Linking chromatin function with metabolic networks: Sir2 family of NAD+-dependent deacetylases

doi:10.1016/S0968-0004(02)00005-1

Trends in Biochemical Sciences

Volume 28, Issue 1, January 2003, Pages 41-48

https://doi.org/10.1016/S0968-0004(02)00005-1 Get rights and content

Abstract

Chromatin remodeling enzymes rely on coenzymes derived from metabolic pathways, suggesting a tight synchronization among apparently diverse cellular processes. A unique example of this link is the recently described NAD⁺-dependent protein and/or histone deacetylases. The founding member of this family – yeast silent information regulator 2 (ySir2) – is involved in gene silencing, chromosomal stability and ageing. Sir2-like enzymes catalyze a reaction in which the cleavage of NAD⁺and histone and/or protein deacetylation are coupled to the formation of O-acetyl-ADP-ribose, a novel metabolite. The dependence of the reaction on both NAD⁺ and the generation of this potential second messenger offers new clues to understanding the function and regulation of nuclear, cytoplasmic and mitochondrial Sir2-like enzymes.

Section snippets

Control of chromatin structure

The structure of chromatin is controlled by enzymes that use co-substrates to alter their state either chemically or physically. Chromatin-modifying enzymes require coenzymes that are metabolic intermediates, but there is a lack of information about the regulatory link between nuclear events and metabolic networks. To fully understand the mechanisms that control chromatin-based events, one has to consider how parameters such as energy status, redox status and cellular stress are linked to the

HDACs and the Sir2 family of NAD⁺-dependent deacetylases

Currently, there are three known classes of HDACs, which are categorized by their homology to enzymes first identified in yeast [15]. Yeast RPD3, HDA1 and silent information regulator 2 (Sir2) are the founding members of class 1, 2 and 3, respectively. Conserved from yeast to humans, classes 1 and 2 are inhibited by trichostatin A and appear to use a divalent zinc-binding motif [16]. The metal-coordinated active site activates an H₂O molecule for direct targeting and hydrolysis of the acetyl

Gene silencing, longevity and chromosomal stability: Sir2 biological functions

Most of our current understanding of Sir2 cellular function is derived from genetic studies in yeast. In yeast, Sir2 (ySir2) is required for silencing at telomeres 19, 20, 21, for the mating-type loci 19, 22 and for rDNA 23, 24, 25, 26, 27. At telomeres and the mating-type loci, ySir2 is found in a multiprotein complex with Sir3 and Sir4 19, 20, 28, 29, 30. The Sir complex contributes to the stability and maintenance of telomeric repeats [31]. At rDNA, ySir2 is associated with both the Net1

Sir2 molecular function unfolds: mechanism of catalysis

The first indication that Sir2 and its homologs were enzymes originated from the observation that CobB – a Sir2 homolog in Salmonella typhimurium – could partially rescue a defect of the phosphoribosyltransferase gene CobT involved in cobalamin biosynthesis [46]. The suggestion that Sir2 might harbor ribosyltransferase activity led to subsequent studies reporting weak NAD⁺-dependent protein ADP-ribosyltransferase activity 17, 47. Unfortunately, it was difficult to ascertain whether this

Structures of Sir2 homologs

Two Archaeal Sir2 homologs (Af1-Sir2 and Af2-Sir2) 51, 53, 54 and one human homolog SIRT2 [52] have been reported by four different research groups, the findings of which have helped to understand the molecular mechanism of the Sir2 proteins. The first report, by Min et al. [51], showed Af1-Sir2 in complex with NAD⁺ (Fig. 3). Chang et al. reported structures of Af1-Sir2 in complex with ADP-ribose and 2-O-acetyl-ADP ribose, and Avalos et al. reported a complex of Af2-Sir2 bound to an acetylated

Substrate specificity, subcellular localization and production of OAADPr

Histones are probable in vivo substrates for ySir2, which displays strong histone deacetylase activity in vitro and is found at silent chromatin, where histones are hypo-acetylated relative to levels found on active chromatin (reviewed in [55]). That bacteria do not have canonical histones yet harbor Sir2 homologs supports the idea of a diverse function and alternate targets for deacetylation. Although a comprehensive analysis of substrate specificity has not been determined, several

