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The growing landscape of lysine acetylation links metabolism and cell signalling

Nature Reviews Molecular Cell Biology volume 15, pages 536–550 (2014)Cite this article

Subjects

Key Points

  • Advances in mass spectrometry-based proteomics have enabled the global identification and characterization of thousands of acetylation sites, ushering in the age of acetylomics.

  • Acetylation intersects with cellular metabolism at multiple levels: metabolic intermediates regulate acetyltransferases and deacetylases, acetylation can affect metabolic pathways, and metabolites may directly acetylate proteins through non-enzymatic mechanisms.

  • Acetylation regulates protein function by affecting protein interactions with nucleic acids and with other proteins, the catalytic activity of proteins, and protein localization.

  • Emerging data indicate that other types of acylations, such as succinylation and glutarylation, are also linked to metabolic activity and are regulated by sirtuin-class deacylases.

Abstract

Lysine acetylation is a conserved protein post-translational modification that links acetyl-coenzyme A metabolism and cellular signalling. Recent advances in the identification and quantification of lysine acetylation by mass spectrometry have increased our understanding of lysine acetylation, implicating it in many biological processes through the regulation of protein interactions, activity and localization. In addition, proteins are frequently modified by other types of acylations, such as formylation, butyrylation, propionylation, succinylation, malonylation, myristoylation, glutarylation and crotonylation. The intricate link between lysine acylation and cellular metabolism has been clarified by the occurrence of several such metabolite-sensitive acylations and their selective removal by sirtuin deacylases. These emerging findings point to new functions for different lysine acylations and deacylating enzymes and also highlight the mechanisms by which acetylation regulates various cellular processes.

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Figure 1: Mass spectrometry-based global analysis of lysine acetylation.
Figure 2: Compartmentalized synthesis of acetyl-CoA.
Figure 3: Metabolic regulation of acetylation and deacetylation.
Figure 4: Regulating protein function by reversible lysine acetylation.

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References

  1. Uy, R. & Wold, F. Posttranslational covalent modification of proteins. Science 198, 890–896 (1977).

    Article  CAS  PubMed  Google Scholar 

  2. Walsh, C. T., Garneau-Tsodikova, S. & Gatto, G. J. Jr. Protein posttranslational modifications: the chemistry of proteome diversifications. Angew. Chem. Int. ed. 44, 7342–7372 (2005).

    Article  CAS  Google Scholar 

  3. Jensen, O. N. Interpreting the protein language using proteomics. Nature Rev. Mol. Cell Biol. 7, 391–403 (2006).

    Article  CAS  Google Scholar 

  4. Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of Rna synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).

    Article  CAS  PubMed  Google Scholar 

  5. Cohen, P. The origins of protein phosphorylation. Nature Cell Biol. 4, E127–130 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. L'Hernault, S. W. & Rosenbaum, J. L. Chlamydomonas α-tubulin is posttranslationally modified by acetylation on the epsilon-amino group of a lysine. Biochemistry 24, 473–478 (1985).

    Article  CAS  PubMed  Google Scholar 

  7. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Ott, M. et al. Acetylation of the HIV-1 Tat protein by p300 is important for its transcriptional activity. Curr. Biol. 9, 1489–1492 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Roth, S. Y., Denu, J. M. & Allis, C. D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Lee, K. K. & Workman, J. L. Histone acetyltransferase complexes: one size doesn't fit all. Nature Rev. Mol. Cell Biol. 8, 284–295 (2007).

    Article  CAS  Google Scholar 

  11. Berndsen, C. E. & Denu, J. M. Catalysis and substrate selection by histone/protein lysine acetyltransferases. Curr. Opin. Struct. Biol. 18, 682–689 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Rev. Genet. 10, 32–42 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Finkel, T., Deng, C. X. & Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 460, 587–591 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Filippakopoulos, P. & Knapp, S. The bromodomain interaction module. FEBS Lett. 586, 2692–2704 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Lange, M. et al. Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex. Genes Dev. 22, 2370–2384 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zeng, L. et al. Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466, 258–262 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qiu, Y. et al. Combinatorial readout of unmodified H3R2 and acetylated H3K14 by the tandem PHD finger of MOZ reveals a regulatory mechanism for HOXA9 transcription. Genes Dev. 26, 1376–1391 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim, S. C. et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618 (2006). This study applied an antibody-based enrichment approach and MS-based proteomics to map acetylation sites in HeLa cells and mouse liver mitochondria, and identified acetylation as a frequent modification of mitochondrial proteins.

