, which in turn may play an important role in the treatment of various disorders such as type II diabetes, obesity, cancer, aging and different neurodegenerative diseases. In particular, a number of studies have unequivocally supported the idea of sirtuins having therapeutic potential in neurodegenerative diseases such as stroke, ischemic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. To exploit the therapeutic potential of sirtuins, their manipulation in terms of development of small-molecule modulators, inhibitors and analogs has increased dramatically since their inception, in both scientific and industrial worlds. Studies on the structure and catalytic core of sirtuins along with chemical mechanisms and substrate specificity have provided important input into the design and synthesis of sirtuin modulators. To study the role of sirtuins in the biological system, it has become extremely important to understand the molecular and chemical structure of sirtuins. In this review, we have discussed the biological role of sirtuins in various neurodegenerative diseases, and also provided an insight into their chemical structure.

Fig. 1

The proposed chemical mechanism of the deacetylation reaction of sirtuins. The first step involves the nucleophilic attack of the anomeric (1′C) carbon via S_N1 or S_N2 mechanism to form the O-alkylamidate intermediate. The second step involves activation of the 2′-hydroxyl of the ribose followed by subsequent formation of the 1,2′-cyclic intermediate, which undergoes several transformations that lead to the elimination of the deacetylated lysine and water addition to form 2′-OAADPr.

Fig. 2

The three-dimensional protein structure of S. cerevisiae Hst2 depicting the major domains. The figure shows the large domain and the small domain connected by four loops, the largest of which forms the cofactor binding loop. The Zn⁺² binding site is also clearly shown.

Fig. 3

NAD⁺ binding pocket with Hst2 shown in tan surface representation. A, B and C binding sites are indicated by circles. Site A: adenine-ribose binding site; site B: nicotinamide ribose binding site (the cofactor binding loop forms the ceiling of site B); site C: nicotinamide moiety binding site. Figure reproduced and modified from Sanders et al. [44].