Shedding light on structure, function and regulation of human sirtuins: a comprehensive review

Abstract

Sirtuins play an important role in signalling pathways associated with various metabolic regulations. They possess mono-ADP-ribosyltransferase or deacylase activity like demalonylase, deacetylase, depalmitoylase, demyristoylase and desuccinylase activity. Sirtuins are histone deacetylases which depends upon nicotinamide adenine dinucleotide (NAD) that deacetylate lysine residues. There are a total of seven human sirtuins that have been identified namely, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7. The subcellular location of mammalian sirtuins, SIRT1, SIRT6, and SIRT7 are in the nucleus; SIRT3, SIRT4, and SIRT5 are in mitochondria, and SIRT2 is in cytoplasm. Structurally sirtuins contains a N-terminal, a C-terminal and a Zn⁺ binding domain. The sirtuin family has been found to be crucial for maintaining lipid and glucose homeostasis, and also for regulating insulin secretion and sensitivity, DNA repair pathways, neurogenesis, inflammation, and ageing. Based on the literature, sirtuins are overexpressed and play an important role in tumorigenicity in various types of cancer such as non-small cell lung cancer, colorectal cancer, etc. In this review, we have discussed about the different types of human sirtuins along with their structural and functional features. We have also discussed about the various natural and synthetic regulators of sirtuin activities like resveratrol. Our overall study shows that the correct regulation of sirtuins can be a good target for preventing and treating various diseases for improving the human lifespan. To investigate the true therapeutic potential of sirtuin proteins and their efficacy in a variety of pathological diseases, a better knowledge of the link between the structure and function of sirtuin proteins would be necessary.

Keywords: Ageing; Deacetylase; Nicotinamide adenine dinucleotide; Rossmann fold; Sirtuins.

Fig. 1

Structure of SIRT1 (PDB ID: 4IG9). The NAD⁺ binding region is made up of a core six-stranded parallel β sheet with strands β1-3 and β7-9, as well as eight helices namely, αA, αB, αG, αH, and αJ-M, that pack against the β sheet core. The helical module is made up of four α helices namely, αC-F, while the Zn²⁺binding unit is made up of three β strands, β4 to β6 and one helix αI. The CTR creates a β hairpin shape that covers a fundamentally unchanging, hydrophobic region, complementing the β sheet of the NAD⁺ binding domain

Fig. 2

Structure of SIRT2 (PDB ID: 3ZGO). The catalytic core of SIRT2 is a prolonged structure, consisting of one larger and one smaller domain. The larger domain is comprised of six β-strands with β1–3 and β7–9, which forms a parallel β-sheet and six α-helices namely, α1, α7, α8 and α10–α12, that pack against the β-sheet. The smaller domain is made up of two structural modules. The primary insertion includes a helical module which is formed by folding four α-helices (α3–α6) together. A short three-stranded antiparallel β-sheet (β4, β5 and β6) is present in the second module, along with an α-helix (α9) and a zinc atom. The zinc-binding region is made up of a three-stranded antiparallel β-sheet and ~ 45° angled α-helix (α9) to the plane of the β-sheet

Fig. 3

Structure of SIRT3 (PDB ID: 3GLS). SIRT3 has a two-domain structure, like other sirtuins, consisting of a large and a smaller domain. Large domain is a type of Rossmann fold for NAD⁺ binding. The smaller domain consists of a helical bundle and a zinc binding region, which is created by two extending loops from the large domain

Fig. 4

Structure of SIRT5 (PDB ID: 2NYR). SIRT5 is made up of 14 α-helices and 9 β-strands that are grouped in two globular domains: a larger domain and a smaller domain. A large Rossmann fold domain is found in NAD + /NADH binding proteins. It consists of a core β-sheet formed by six parallel β -strands (β1– β3 and β7– β9) and nine α-helices (α1, α2, α6, α7, and α10– α14) that pack against the β-sheet. A smaller zinc-binding domain is made up of five α-helices (α3– α5, α8, and α9) and a three-stranded antiparallel β-sheet (β4, β5, and β6). The smaller zinc binding region shows structural variations between SIRT5 and crystal structure of other sirtuins. Helix α9 and the 16 amino acid residue loop that precedes the helix form a specific insertion in human SIRT5

Fig. 5

Structure of SIRT6 (PDB ID: 3K35). SIRT6 has two globular domains, each with eight α-helices and nine β-strands. A large Rossmann fold domain for NAD + binding is made up of six-stranded (β1, β2, β3, β7, β8, and β9) parallel β sheet amid between two helices (α6 and α7) on one side and four helices (α1, α4, α5, and α8) on the other side. The smaller domain, which contains a zinc-binding motif is formed by two extending loops (linking β 3 and α6) from the large domain and includes a three-stranded antiparallel β -sheet (β 4, β 5, and β 6). A short loop replaces the helix bundle, interacting with the loop between α2 and α3, engaging with a small area on the zinc binding unit. The dashed line represents the missing residues along the protein backbone

Fig. 6

Structure of SIRT7 (PDB ID: 5IQZ). SIRT7-NTD (SIRT7 N-terminal domain) is made up of three helices, α1 to α3, including a short 3₁₀ helix connecting α1 & α2. α1 is the longest helix. The α2 & α3 are short helices and are almost perpendicular to the α1

Fig. 7

Activators of sirtuins a butein, b isoliquiritigenin, c piceatannol, d resveratrol and e SRT1720

Fig. 8

Inhibitors of sirtuins a Splitomicin, b HR73, c Sirtinol, d AGK2, e Cambinol, f Salermide and g Suramin