    Article  CAS  PubMed  Google Scholar 

  19. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009). Describes in human cells the first proteome-wide and in-depth survey of lysine acetylation.

    Article  CAS  PubMed  Google Scholar 

  20. Wang, Q. et al. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 327, 1004–1007 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010). Together with the reference 20, reported that acetylation of metabolic enzymes regulates flux through metabolic pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Henriksen, P. et al. Proteome-wide analysis of lysine acetylation suggests its broad regulatory scope in Saccharomyces cerevisiae. Mol. Cell Proteom. 11, 1510–1522 (2012).

    Article  CAS  Google Scholar 

  23. Lundby, A. et al. Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep. 2, 419–431 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Weinert, B. T. et al. Proteome-wide mapping of the Drosophila acetylome demonstrates a high degree of conservation of lysine acetylation. Sci. Signal. 4, ra48 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Finkemeier, I., Laxa, M., Miguet, L., Howden, A. J. & Sweetlove, L. J. Proteins of diverse function and subcellular location are lysine acetylated in Arabidopsis. Plant Physiol. 155, 1779–1790 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim, G. W. & Yang, X. J. Comprehensive lysine acetylomes emerging from bacteria to humans. Trends Biochem. Sci. 36, 211–220 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Soufi, B., Soares, N. C., Ravikumar, V. & Macek, B. Proteomics reveals evidence of cross-talk between protein modifications in bacteria: focus on acetylation and phosphorylation. Curr. Opin. Microbiol. 15, 357–363 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Choudhary, C. & Mann, M. Decoding signalling networks by mass spectrometry-based proteomics. Nature Rev. Mol. Cell Biol. 11, 427–439 (2010).

    Article  CAS  Google Scholar 

  29. Yates, J. R., 3rd & Kelleher, N. L. Top down proteomics. Anal. Chem. 85, 6151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Garcia, B. A., Pesavento, J. J., Mizzen, C. A. & Kelleher, N. L. Pervasive combinatorial modification of histone H3 in human cells. Nature Methods 4, 487–489 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Hebert, A. S. et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 49, 186–199 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, Y. et al. Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol. Cell Proteom. 11, 1048–1062 (2012).

    Article  CAS  Google Scholar 

  33. Ong, S. E. & Mann, M. Mass spectrometry-based proteomics turns quantitative. Nature Chem. Biol. 1, 252–262 (2005).

    Article  CAS  Google Scholar 

  34. Bantscheff, M., Lemeer, S., Savitski, M. M. & Kuster, B. Quantitative mass spectrometry in proteomics: critical review update from 2007 to the present. Anal. Bioanal. Chem. 404, 939–965 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Ong, S. E. et al. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol. Cell Proteom. 1, 376–386 (2002).

    Article  CAS  Google Scholar 

  36. Sol, E. M. et al. Proteomic investigations of lysine acetylation identify diverse substrates of mitochondrial deacetylase sirt3. PloS One 7, e50545 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Beli, P. et al. Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response. Mol. Cell 46, 212–225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ross, P. L. et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol. Cell Proteom. 3, 1154–1169 (2004).

    Article  CAS  Google Scholar 

  39. Schilling, B. et al. Platform-independent and label-free quantitation of proteomic data using MS1 extracted ion chromatograms in skyline: application to protein acetylation and phosphorylation. Mol. Cell Proteom. 11, 202–214 (2012).

    Article  CAS  Google Scholar 

  40. Rardin, M. J. et al. Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc. Natl Acad. Sci. USA 110, 6601–6606 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Cox, J. et al. MaxLFQ allows accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction. Mol. Cell Proteom. http://dx.doi.org/10.1074/mcp.M113.031591 (2014).

