Molecular Characterization of Propionyllysines in Non-histone Proteins

Lysine propionylation and butyrylation are protein modifications that were recently identified in histones. The molecular components involved in the two protein modification pathways are unknown, hindering further functional studies. Here we report identification of the first three in vivo non-histone protein substrates of lysine propionylation in eukaryotic cells: p53, p300, and CREB-binding protein. We used mass spectrometry to map lysine propionylation sites within these three proteins. We also identified the first two in vivo eukaryotic lysine propionyltransferases, p300 and CREB-binding protein, and the first eukaryotic depropionylase, Sirt1. p300 was able to perform autopropionylation on lysine residues in cells. Our results suggest that lysine propionylation, like lysine acetylation, is a dynamic and regulatory post-translational modification. Based on these observations, it appears that some enzymes are common to the lysine propionylation and lysine acetylation regulatory pathways. Our studies therefore identified first several important players in lysine propionylation pathway. Lysine propionylation and butyrylation are protein modifications that were recently identified in histones. The molecular components involved in the two protein modification pathways are unknown, hindering further functional studies. Here we report identification of the first three in vivo non-histone protein substrates of lysine propionylation in eukaryotic cells: p53, p300, and CREB-binding protein. We used mass spectrometry to map lysine propionylation sites within these three proteins. We also identified the first two in vivo eukaryotic lysine propionyltransferases, p300 and CREB-binding protein, and the first eukaryotic depropionylase, Sirt1. p300 was able to perform autopropionylation on lysine residues in cells. Our results suggest that lysine propionylation, like lysine acetylation, is a dynamic and regulatory post-translational modification. Based on these observations, it appears that some enzymes are common to the lysine propionylation and lysine acetylation regulatory pathways. Our studies therefore identified first several important players in lysine propionylation pathway. Acetylation of the ɛ-amino group of lysine residues, or lysine acetylation (LysAc), is one of several abundant post-translational modifications of the lysine side chain, and it has important roles in cellular physiology. Lysine acetylation was first identified in the 1960s in histones (1Allfrey 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. U. S. A. 1964; 51: 786-794Crossref PubMed Scopus (1713) Google Scholar). Discovery of enzymes responsible for adding and removing acetyl groups (histone acetyltransferases (HATs) 1The abbreviations used are: HAT, histone acetyltransferases; CBP, CREB-binding protein; HDAC, histone deacetylase; LysAc, lysine acetylation; LysButy, lysine butyrylation; LysProp, lysine propionylation; MS, spectrometry; MS/MS, tandem mass spectrometry; HPLC, high pressure liquid chromatography; HA, hemagglutinin, PCAF, p300/CBP associate factor; MOF, male-absent on the first; HBO1, histone acetyltransferase bound to ORC1. 1The abbreviations used are: HAT, histone acetyltransferases; CBP, CREB-binding protein; HDAC, histone deacetylase; LysAc, lysine acetylation; LysButy, lysine butyrylation; LysProp, lysine propionylation; MS, spectrometry; MS/MS, tandem mass spectrometry; HPLC, high pressure liquid chromatography; HA, hemagglutinin, PCAF, p300/CBP associate factor; MOF, male-absent on the first; HBO1, histone acetyltransferase bound to ORC1. and histone deacetylases (HDACs)) as well as non-histone substrate proteins (e.g. p53) in the mid-1990s marked a turning point in the field of lysine acetylation biology (2Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar, 3Gu W. Shi X.L. Roeder R.G. Synergistic activation of transcription by CBP and p53.Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 4Taunton J. Hassig C.A. Schreiber S.L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.Science. 1996; 272: 408-411Crossref PubMed Scopus (1524) Google Scholar). Extensive studies over the past decade have established that lysine acetylation has diverse cellular functions and plays an important role in multiple diseases (5Kouzarides T. Acetylation: a regulatory modification to rival phosphorylation?.EMBO J. 2000; 19: 1176-1179Crossref PubMed Scopus (998) Google Scholar, 6Haigis M.C. Guarente L.P. Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction.Genes Dev. 2006; 20: 2913-2921Crossref PubMed Scopus (1070) Google Scholar, 7McKinsey T.A. Olson E.N. Cardiac histone acetylation–therapeutic opportunities abound.Trends Genet. 2004; 20: 206-213Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8Yang X.J. Seto E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention.Oncogene. 2007; 26: 5310-5318Crossref PubMed Scopus (754) Google Scholar, 9Cohen T. Yao T.P. AcK-knowledge reversible acetylation.Sci. STKE. 2004; 245: pe42Google Scholar, 10Michan S. Sinclair D. Sirtuins in mammals: insights into their biological function.Biochem. J. 2007; 404: 1-13Crossref PubMed Scopus (1361) Google Scholar).The high abundance of lysine acetylation in mammalian cells, as demonstrated in a proteomics screen (11Kim S.C. Sprung R. Chen Y. Xu Y. Ball H. Pei J. Cheng T. Kho Y. Xiao H. Xiao L. Grishin N.V. White M. Yang X.J. Zhao Y. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.Mol. Cell. 2006; 23: 607-618Abstract Full Text Full Text PDF PubMed Scopus (1203) Google Scholar), led us to hypothesize that the ɛ-amino group of lysine residues undergoes the structurally similar modifications of propionylation and butyrylation (LysProp and LysButy, respectively) (12Chen Y. Sprung R. Tang Y. Ball H. Sangras B. Kim S.C. Falck J.R. Peng J. Gu W. Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones.Mol. Cell. Proteomics. 2007; 6: 812-819Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar). We confirmed our hypothesis in human histones and verified the discovery by 1) comparing the tandem mass spectra of the modified histone peptides with spectra obtained from synthetic peptides and 2) identifying the first two in vitro propionyl- and butyryltransferases, p300 and CBP (12Chen Y. Sprung R. Tang Y. Ball H. Sangras B. Kim S.C. Falck J.R. Peng J. Gu W. Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones.Mol. Cell. Proteomics. 2007; 6: 812-819Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar). We also demonstrated that these two enzymes, which are also acetyltransferases, can carry out in vitro autopropionylation and autobutyrylation on lysine residues. In unpublished work 2Z. Cheng and Y. Zhao, unpublished data. 2Z. Cheng and Y. Zhao, unpublished data. we have also found lysine propionylation and butyrylation of histones from Saccharomyces cerevisiae. Lysine propionylation was subsequently reported in the Salmonella enterica propionyl-CoA synthetase enzyme PrpE (13Garrity 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. 2007; 282: 30239-30245Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Elegant enzymological studies by Smith and Denu (14Smith B.C. Denu J.M. Acetyl-lysine analog peptides as mechanistic probes of protein deacetylases.J. Biol. Chem. 2007; 282: 37256-37265Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar) suggest that some HDACs have measurable activity toward peptides containing propionyllysine and butyryllysine residues. Given the unique metabolic roles of acetyl-CoA, propionyl-CoA, and butyryl-CoA, which are the co-substrates for the modification reactions, as well as subtle structural differences among the modifications, we propose that lysine propionylation and lysine butyrylation have different biological functions than lysine acetylation. However, in vivo regulatory enzymes and non-histone substrates in eukaryotic cells remain to be characterized, hindering biological studies of the two modification pathways.p53 is a short-lived protein whose activity is maintained at low levels in normal cells. Tight regulation of p53 is essential for its effect on tumorigenesis as well as maintaining normal cell growth. The cellular functions of p53 are rapidly activated in response to stress. Although the mechanisms of p53 activation are not fully understood, they are generally thought to entail post-translational modifications of p53, such as ubiquitination, phosphorylation, and acetylation (15Brooks C.L. Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation.Curr. Opin. Cell Biol. 2003; 15: 164-171Crossref PubMed Scopus (630) Google Scholar, 16Levine A.J. Hu W. Feng Z. The P53 pathway: what questions remain to be explored?.Cell Death Differ. 2006; 13: 1027-1036Crossref PubMed Scopus (526) Google Scholar, 17Janicke R.U. Sohn D. Schulze-Osthoff K. The dark side of a tumor suppressor: anti-apoptotic p53.Cell Death Differ. 2008; 15: 959-976Crossref PubMed Scopus (139) Google Scholar). In fact, p53 was the first non-histone protein found to be acetylated on lysine residues (3Gu W. Shi X.L. Roeder R.G. Synergistic activation of transcription by CBP and p53.Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 2Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar, 18Tang Y. Zhao W. Chen Y. Zhao Y. Gu W. Acetylation is indispensable for p53 activation.Cell. 2008; 133: 612-626Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar). Lysine acetylation status modulates p53-regulated effects in both cell cycle arrest and apoptosis. We recently demonstrated that p53 can also be lysine and in by p300 and it p53 is also and by the enzymes in human into biological at the molecular is on the identification and of the which remain for lysine propionylation pathway. The work was to in vivo non-histone substrates of lysine propionylation in eukaryotic cells and the enzymes responsible for adding and removing the propionylation is identified in histones (12Chen Y. Sprung R. Tang Y. Ball H. Sangras B. Kim S.C. Falck J.R. Peng J. Gu W. Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones.Mol. Cell. Proteomics. 2007; 6: 812-819Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar), like lysine acetylation, is in non-histone proteins unknown, as the of the enzymes responsible for the modification. we that (1Allfrey 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. U. S. A. 1964; 51: 786-794Crossref PubMed Scopus (1713) Google Scholar) lysine propionylation is in three non-histone proteins p300, and (2Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar) p300 and CBP can lysine propionylation of (3Gu W. Shi X.L. Roeder R.G. Synergistic activation of transcription by CBP and p53.Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar) p300 and CBP have propionylation and J. Hassig C.A. Schreiber S.L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.Science. 1996; 272: 408-411Crossref PubMed Scopus (1524) Google Scholar) is a that lysine propionylation from p53 and results that lysine acetylation and lysine propionylation pathways are to substrates and regulatory enzymes in Although three regulatory enzymes for lysine acetylation p300, and also lysine propionylation, and the three HATs to have and are to their activity to lysine acetylation or have activity to lysine propionylation, at for the substrate that for lysine acetylation is than that for lysine propionylation and lysine the mass for lysine is that that of acetylated lysine not the for the three modifications are not with the of the is by the that two lysine butyrylation sites and were identified in CBP and three lysine butyrylation sites and in p53, not their propionyllysine that be the of enzymes that lysine butyrylation to lysine Lysine propionylation status can be by among three substrate the of enzymes in cells the of which be by also be that we are to to propionyllysine and butyryllysine sites among the three substrate proteins as of p300/CBP and of p53 were used in our studies a are the levels of acetylation and propionylation at a lysine by the In the of the and status be by the activity of the enzyme toward the substrate and and also by the of the two is by the of and the of the which in the lysine modification is also possible that some one to the as a is cells or The of is also for the are involved in the is on what are functional differences and in a substrate Although and propionyllysine are structurally they differences in acetylated and proteins associate with has identified in several proteins to be substrates for lysine acetylation p53, p300, and we that a of substrates also be lysine and lysine regulatory enzymes for and be found among enzymes to be acetyltransferases or Acetylation of the ɛ-amino group of lysine residues, or lysine acetylation (LysAc), is one of several abundant post-translational modifications of the lysine side chain, and it has important roles in cellular physiology. Lysine acetylation was first identified in the 1960s in histones (1Allfrey 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. U. S. A. 1964; 51: 786-794Crossref PubMed Scopus (1713) Google Scholar). Discovery of enzymes responsible for adding and removing acetyl groups (histone acetyltransferases (HATs) 1The abbreviations used are: HAT, histone acetyltransferases; CBP, CREB-binding protein; HDAC, histone deacetylase; LysAc, lysine acetylation; LysButy, lysine butyrylation; LysProp, lysine propionylation; MS, spectrometry; MS/MS, tandem mass spectrometry; HPLC, high pressure liquid chromatography; HA, hemagglutinin, PCAF, p300/CBP associate factor; MOF, male-absent on the first; HBO1, histone acetyltransferase bound to ORC1. 1The abbreviations used are: HAT, histone acetyltransferases; CBP, CREB-binding protein; HDAC, histone deacetylase; LysAc, lysine acetylation; LysButy, lysine butyrylation; LysProp, lysine propionylation; MS, spectrometry; MS/MS, tandem mass spectrometry; HPLC, high pressure liquid chromatography; HA, hemagglutinin, PCAF, p300/CBP associate factor; MOF, male-absent on the first; HBO1, histone acetyltransferase bound to ORC1. and histone deacetylases (HDACs)) as well as non-histone substrate proteins (e.g. p53) in the mid-1990s marked a turning point in the field of lysine acetylation biology (2Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar, 3Gu W. Shi X.L. Roeder R.G. Synergistic activation of transcription by CBP and p53.Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 4Taunton J. Hassig C.A. Schreiber S.L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.Science. 1996; 272: 408-411Crossref PubMed Scopus (1524) Google Scholar). Extensive studies over the past decade have established that lysine acetylation has diverse cellular functions and plays an important role in multiple diseases (5Kouzarides T. Acetylation: a regulatory modification to rival phosphorylation?.EMBO J. 2000; 19: 1176-1179Crossref PubMed Scopus (998) Google Scholar, 6Haigis M.C. Guarente L.P. Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction.Genes Dev. 2006; 20: 2913-2921Crossref PubMed Scopus (1070) Google Scholar, 7McKinsey T.A. Olson E.N. Cardiac histone acetylation–therapeutic opportunities abound.Trends Genet. 2004; 20: 206-213Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8Yang X.J. Seto E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention.Oncogene. 2007; 26: 5310-5318Crossref PubMed Scopus (754) Google Scholar, 9Cohen T. Yao T.P. AcK-knowledge reversible acetylation.Sci. STKE. 2004; 245: pe42Google Scholar, 10Michan S. Sinclair D. Sirtuins in mammals: insights into their biological function.Biochem. J. 2007; 404: 1-13Crossref PubMed Scopus (1361) Google Scholar). The high abundance of lysine acetylation in mammalian cells, as demonstrated in a proteomics screen (11Kim S.C. Sprung R. Chen Y. Xu Y. Ball H. Pei J. Cheng T. Kho Y. Xiao H. Xiao L. Grishin N.V. White M. Yang X.J. Zhao Y. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.Mol. Cell. 2006; 23: 607-618Abstract Full Text Full Text PDF PubMed Scopus (1203) Google Scholar), led us to hypothesize that the ɛ-amino group of lysine residues undergoes the structurally similar modifications of propionylation and butyrylation (LysProp and LysButy, respectively) (12Chen Y. Sprung R. Tang Y. Ball H. Sangras B. Kim S.C. Falck J.R. Peng J. Gu W. Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones.Mol. Cell. Proteomics. 2007; 6: 812-819Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar). We confirmed our hypothesis in human histones and verified the discovery by 1) comparing the tandem mass spectra of the modified histone peptides with spectra obtained from synthetic peptides and 2) identifying the first two in vitro propionyl- and butyryltransferases, p300 and CBP (12Chen Y. Sprung R. Tang Y. Ball H. Sangras B. Kim S.C. Falck J.R. Peng J. Gu W. Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones.Mol. Cell. Proteomics. 2007; 6: 812-819Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar). We also demonstrated that these two enzymes, which are also acetyltransferases, can carry out in vitro autopropionylation and autobutyrylation on lysine residues. In unpublished work 2Z. Cheng and Y. Zhao, unpublished data. 2Z. Cheng and Y. Zhao, unpublished data. we have also found lysine propionylation and butyrylation of histones from Saccharomyces cerevisiae. Lysine propionylation was subsequently reported in the Salmonella enterica propionyl-CoA synthetase enzyme PrpE (13Garrity 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. 2007; 282: 30239-30245Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Elegant enzymological studies by Smith and Denu (14Smith B.C. Denu J.M. Acetyl-lysine analog peptides as mechanistic probes of protein deacetylases.J. Biol. Chem. 2007; 282: 37256-37265Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar) suggest that some HDACs have measurable activity toward peptides containing propionyllysine and butyryllysine residues. Given the unique metabolic roles of acetyl-CoA, propionyl-CoA, and butyryl-CoA, which are the co-substrates for the modification reactions, as well as subtle structural differences among the modifications, we propose that lysine propionylation and lysine butyrylation have different biological functions than lysine acetylation. However, in vivo regulatory enzymes and non-histone substrates in eukaryotic cells remain to be characterized, hindering biological studies of the two modification pathways. p53 is a short-lived protein whose activity is maintained at low levels in normal cells. Tight regulation of p53 is essential for its effect on tumorigenesis as well as maintaining normal cell growth. The cellular functions of p53 are rapidly activated in response to stress. Although the mechanisms of p53 activation are not fully understood, they are generally thought to entail post-translational modifications of p53, such as ubiquitination, phosphorylation, and acetylation (15Brooks C.L. Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation.Curr. Opin. Cell Biol. 2003; 15: 164-171Crossref PubMed Scopus (630) Google Scholar, 16Levine A.J. Hu W. Feng Z. The P53 pathway: what questions remain to be explored?.Cell Death Differ. 2006; 13: 1027-1036Crossref PubMed Scopus (526) Google Scholar, 17Janicke R.U. Sohn D. Schulze-Osthoff K. The dark side of a tumor suppressor: anti-apoptotic p53.Cell Death Differ. 2008; 15: 959-976Crossref PubMed Scopus (139) Google Scholar). In fact, p53 was the first non-histone protein found to be acetylated on lysine residues (3Gu W. Shi X.L. Roeder R.G. Synergistic activation of transcription by CBP and p53.Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 2Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar, 18Tang Y. Zhao W. Chen Y. Zhao Y. Gu W. Acetylation is indispensable for p53 activation.Cell. 2008; 133: 612-626Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar). Lysine acetylation status modulates p53-regulated effects in both cell cycle arrest and apoptosis. We recently demonstrated that p53 can also be lysine and in by p300 and it p53 is also and by the enzymes in human cells. into biological at the molecular is on the identification and of the which remain for lysine propionylation pathway. The work was to in vivo non-histone substrates of lysine propionylation in eukaryotic cells and the enzymes responsible for adding and removing the modification. propionylation is identified in histones (12Chen Y. Sprung R. Tang Y. Ball H. Sangras B. Kim S.C. Falck J.R. Peng J. Gu W. Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones.Mol. Cell. Proteomics. 