The Causes and Consequences of Nonenzymatic Protein Acylation. Issue 11 (November 2018)

• Record Type: Journal Article
• Authors: James, Andrew M.; Smith, Cassandra L.; Smith, Anthony C.; Robinson, Alan J.; Hoogewijs, Kurt; Murphy, Michael P.
• Is Part Of: Trends in biochemical sciences. Volume 43:Issue 11(2018)
• Page Start: 921
• Page End: 932
• Publication Date: 2018-11
• Subjects: Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2018.07.002
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Thousands of protein acyl modification sites have now been identified in vivo . However, at most sites the acylation stoichiometry is low, making functional enzyme-driven regulation in the majority of cases unlikely. As unmediated acylation can occur on the surface of proteins when acyl-CoA thioesters react with nucleophilic cysteine and lysine residues, slower nonenzymatic processes likely underlie most protein acylation. Here, we review how nonenzymatic acylation of nucleophilic lysine and cysteine residues occurs; the factors that enhance acylation at particular sites; and the strategies that have evolved to limit protein acylation. We conclude that protein acylation is an unavoidable consequence of the central role of reactive thioesters in metabolism. Finally, we propose a hypothesis for why low-stoichiometry protein acylation is selected against by evolution and how it might contribute to degenerative processes such as aging. Highlights: Nucleophilic protein residues can react with the thioester carbonyl of acyl-CoAs, leading to the continuous transfer of acyl groups to protein. Here, we discuss the chemistry of this reaction. The cell has a range of mitigating strategies that limit the accumulation of acyl modifications on protein. Here, we discuss known mechanisms for limiting acyl modifications as well as additional proteins that could have a role in preventing acylation. Sites of acylation are less conserved in vertebrates as well as longer-lived mammalian species, suggesting low-level protein acylation is a stress. Here, we discuss how low-stoichiometry acylation could have deleterious consequences.