  42. Zhang, J. et al. Lysine acetylation is a highly abundant and evolutionarily conserved modification in Escherichia coli. Mol. Cell Proteom. 8, 215–225 (2009). Showed that acetylation is a frequently occurring modification in bacteria.

    Article  CAS  Google Scholar 

  43. Beltrao, P. et al. Systematic functional prioritization of protein posttranslational modifications. Cell 150, 413–425 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gnad, F. et al. Evolutionary constraints of phosphorylation in eukaryotes, prokaryotes, and mitochondria. Mol. Cell Proteom. 9, 2642–2653 (2010).

    Article  CAS  Google Scholar 

  45. Macek, B. et al. Phosphoproteome analysis of E. coli reveals evolutionary conservation of bacterial Ser/Thr/Tyr phosphorylation. Mol. Cell Proteom. 7, 299–307 (2008).

    Article  CAS  Google Scholar 

  46. van Noort, V. et al. Cross-talk between phosphorylation and lysine acetylation in a genome-reduced bacterium. Mol. Systems Biol. 8, 571 (2012).

    Article  CAS  Google Scholar 

  47. Boekhorst, J., van Breukelen, B., Heck, A. Jr & Snel, B. Comparative phosphoproteomics reveals evolutionary and functional conservation of phosphorylation across eukaryotes. Genome Biol. 9, R144 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tan, C. S. et al. Comparative analysis reveals conserved protein phosphorylation networks implicated in multiple diseases. Sci. Signal. 2, ra39 (2009).

    Article  PubMed  Google Scholar 

  49. Iakoucheva, L. M. et al. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res. 32, 1037–1049 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kemp, B. E. & Pearson, R. B. Protein kinase recognition sequence motifs. Trends Biochem. Sci. 15, 342–346 (1990).

    Article  CAS  PubMed  Google Scholar 

  51. Shahbazian, M. D. & Grunstein, M. Functions of site-specific histone acetylation and deacetylation. Annu. Rev. Biochem. 76, 75–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Gerber, S. A., Rush, J., Stemman, O., Kirschner, M. W. & Gygi, S. P. Absolute quantification of proteins and phosphoproteins from cell lysates by tandem MS. Proc. Natl Acad. Sci. USA 100, 6940–6945 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Weinert, B. T. et al. Acetylation Dynamics and Stoichiometry in Saccharomyces cerevisiae. Mol. Systems Biol. 10, 716 (2014). The first proteome-wide estimation of acetylation site stoichiometry in budding yeast. This revealed that most acetylation sites occur at a low stoichiometry and are regulated in a compartment-specific manner.

    Article  CAS  Google Scholar 

  54. Olsen, J. V. et al. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal. 3, ra3 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Wu, R. et al. A large-scale method to measure absolute protein phosphorylation stoichiometries. Nature Methods 8, 677–683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wellen, K. E. & Thompson, C. B. A two-way street: reciprocal regulation of metabolism and signalling. Nature Rev. Mol. Cell Biol. 13, 270–276 (2012).

    Article  CAS  Google Scholar 

  57. He, W., Newman, J. C., Wang, M. Z., Ho, L. & Verdin, E. Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol. Metab. 23, 467–476 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Lin, H., Su, X. & He, B. Protein lysine acylation and cysteine succination by intermediates of energy metabolism. ACS Chem. Biol. 7, 947–960 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gut, P. & Verdin, E. The nexus of chromatin regulation and intermediary metabolism. Nature 502, 489–498 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Takahashi, H., McCaffery, J. M., Irizarry, R. A. & Boeke, J. D. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol. Cell 23, 207–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Pougovkina, O. et al. Mitochondrial protein acetylation is driven by acetyl-CoA from fatty acid oxidation. Hum. Mol. Genet. 23, 3513–3522 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Schwer, B. et al. Calorie restriction alters mitochondrial protein acetylation. Aging Cell 8, 604–606 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Park, P. H., Miller, R. & Shukla, S. D. Acetylation of histone H3 at lysine 9 by ethanol in rat hepatocytes. Biochem. Biophys. Res. Commun. 306, 501–504 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Picklo, M. J. Sr. Ethanol intoxication increases hepatic N-lysyl protein acetylation. Biochem. Biophys. Res. Commun. 376, 615–619 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Fritz, K. S., Galligan, J. J., Hirschey, M. D., Verdin, E. & Petersen, D. R. Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice. J. Proteome Res. 11, 1633–1643 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Albaugh, B. N., Arnold, K. M. & Denu, J. M. KAT(ching) metabolism by the tail: insight into the links between lysine acetyltransferases and metabolism. Chembiochem 12, 290–298 (2011). Identified Sir2 as the first sirtuin-family deacetylase in yeast.