2007; 6: 812-819Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar), like lysine acetylation, is in non-histone proteins unknown, as the of the enzymes responsible for the modification. we that (1Allfrey 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. U. S. A. 1964; 51: 786-794Crossref PubMed Scopus (1713) Google Scholar) lysine propionylation is in three non-histone proteins p300, and (2Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar) p300 and CBP can lysine propionylation of (3Gu W. Shi X.L. Roeder R.G. Synergistic activation of transcription by CBP and p53.Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar) p300 and CBP have propionylation and J. Hassig C.A. Schreiber S.L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.Science. 1996; 272: 408-411Crossref PubMed Scopus (1524) Google Scholar) is a that lysine propionylation from p53 and results that lysine acetylation and lysine propionylation pathways are to substrates and regulatory enzymes in Although three regulatory enzymes for lysine acetylation p300, and also lysine propionylation, and the three HATs to have and are to their activity to lysine acetylation or have activity to lysine propionylation, at for the substrate that for lysine acetylation is than that for lysine propionylation and lysine the mass for lysine is that that of acetylated lysine not the for the three modifications are not with the of the is by the that two lysine butyrylation sites and were identified in CBP and three lysine butyrylation sites and in p53, not their propionyllysine that be the of enzymes that lysine butyrylation to lysine Lysine propionylation status can be by among three substrate the of enzymes in cells the of which be by also be that we are to to propionyllysine and butyryllysine sites among the three substrate proteins as of p300/CBP and of p53 were used in our studies a are the levels of acetylation and propionylation at a lysine by the In the of the and status be by the activity of the enzyme toward the substrate and and also by the of the two is by the of and the of the which in the lysine modification is also possible that some one to the as a is cells or The of is also for the are involved in the is on what are functional differences and in a substrate Although and propionyllysine are structurally they differences in acetylated and proteins associate with has identified in several proteins to be substrates for lysine acetylation p53, p300, and we that a of substrates also be lysine and lysine regulatory enzymes for and be found among enzymes to be acetyltransferases or Lysine propionylation is identified in histones (12Chen Y. Sprung R. Tang Y. Ball H. Sangras B. Kim S.C. Falck J.R. Peng J. Gu W. Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones.Mol. Cell. Proteomics. 2007; 6: 812-819Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar), like lysine acetylation, is in non-histone proteins unknown, as the of the enzymes responsible for the modification. we that (1Allfrey 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. U. S. A. 1964; 51: 786-794Crossref PubMed Scopus (1713) Google Scholar) lysine propionylation is in three non-histone proteins p300, and (2Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar) p300 and CBP can lysine propionylation of (3Gu W. Shi X.L. Roeder R.G. Synergistic activation of transcription by CBP and p53.Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar) p300 and CBP have propionylation and J. Hassig C.A. Schreiber S.L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.Science. 1996; 272: 408-411Crossref PubMed Scopus (1524) Google Scholar) is a that lysine propionylation from p53 and results that lysine acetylation and lysine propionylation pathways are to substrates and regulatory enzymes in Although three regulatory enzymes for lysine acetylation p300, and also lysine propionylation, and the three HATs to have and are to their activity to lysine acetylation or have activity to lysine propionylation, at for the substrate Our that for lysine acetylation is than that for lysine propionylation and lysine the mass for lysine is that that of acetylated lysine not the for the three modifications are not with the of the is by the that two lysine butyrylation sites and were identified in CBP and three lysine butyrylation sites and in p53, not their propionyllysine that be the of enzymes that lysine butyrylation to lysine Lysine propionylation status can be by among three substrate the of enzymes in cells the of which be by also be that we are to to propionyllysine and butyryllysine sites among the three substrate proteins as of p300/CBP and of p53 were used in our Our studies a are the levels of acetylation and propionylation at a lysine by the In the of the and status be by the activity of the enzyme toward the substrate and and also by the of the two is by the of and the of the which in the lysine modification is also possible that some one to the as a is cells or The of is also for the are involved in the is on what are functional differences and in a substrate Although and propionyllysine are structurally they differences in acetylated and proteins associate with proteins. has identified in several proteins to be substrates for lysine acetylation p53, p300, and we that a of substrates also be lysine and lysine regulatory enzymes for and be found among enzymes to be acetyltransferases or with with

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