Using co-substrates to link nuclear functions with metabolic networks

The strict requirement for NAD⁺ begs many interesting questions, such as: why is NAD⁺ required in the Sir2-like enzyme deacetylation reaction? In terms of the chemical reaction, consumption of NAD⁺ for the hydrolysis of an acetyl group would appear to be a waste of precious cellular resources. As mentioned previously, class 1 and 2 HDACs efficiently catalyze this reaction without the need for co-substrates like NAD⁺ (Fig. 1). Thus, facilitating the rate of catalysis is not a viable explanation

Concluding remarks

New discoveries in this area are inevitable. Recent work on Sir2 and other nuclear coenzyme-dependent proteins highlights the need for a better molecular understanding of these enzymes and the processes they regulate. Future work needs to be targeted towards unraveling the link between metabolic networks and nuclear function in general.

Acknowledgements

I would like to thank the members of my laboratory, as well as Leonard Guarente, Susan Gasser, Rolf Sternglanz, David Sinclair and Mathias Ziegler for discussions. I also thank Cynthia Wolberger and Jose Avalos for providing Fig. 4, and Mike Jackson for creating Fig. 1, Fig. 2.

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Citation Excerpt :
Sirtuins are a phylogenetically ancient class of lysine deacetylases (KDACs) found in all three kingdoms of life with connections to cancer development, aging and metabolic disorders (Sebastian et al., 2012). Sirtuins utilize the ubiquitous redox cofactor NAD+ as a stoichiometric co-substrate (Denu, 2003), cleaving it in nicotinamide (NAM) and O-acetyl-ADP ribose (OAADPR) (Jackson and Denu, 2002; Tanner et al., 2000; Tanny and Moazed, 2001). Why these enzymes couple the deacetylation of their substrate to the cleavage of a high-energy bond is mysterious since KDACs of class I, II and IV achieve them same using water instead.
Metabolic activity and epigenetic regulation of gene expression are intimately coupled. The mechanisms linking the two are incompletely understood. Sirtuins catalyse the removal of acetyl groups from lysine side chains of proteins using NAD⁺ as a stoichiometric cofactor, thereby connecting the acetylation state of histones to energy supply of the cell. Here, we investigate the impact of lysine acetylation turnover by sirtuins on cell physiology by engineering Sirtase, an enzyme that self-acetylates and deacetylates in futile cycles. Expression of Sirtase in E. coli leads to the consumption of the majority of the cellular NAD⁺ supply, indicating that there is little negative feedback from reaction products, O-acetyl-ADP-ribose and nicotinamde, on sirtuin activity. Targeting Sirtase to a partially defective E silencer of the budding yeast mating type locus restores silencing, indicating that lysine acetylation turnover stabilizes heterochromatin in yeast. We speculate that this could be the consequence of local acetyl-CoA depletion because the effect is equally pronounced if the sirtuin moiety of Sirtase is exchanged with Hos3, a NAD⁺-independent deacetylase. Our findings support the concept that metabolism and epigenetic regulation are linked via modulation of heterochromatin stability by lysine acetylation turnover.
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Nuestro objetivo es comparar los niveles séricos de SIRT1 en pacientes con hipogonadismo hipogonadotrópico (IHH) y en sujetos sanos.
Veinticinco pacientes masculinos con IHH y 30 hombres como grupo control fueron incluidos en el estudio. Se determinaron los niveles séricos de SIRT1, los niveles hormonales y los parámetros bioquímicos en ambos grupos y se compararon los niveles séricos de SIRT1, testosterona, gonadrotropinas, la edad, el índice de masa corporal y la resistencia a la insulina.
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Trends in Biochemical Sciences

Linking chromatin function with metabolic networks: Sir2 family of NAD+-dependent deacetylases

Abstract

Section snippets

Control of chromatin structure

HDACs and the Sir2 family of NAD+-dependent deacetylases

Gene silencing, longevity and chromosomal stability: Sir2 biological functions

Sir2 molecular function unfolds: mechanism of catalysis

Structures of Sir2 homologs

Substrate specificity, subcellular localization and production of OAADPr

Using co-substrates to link nuclear functions with metabolic networks

Concluding remarks

Acknowledgements

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Linking chromatin function with metabolic networks: Sir2 family of NAD⁺-dependent deacetylases

HDACs and the Sir2 family of NAD⁺-dependent deacetylases