    Article  CAS  PubMed  Google Scholar 

  68. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Avalos, J. L., Bever, K. M. & Wolberger, C. Mechanism of sirtuin inhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a Sir2 enzyme. Mol. Cell 17, 855–868 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Huang, H. et al. L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro. PloS One 7, e49062 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hait, N. C. et al. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325, 1254–1257 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Thangaraju, M., Carswell, K. N., Prasad, P. D. & Ganapathy, V. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem. J. 417, 379–389 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Millard, C. J. et al. Class I HDACs share a common mechanism of regulation by inositol phosphates. Mol. Cell 51, 57–67 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Guan, K. L. & Xiong, Y. Regulation of intermediary metabolism by protein acetylation. Trends Biochem. Sci. 36, 108–116 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hirschey, M. D., Shimazu, T., Huang, J. Y., Schwer, B. & Verdin, E. SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harbor Symposia Quantitative Biol. 76, 267–277 (2011).

    Article  CAS  Google Scholar 

  78. Paik, W. K., Pearson, D., Lee, H. W. & Kim, S. Nonenzymatic acetylation of histones with acetyl-CoA. Biochim. Biophys. Acta 213, 513–522 (1970).

    Article  CAS  PubMed  Google Scholar 

  79. Wagner, G. R. & Payne, R. M. Widespread and enzyme-independent Nepsilon-acetylation and Nepsilon-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J. Biol. Chem. 288, 29036–29045 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Weinert, B. T. et al. Acetyl-phosphate is a critical determinant of lysine acetylation in E. coli. Mol. Cell 51, 265–272 (2013). Identified acetyl-phosphate as the acetyl group donor in bacteria, and showed that most acetylation in bacteria occurs through a non-enzymatic mechanism.

    Article  CAS  PubMed  Google Scholar 

  81. Moellering, R. E. & Cravatt, B. F. Functional lysine modification by an intrinsically reactive primary glycolytic metabolite. Science 341, 549–553 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wagner, G. R. & Hirschey, M. D. Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol. Cell 54, 5–16 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ghanta, S., Grossmann, R. E. & Brenner, C. Mitochondrial protein acetylation as a cell-intrinsic, evolutionary driver of fat storage: chemical and metabolic logic of acetyl-lysine modifications. Crit. Rev. Biochem. Mol. Biol. 48, 561–574 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wolfe, A. J. The acetate switch. Microbiol. Mol. Biol. Rev. 69, 12–50 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jiang, T., Zhou, X., Taghizadeh, K., Dong, M. & Dedon, P. C. N-formylation of lysine in histone proteins as a secondary modification arising from oxidative DNA damage. Proc. Natl Acad. Sci. USA 104, 60–65 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Xiong, Y. & Guan, K. L. Mechanistic insights into the regulation of metabolic enzymes by acetylation. J. Cell Biol. 198, 155–164 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dillon, N. & Festenstein, R. Unravelling heterochromatin: competition between positive and negative factors regulates accessibility. Trends Genet. 18, 252–258 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Tse, C., Sera, T., Wolffe, A. P. & Hansen, J. C. Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III. Mol. Cell. Biol. 18, 4629–4638 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kimura, A., Umehara, T. & Horikoshi, M. Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Nature Genet. 32, 370–377 (2002).

