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. 2012 Mar 8:3:32.
doi: 10.3389/fphar.2012.00032. eCollection 2012.

Sirtuins as regulators of the yeast metabolic network

Markus Ralser  1 , Steve Michel, Michael Breitenbach
Affiliations

Sirtuins as regulators of the yeast metabolic network

Markus Ralser et al. Front Pharmacol. .

Abstract

There is growing evidence that the metabolic network is an integral regulator of cellular physiology. Dynamic changes in metabolite concentrations, metabolic flux, or network topology act as reporters of biological or environmental signals, and are required for the cell to trigger an appropriate biological reaction. Changes in the metabolic network are recognized by specific sensory macromolecules and translated into a transcriptional or translational response. The protein family of sirtuins, discovered more than 30 years ago as regulators of silent chromatin, seems to fulfill the role of a metabolic sensor during aging and conditions of caloric restriction. The archetypal sirtuin, yeast silentinformationregulator2 (SIR2), is an NAD(+) dependent protein deacetylase that interacts with metabolic enzymes glyceraldehyde-3-phosphate dehydrogenase and alcohol dehydrogenase, as well as enzymes involved in NAD(H) synthesis, that provide or deprive NAD(+) in its close proximity. This influences sirtuin activity, and facilitates a dynamic response of the metabolic network to changes in metabolism with effects on physiology and aging. The molecular network downstream Sir2, however, is complex. In just two orders, Sir2's metabolism related interactions span half of the yeast proteome, and are connected with virtually every physiological process. Thus, although it is fundamental to analyze single molecular mechanisms, it is at the same time crucial to consider this genome-scale complexity when correlating single molecular events with complex phenotypes such as aging, cell growth, or stress resistance.

Keywords: aging; caloric restriction; glycolysis; metabolic network; nicotinamide; pentose phosphate pathway; redox state; sirtuins.

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Figures

Figure 1
Figure 1
A metabolism-centric interaction network for Sir2. (A) Network of 84 direct interactors of Sir2; the 40 genes associated with the GO term “metabolism” and/or “carbohydrate metabolism” are highlighted in blue or purple, respectively. (See Table A1 in Appendix for GO terms associated with these Sir2 interactors). (B) The network (A) expanded with the direct interactors of the 40 genes with annotated metabolic function. This network containing first and second order metabolism related Sir2 interactors interconnects with 2888 vertices half of the yeast proteome. We apologize that due to this complexity, not all genes names may be readable. (A,B) Physical- and genetic-interactors for Sir2 were obtained from the BioGrid database as of December 2011 and illustrated with OSPrey (Stark et al., 2006).
Figure 2
Figure 2
NAD+ feeding or depletion in the Sir2 microenvironment. (A) The NAD(H) metabolizing glycolytic enzyme GAPDH (Tdh3) is found in the same protein complex as Sir2. At high glycolytic flux, GAPDH deprives NAD+ in close proximity to Sir2; during gluconeogenesis it generates NAD+. Genetic interplay of Tdh3 and Sir2 influences the rate of mitotic recombination. (B) The predominant cytoplasmic alcohol dehydrogenase (Adh11) also complexes with Sir2. Adh1 overexpression increased the NAD+/NADH ratio and Sir2 activity as well as prolonged yeast replicative lifespan. (C) Mitochondrial malate dehydrogenase Mdh1 is up-regulated during caloric restriction. Its overexpression increases NADH oxidation and prolongs replicative lifespan in a Sir2 dependent manner. Complex formation between Sir2 and Mdh1 has not been reported, but both proteins are interconnected through a dense genetic interaction network involving Rad53, Aat1, Fob1, and Hst1 (blue circle).
Figure 3
Figure 3
An interaction network for SIR2 and HST1-4 indicates metabolism-specificity for SIR2. Genetic and physical interaction data for SIR2 and HST1, HST2, HST3, and HST4 was obtained from yeast BioGrid database (01/2012; Stark et al., 2006). Genes associated with GO terms metabolism are highlighted in blue, those for carbon metabolism in pink. Sir2 has the highest number of metabolism related interactors. Moreover, metabolism related HST1-4 interactors predominantly contain proteins involved in assembly, disassembly and repair of chromatin and DNA, rather then enzymes of primary and intermediary metabolism. (See Table A1 in Appendix for GO terms associated with Sir2 interactors).
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