Abstract
The acetylation/acylation (ac(et)ylation) of lysine side chains isa dynamic post-translational modification (PTM) regulating fundamental cellular processes with implications on the organisms' ageing process: metabolism, transcription, translation, cell proliferation, regulation of the cytoskeleton and DNA damage repair. First identified to occur onhistones, later studies revealed the presence of lysine ac(et)ylation in organisms of all kingdoms of life, in proteins covering all essential cellular processes. A remarkable finding showed that the NAD+-dependent sirtuin deacetylase Sir2 has an impact on replicative lifespan in Saccharomyces cerevisiae suggesting that lysine acetylation has a direct role in the ageing process. Later studies identified sirtuins as mediators for beneficial effects of caloric/dietary restriction on the organisms' health- or lifespan. However, the molecular mechanisms underlying these effects are only incompletely understood. Progress in mass-spectrometry, structural biology, synthetic and semi-synthetic biology deepened our understanding of this PTM. This review summarizes recent developments in the research field. It shows how lysine ac(et)ylation regulates protein function, how it is regulated enzymatically and non-enzymatically, how a dysfunction in this post-translational machinery contributes to disease development. A focus is set on sirtuins and lysine acyltransferases as these are direct sensors and mediators of the cellular metabolic state. Finally, this review highlights technological advances to study lysine ac(et)ylation.
Highlights
The human genome encodes approximately 20,000–25,000 proteins (International Human Genome Sequencing 2004)
A remarkable finding showed that the NAD+-dependent sirtuin deacetylase Sir2 has an impact on replicative lifespan in Saccharomyces cerevisiae suggesting that lysine acetylation has a direct role in the ageing process
Lysine ac(et)ylation is a very important regulatory system, by which the cellular metabolic state can directly be translated to altered protein activities important for the regulation of essential cellular processes, such as transcription, DNA damage repair, translation and metabolic adjustment to altered conditions
Summary
The human genome encodes approximately 20,000–25,000 proteins (International Human Genome Sequencing 2004). As CobB is the only sirtuin deacetylase in E. coli, it most likely developed during evolution as a highly promiscuous enzyme protecting against a decrease in protein functionalities due to increase in chemical ac(et)ylation caused by elevated levels of acetyl-CoA or acetyl-phosphate as a consequence of processes such as metabolic fuel switching (Figure 4(A) and (D)).
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