    Article  PubMed  Google Scholar 

  90. Cullen, B. R. HIV-1 auxiliary proteins: making connections in a dying cell. Cell 93, 685–692 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Dorr, A. et al. Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. EMBO J. 21, 2715–2723 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mujtaba, S. et al. Structural basis of lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain. Mol. Cell 9, 575–586 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Zeng, L. & Zhou, M. M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 513, 124–128 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Winston, F. & Allis, C. D. The bromodomain: a chromatin-targeting module? Nature Struct. Biol. 6, 601–604 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Agalioti, T., Chen, G. & Thanos, D. Deciphering the transcriptional histone acetylation code for a human gene. Cell 111, 381–392 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Wagner, S. A. et al. A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol. Cell Proteomics 10, M111.013284 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Massague, J. & Wotton, D. Transcriptional control by the TGF-β/Smad signaling system. EMBO J. 19, 1745–1754 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yan, X. & Chen, Y. G. Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling. Biochem. J. 434, 1–10 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Gronroos, E., Hellman, U., Heldin, C. H. & Ericsson, J. Control of Smad7 stability by competition between acetylation and ubiquitination. Mol. Cell 10, 483–493 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Simonsson, M., Heldin, C. H., Ericsson, J. & Gronroos, E. The balance between acetylation and deacetylation controls Smad7 stability. J. Biol. Chem. 280, 21797–21803 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Levine, A. J. & Oren, M. The first 30 years of p53: growing ever more complex. Nature Rev. Cancer 9, 749–758 (2009).

    Article  CAS  Google Scholar 

  103. Meek, D. W. & Anderson, C. W. Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb. Perspect. Biol. 1, a000950 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ito, A. et al. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 21, 6236–6245 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ivanov, G. S. et al. Methylation-acetylation interplay activates p53 in response to DNA damage. Mol. Cell. Biol. 27, 6756–6769 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Darnell, J. E. Jr., Kerr, I. M. & Stark, G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    Article  CAS  PubMed  Google Scholar 

  107. Tang, X. et al. Acetylation-dependent signal transduction for type I interferon receptor. Cell 131, 93–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Fujino, T., Kondo, J., Ishikawa, M., Morikawa, K. & Yamamoto, T. T. Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxidation of acetate. J. Biol. Chem. 276, 11420–11426 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. & Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl Acad. Sci. USA 103, 10224–10229 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Hallows, W. C., Yu, W. & Denu, J. M. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J. Biol. Chem. 287, 3850–3858 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Walter, R. A. et al. The role of the C-terminal region in phosphoglycerate mutase. Biochem. J. 337, 89–95 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Thompson, P. R. et al. Regulation of the p300 HAT domain via a novel activation loop. Nature Struct. Mol. Biol. 11, 308–315 (2004).

    Article  CAS  Google Scholar 

  113. Stavropoulos, P., Nagy, V., Blobel, G. & Hoelz, A. Molecular basis for the autoregulation of the protein acetyl transferase Rtt109. Proc. Natl Acad. Sci. USA 105, 12236–12241 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Yuan, H. et al. MYST protein acetyltransferase activity requires active site lysine autoacetylation. EMBO J. 31, 58–70 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Karanam, B., Jiang, L., Wang, L., Kelleher, N. L. & Cole, P. A. Kinetic and mass spectrometric analysis of p300 histone acetyltransferase domain autoacetylation. J. Biol. Chem. 281, 40292–40301 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Black, J. C., Mosley, A., Kitada, T., Washburn, M. & Carey, M. The SIRT2 deacetylase regulates autoacetylation of p300. Mol. Cell 32, 449–455 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nature Rev. Cancer 8, 438–449 (2008).

    Article  CAS  Google Scholar 

  118. Inuzuka, H. et al. Acetylation-dependent regulation of Skp2 function. Cell 150, 179–193 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ventura, M. et al. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase is regulated by acetylation. Int. J. Biochem. Cell Biol. 42, 1672–1680 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Burgering, B. M. A brief introduction to FOXOlogy. Oncogene 27, 2258–2262 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Matsuzaki, H. et al. Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc. Natl Acad. Sci. USA 102, 11278–11283 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Jing, E., Gesta, S. & Kahn, C. R. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell. Metabolism 6, 105–114 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sylvestersen, K. B., Young, C. & Nielsen, M. L. Advances in characterizing ubiquitylation sites by mass spectrometry. Curr. Opin. Chem. Biol. 17, 49–58 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Wisniewski, J. R., Zougman, A. & Mann, M. Nepsilon-formylation of lysine is a widespread post-translational modification of nuclear proteins occurring at residues involved in regulation of chromatin function. Nucleic Acids Res. 36, 570–577 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Rosen, R. et al. Probing the active site of homoserine trans-succinylase. FEBS Lett. 577, 386–392 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Kawai, Y. et al. Formation of Nepsilon-(succinyl)lysine in vivo: a novel marker for docosahexaenoic acid-derived protein modification. J. Lipid Res. 47, 1386–1398 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Zhang, Z. et al. Identification of lysine succinylation as a new post-translational modification. Nature Chem. Biol. 7, 58–63 (2011).

