Pathways of Non-enzymatic Lysine Acylation.

Tim Baldensperger,Marcus A Glomb

doi:10.3389/fcell.2021.664553

Abstract

Posttranslational protein modification by lysine acylation is an emerging mechanism of cellular regulation and fine-tunes metabolic processes to environmental changes. In this review we focus on recently discovered pathways of non-enzymatic lysine acylation by reactive acyl-CoA species, acyl phosphates, and α-dicarbonyls. We summarize the metabolic sources of these highly reactive intermediates, demonstrate their reaction mechanisms, give an overview of the resulting acyl lysine modifications, and evaluate the consequences for cellular regulatory processes. Finally, we discuss interferences between lysine acylation and lysine ubiquitylation as a potential molecular mechanism of dysregulated protein homeostasis in aging and related diseases.

Highlights

Acetylation of lysine side chains was first discovered in histone proteins by Phillips in 1963 (Phillips, 1963)
Research focuses on biological functions of these recently discovered posttranslational modifications and novel insights are constantly published
Ubiquitin is a small protein consisting of 76 amino acids and was discovered “ubiquitously” in tissues of eukaryotic organisms (Goldstein et al, 1975)

Summary

INTRODUCTION

Acetylation of lysine side chains was first discovered in histone proteins by Phillips in 1963 (Phillips, 1963). Reactive acyl-CoA species like acetyl-CoA, succinyl-CoA, and malonyl-CoA are central intermediates in metabolism of carbohydrates, proteins, and lipids They are highly abundant and reactive precursors for non-enzymatic protein modification (Gao et al, 2007). Acetyl-CoA and other acyl-CoA-thioesters are able to modify lysine residues independently of enzymes as well (Figure 2A) This non-enzymatic pathway was already described in the beginning of research about regulation of transcription by histone acetylation (Paik et al, 1970). The corresponding acyl lysine modifications 2-methylbutyrylation and isovalerylation are concentrated in the same range as crotonylation While this seems rather low abundant, their precursors are highly specific for branched-chain amino acid metabolism and may be important regulators of these pathways (Baldensperger et al, 2019). The formation of 3-hydroxybutyrylation is enzymatically facilitated by p300 and CBP (Liu et al, 2019; Huang et al, 2021)

ACYLATION BY ACYL PHOSPHATES

DISCUSSION

Findings

Benzoyl lysine Malonyl lysine Succinyl lysine