The Acyl-CoA Specificity of Human Lysine Acetyltransferase KAT2A

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2022 Aug 22

PMID 35995428

Authors

Ananya Anmangandla

Yuxiang Ren

Qin Fu

Sheng Zhang

Hening Lin

Affiliations

Soon will be listed here.

Abstract

Protein post-translational modifications serve to regulate a broad range of cellular functions including signal transduction, transcription, and metabolism. Protein lysine residues undergo many post-translational acylations and are regulated by a range of enzymes, such as histone acetyl transferases (HATs) and histone deacetylases (HDACs). KAT2A, well characterized as a lysine acetyltransferase for both histone and nonhistone substrates, has been reported to tolerate additional acyl-CoA substrates, such as succinyl-CoA, and shows nonacetyl transferase activity in specific biological contexts. In this work, we investigate the acyl-CoA substrate preference of KAT2A and attempt to determine whether and to what extent additional acyl-CoA substrates may be utilized by KAT2A in a cellular context. We show that while KAT2A can bind and utilize malonyl-CoA, its activity with succinyl-CoA or glutaryl-CoA is very weak, and acetylation is still the most efficient activity for KAT2A and in cells.

Citing Articles

Mechanisms of metabolism-coupled protein modifications.

Zhang B, Schroeder F Nat Chem Biol. 2025; .

PMID: 39775169 DOI: 10.1038/s41589-024-01805-z.

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease.

Lian W, Wu R, Lin Y, Chen Y, Jahr H, Wang F Antioxidants (Basel). 2024; 13(4).

PMID: 38671918 PMC: 11047415. DOI: 10.3390/antiox13040470.

Post-translational modulation of cell signalling through protein succinylation.

Kubatzky K, Gao Y, Yu D Explor Target Antitumor Ther. 2024; 4(6):1260-1285.

PMID: 38213532 PMC: 10776603. DOI: 10.37349/etat.2023.00196.

Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRAS Inhibitor MRTX1133.

Orsburn B J Proteome Res. 2023; 22(12):3703-3713.

PMID: 37983312 PMC: 10696623. DOI: 10.1021/acs.jproteome.3c00212.

A chemical catalyst enabling histone acylation with endogenous acyl-CoA.

Habazaki M, Mizumoto S, Kajino H, Kujirai T, Kurumizaka H, Kawashima S Nat Commun. 2023; 14(1):5790.

PMID: 37737243 PMC: 10517024. DOI: 10.1038/s41467-023-41426-z.

References

Wang L, Dent S . Functions of SAGA in development and disease. Epigenomics. 2014; 6(3):329-39. PMC: 4159956. DOI: 10.2217/epi.14.22. View

Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M . The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics. 2011; 10(12):M111.012658. PMC: 3237090. DOI: 10.1074/mcp.M111.012658. View

Du J, Zhou Y, Su X, Yu J, Khan S, Jiang H . Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011; 334(6057):806-9. PMC: 3217313. DOI: 10.1126/science.1207861. View

Grant P, Duggan L, Cote J, Roberts S, Brownell J, Candau R . Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev. 1997; 11(13):1640-50. DOI: 10.1101/gad.11.13.1640. View

Leemhuis H, Packman L, Nightingale K, Hollfelder F . The human histone acetyltransferase P/CAF is a promiscuous histone propionyltransferase. Chembiochem. 2008; 9(4):499-503. DOI: 10.1002/cbic.200700556. View

Wang Z, Cole P . The Chemical Biology of Reversible Lysine Post-translational Modifications. Cell Chem Biol. 2020; 27(8):953-969. PMC: 7487139. DOI: 10.1016/j.chembiol.2020.07.002. View

Huang H, Zhang D, Wang Y, Perez-Neut M, Han Z, Zheng Y . Lysine benzoylation is a histone mark regulated by SIRT2. Nat Commun. 2018; 9(1):3374. PMC: 6113264. DOI: 10.1038/s41467-018-05567-w. View

Wiper-Bergeron N, Abdou Salem H, Tomlinson J, Wu D, Hache R . Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPbeta by GCN5. Proc Natl Acad Sci U S A. 2007; 104(8):2703-8. PMC: 1815245. DOI: 10.1073/pnas.0607378104. View

Colak G, Pougovkina O, Dai L, Tan M, Te Brinke H, Huang H . Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation. Mol Cell Proteomics. 2015; 14(11):3056-71. PMC: 4638046. DOI: 10.1074/mcp.M115.048850. View

10.

Wang M, Lin H . Understanding the Function of Mammalian Sirtuins and Protein Lysine Acylation. Annu Rev Biochem. 2021; 90:245-285. DOI: 10.1146/annurev-biochem-082520-125411. View

11.

Chen Y, Sprung R, Tang Y, Ball H, Sangras B, Kim S . Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol Cell Proteomics. 2007; 6(5):812-9. PMC: 2911958. DOI: 10.1074/mcp.M700021-MCP200. View

12.

Nemeria N, Gerfen G, Nareddy P, Yang L, Zhang X, Szostak M . The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species. Free Radic Biol Med. 2017; 115:136-145. DOI: 10.1016/j.freeradbiomed.2017.11.018. View

13.

Paolinelli R, Mendoza-Maldonado R, Cereseto A, Giacca M . Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Nat Struct Mol Biol. 2009; 16(4):412-20. DOI: 10.1038/nsmb.1583. View

14.

Tan M, Peng C, Anderson K, Chhoy P, Xie Z, Dai L . Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 2014; 19(4):605-17. PMC: 4108075. DOI: 10.1016/j.cmet.2014.03.014. View

15.

Ringel A, Wolberger C . Structural basis for acyl-group discrimination by human Gcn5L2. Acta Crystallogr D Struct Biol. 2016; 72(Pt 7):841-8. PMC: 4932917. DOI: 10.1107/S2059798316007907. View

16.

Sabari B, Tang Z, Huang H, Yong-Gonzalez V, Molina H, Kong H . Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell. 2015; 58(2):203-15. PMC: 4501262. DOI: 10.1016/j.molcel.2015.02.029. View

17.

Wagner G, Payne R . Widespread and enzyme-independent Nε-acetylation and Nε-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J Biol Chem. 2013; 288(40):29036-45. PMC: 3790002. DOI: 10.1074/jbc.M113.486753. View

18.

Yang Y, Anderson E, Zhang S . Evaluation of six sample preparation procedures for qualitative and quantitative proteomics analysis of milk fat globule membrane. Electrophoresis. 2018; 39(18):2332-2339. PMC: 6146045. DOI: 10.1002/elps.201800042. View

19.

Zougman A, Selby P, Banks R . Suspension trapping (STrap) sample preparation method for bottom-up proteomics analysis. Proteomics. 2014; 14(9):1006-0. DOI: 10.1002/pmic.201300553. View

20.

Wagner G, Bhatt D, OConnell T, Thompson J, Dubois L, Backos D . A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation. Cell Metab. 2017; 25(4):823-837.e8. PMC: 5399522. DOI: 10.1016/j.cmet.2017.03.006. View