    Article  CAS  Google Scholar 

  129. Peng, C. et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell Proteomics 10, M111.012658 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Garrity, J., Gardner, J. G., Hawse, W., Wolberger, C. & Escalante-Semerena, J. C. N-lysine propionylation controls the activity of propionyl-CoA synthetase. J. Biol. Chem. 282, 30239–30245 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Chen, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell Proteom. 6, 812–819 (2007).

    Article  CAS  Google Scholar 

  132. Cheng, Z. et al. Molecular characterization of propionyllysines in non-histone proteins. Mol. Cell Proteom. 8, 45–52 (2009).

    Article  CAS  Google Scholar 

  133. Tan, M. et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell. Metabolism 19, 605–617 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhang, K., Chen, Y., Zhang, Z. & Zhao, Y. Identification and verification of lysine propionylation and butyrylation in yeast core histones using PTMap software. J. Proteome Res. 8, 900–906 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Leemhuis, H., Packman, L. C., Nightingale, K. P. & Hollfelder, F. The human histone acetyltransferase P/CAF is a promiscuous histone propionyltransferase. Chembiochem 9, 499–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Berndsen, C. E., Albaugh, B. N., Tan, S. & Denu, J. M. Catalytic mechanism of a MYST family histone acetyltransferase. Biochemistry 46, 623–629 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Pougovkina, O., Te Brinke, H., Wanders, R. J., Houten, S. M. & de Boer, V. C. Aberrant protein acylation is a common observation in inborn errors of acyl-CoA metabolism. J. Inherited Metabol. Dis. http://dx.doi.org/10.1007/s10545-014-9684-9 (2014).

  139. Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Eberl, H. C., Spruijt, C. G., Kelstrup, C. D., Vermeulen, M. & Mann, M. A. Map of general and specialized chromatin readers in mouse tissues generated by label-free interaction proteomics. Mol. Cell 40, 368–387 (2013).

    Article  CAS  Google Scholar 

  141. Vermeulen, M. et al. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell 142, 967–980 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. Weinert, B. T. et al. Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Rep. 4, 842–851 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Rardin, M. J. et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell. Metabolism 18, 920–933 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Park, J. et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell 50, 919–930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Colak, G. et al. Identification of lysine succinylation substrates and the succinylation regulatory enzyme CobB in E. coli. Mol. Cell Proteom. 12, 3509–3520 (2013).

    Article  CAS  Google Scholar 

  146. Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011). Discovered SIRT5 as a desuccinylase and demalonylase and identified the mechanism of its selectivity for these modifications.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Van Gool, F. et al. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nature Med. 15, 206–210 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Jiang, H. et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110–113 (2013). Identified SIRT6 as a long-chain deacylase and showed that SIRT6 directly regulates the secretion of TNF through its deacylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Feldman, J. L., Baeza, J. & Denu, J. M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J. Biol. Chem. 288, 31350–31356 C113.511261 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Neumann, H., Peak-Chew, S. Y. & Chin, J. W. Genetically encoding Nε-acetyllysine in recombinant proteins. Nature Chem. Biol. 4, 232–234 (2008). Developed a genetic approach to producing recombinant proteins with site-specific lysine acetylation.

    Article  CAS  Google Scholar 

  152. Lammers, M., Neumann, H., Chin, J. W. & James, L. C. Acetylation regulates cyclophilin A catalysis, immunosuppression and HIV isomerization. Nature Chem. Biol. 6, 331–337 (2010).

