Acetyl-CoA and the Regulation of Metabolism: Mechanisms … – NCBI

Acetyl-CoA and the Regulation of Metabolism: Mechanisms … – NCBI

1 acetyl coa atp

Sensing of acetyl-CoA through protein acetylation modifications

How might cells actually sense the abundance of acetyl-CoA? It is perhaps no coincidence that acetyl-CoA doubles as the acetyl donor for protein acetylation modifications (including histone acetylation) (Fig. 2). The abundance of protein acetylation modifications could therefore reflect the cell’s metabolic state to regulate various protein activities. Studies performed under carbon-rich conditions where acetyl-CoA synthesis is not limiting may mask the contributions of this metabolite in cellular regulation. However, most organisms, as well as particular tissue microenvironments in vivo experience challenges in the nutrient environment that might limit acetyl-CoA biosynthesis or availability (e.g., carbon starvation or hypoxia). Recent studies have begun to provide compelling evidence that many protein acetylation modifications are indeed modulated by acetyl-CoA availability [27,28].

Besides histones, the acetyl-CoA synthetase family of enzymes was also identified to be regulated by reversible acetylation [29-31]. The acetylation of an active site lysine residue was observed to inhibit the activity of acetyl-CoA synthetase as a mechanism of feedback inhibition in response to high acetyl-CoA [32-34]. The deacetylation of these enzymes, catalyzed by sirtuins, restores their activity [32-34]. Subsequent mass spectrometry surveys have now revealed that thousands of other proteins, including many other metabolic enzymes, can be acetylated [35-38]. In some cases, every enzyme in a particular biochemical pathway was found to be acetylated [39]. Although the majority of these modifications were found to be inhibitory, several were reported to be activating [40]. In some instances, the acetylation of particular metabolic enzymes was responsive to glucose levels in the media, suggesting that they could be linked to intracellular acetyl-CoA abundance. Whether specific acetyltransferase enzymes catalyze the majority of these acetylation modifications present on metabolic enzymes is not yet clear.

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The yeast metabolic cycle (YMC) offers a system to investigate whether particular acetylation modifications might be coupled to acetyl-CoA itself. Studies of yeast cells undergoing the YMC during continuous, glucose-limited growth in a chemostat have revealed periodic changes in intracellular acetyl-CoA amounts as yeast cells alternate between growth and quiescent-like phases [22]. Several proteins are dynamically acetylated precisely in phase with the observed acetyl-CoA oscillations [11]. These include histones, several components of the transcriptional coactivator SAGA, a subunit of the SWI/SNF chromatin remodeling complex Snf2p, and a transcriptional coactivator of ribosomal subunit gene expression Ifh1p [11,41]. Interestingly, the dynamic acetylation of all of these proteins is dependent on the acetyltransferase Gcn5p, suggesting this enzyme has the capability of acetylating its substrates in tune with acetyl-CoA fluctuations in vivo. Consistent with this hypothesis, mutations within Gcn5p slow growth, disrupt the yeast metabolic cycle, or alter the cell’s responsiveness to acetate [11,12]. Moreover, acetylation of SAGA subunits appears to aid its recruitment to growth genes [11]. A brief survey of other acetylated proteins that are not known to be Gcn5p substrates showed they are not dynamically acetylated across the YMC [11]. An analysis of the genomic regions bound by these acetylated histones revealed that several marks, in particular H3K9Ac, were present predominantly at growth genes, specifically during the growth phase of the YMC when acetyl-CoA levels rise [11,25]. These considerations suggest that the acetylation of these nuclear-localized proteins collectively functions to promote the activation of growth genes in response to a burst of nucleocytosolic acetyl-CoA.