    Article  CAS  Google Scholar 

  153. Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mullighan, C. G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011). Together with reference 153, identified frequent mutations in p300 and CREBBP acetyltransferases in leukaemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Marks, P. et al. Histone deacetylases and cancer: causes and therapies. Nature Rev. Cancer 1, 194–202 (2001).

    Article  CAS  Google Scholar 

  156. Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer 6, 38–51 (2006).

    Article  CAS  Google Scholar 

  157. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010). Identified a small-molecule chemical inhibitor that prevents the binding of bromodomain to acetylated lysine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Matzuk, M. M. et al. Small-molecule inhibition of BRDT for male contraception. Cell 150, 673–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wu, C. et al. A protease for 'middle-down' proteomics. Nature Methods 9, 822–824 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Yang, Y. Y., Ascano, J. M. & Hang, H. C. Bioorthogonal chemical reporters for monitoring protein acetylation. J. Am. Chem. Soc. 132, 3640–3641 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell Biol. 13, 225–238 (2012).

    Article  CAS  Google Scholar 

  162. Barber, M. F. et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487, 114–118 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Simon, G. M., Cheng, J. & Gordon, J. I. Quantitative assessment of the impact of the gut microbiota on lysine epsilon-acetylation of host proteins using gnotobiotic mice. Proc. Natl Acad. Sci. USA 109, 11133–11138 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Masri, S. et al. Circadian acetylome reveals regulation of mitochondrial metabolic pathways. Proc. Natl Acad. Sci. USA 110, 3339–3344 (2012).

    Article  Google Scholar 

  165. Shaw, P. G., Chaerkady, R., Zhang, Z., Davidson, N. E. & Pandey, A. Monoclonal antibody cocktail as an enrichment tool for acetylome analysis. Anal. Chem. 83, 3623–3626 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Nguyen, T. T. et al. Cyclophilin d modulates mitochondrial acetylome. Circul. Res. 113, 1308–1319 (2013).

    Article  CAS  Google Scholar 

  167. Yang, L. et al. The fasted/fed mouse metabolic acetylome: N6-acetylation differences suggest acetylation coordinates organ-specific fuel switching. J. Proteome Res. 10, 4134–4149 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Still, A. J. et al. Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation. J. Biol. Chem. 288, 26209–26219 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kim, D. et al. The acetylproteome of gram-positive model bacterium Bacillus subtilis. Proteomics 13, 1726–1736 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank their co-workers for their helpful discussions. C.C. is supported by the Hallas Møller Investigator award from the Novo Nordisk Foundation. The Protein Research Center (CPR) is supported by a generous donation from the Novo Nordisk Foundation.

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Authors and Affiliations

  1. The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, 2200, Denmark

    Chunaram Choudhary, Brian T. Weinert & Matthias Mann

  2. Gladstone Institutes, University of California-San Francisco, San Francisco, 94158, California, USA

    Yuya Nishida & Eric Verdin

  3. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany

    Matthias Mann

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  1. Chunaram Choudhary
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  2. Brian T. Weinert
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  3. Yuya Nishida
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  4. Eric Verdin
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  5. Matthias Mann
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PowerPoint slides

Glossary

ε-amino group

The amino group located on the lysine side chain, which can be post-translationally modified by different modifications, such as different types of acylations.

Bromodomain

A small ∼120 amino acid-long protein domain that mediates protein–protein interactions through binding to acetylated lysine. Bromodomains are often found in lysine acetyltransferases and in proteins involved in gene transcription.

Electrospray ionization

A peptide-containing liquid is passed through a charged needle, producing electrosprayed droplets. Upon evaporation of the solvent, intact and protonated peptides (or other analyte molecules) are left in the gas phase.

Plant homeodomain

Zinc finger-containing modules that can recognize methylated (and less frequently acetylated) lysine on chromatin-bound proteins, such as histones and proteins involved in transcription.

Top-down MS

Analysis of intact (non-proteolysed) proteins by mass spectrometry. In principle, it allows the determination of the precise mass of intact protein, and the identification of all possible post-translational modifications.

Bottom-up proteomics

In this approach proteins are proteolysed into small peptides, typically using trypsin and are then analysed by mass spectrometry. This is also referred to as 'shotgun' proteomics, and most commonly used in the large-scale analysis of proteins and post-translational modifications.

Middle-down MS

Analysis of fragments of partially proteolysed, large proteins by mass spectrometry. This approach is useful for the analysis of proteins that are too large and complex to be analysed by the top-down approach.

Click chemistry

The chemistry of tailored reactions that are selective, reliable and can be easily carried out under simple conditions. This approach can be used to label different types of biomolecules, including proteins and peptides, to allow their selective visualization in cells or their retrieval from complex samples.

Sample fractionation

Separation of protein or peptide samples to reduce sample complexity, which is often achieved by different chromatography approaches.

Dynamic range

The ratio between the largest and smallest recorded intensities of peptides in mass spectrometry-based proteomics.

Isoelectric focusing

A technique for separating different biomolecules, such as proteins and peptides, according to differences in their isoelectric point (pI).

Microscale ion-exchange chromatography

Separation of charged molecules, for example, proteins and peptides, based on their affinity to a charged ion-exchange matrix. When separation is performed on small volumes (microlitre-scale) it is termed microscale ion-exchange chromatography.

Label-free quantification

A mass spectroscopy-based proteomics method used to determine the relative amount of proteins in two or more samples, in which peptides and proteins are quantified by comparing peptide intensities (and less often by peptide counts) in different samples.

Stable isotope labelling by amino acids in cell culture

(SILAC). A mass spectroscopy-based proteomics method used to accurately quantify the relative abundance of peptides in two or more samples. Cells are differentially labelled with stable isotope-labelled amino acids, typically with lysine and arginine, and the relative abundance of differently labelled peptides is quantified by mass spectrometry.

Isobaric mass tags

Chemical tags that are isobaric (that is, have identical masses), but during tandem mass spectrometry they fragment into reporter ions of different masses. In mass spectrometry- based proteomics isobaric mass tags are used to label peptides for the relative quantification of proteins in different samples.

Absolute quantification

(AQUA). A method to quantify the absolute amount of peptides or proteins in a sample using a precisely quantified standard of a heavy isotope-labelled synthetic peptide as a reference, which corresponds to a peptide of interest in the sample.

Stoichiometry estimation by partial chemical modification

A strategy to estimate stoichiometry of post-translational modifications, in which a peptide sample is partially chemically modified to an estimated degree and the relative increase following the partial chemical modification, compared to untreated sample, is used to determine the level of modification abundance in the untreated sample.

D-β-hydroxybutyrate

(βOHB). A metabolite that is generated in liver from acetyl-coenzyme A by β-hydroxybutyrate dehydrogenase. It can be used as an energy source in the brain when glucose levels are low.

L-carnitine

Carnitine is a metabolite that is primarily synthesized in the liver and kidneys from the amino acids lysine and methionine. It transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so that they can be broken down through β-oxidation to acetyl-coenzyme A.

Sphingosine-1-phosphate

(S1P). A sphingolipid metabolite formed by phosphorylation of sphingosine by sphingosine kinase. It serves important signalling functions, mostly through its binding to G protein-coupled receptors, but also through inhibition of deacetylases.

Acetyl-phosphate

(AcP). A high-energy metabolic intermediate formed during the interconversion of acetyl-coenzyme A and acetate in bacteria.

Deprotonation

The removal of a proton (H+) from a molecule. At neutral pH, the ε-amino group of a lysine is protonated (NH3+) and its deprotonation is required for acetylation to occur.

Allosteric regulation

Regulation of protein activity by the binding of an effector molecule to an allosteric site (a position that is not the active site), which often leads to a conformational change that affects the function of the protein.

SAGA complex

(Spt-Ada-Gcn5 acetyltransferase complex). A protein complex that contains acetyltransferase and deubiquitylase activities, and that is involved in a variety of chromatin-associated functions, prominently in gene transcription.

SWI/SNF complex

A protein complex with ATPase activity that uses the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin.

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Choudhary, C., Weinert, B., Nishida, Y. et al. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol 15, 536–550 (2014). https://doi.org/10.1038/nrm3841

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