Bacterial GCN5-Related N-Acetyltransferases: From Resistance to Regulation

Abstract

The GCN5-related N-acetyltransferases family (GNAT) is an important family of proteins that includes more than 100000 members among eukaryotes and prokaryotes. Acetylation appears as a major regulatory post-translational modification and is as widespread as phosphorylation. N-Acetyltransferases transfer an acetyl group from acetyl-CoA to a large array of substrates, from small molecules such as aminoglycoside antibiotics to macromolecules. Acetylation of proteins can occur at two different positions, either at the amino-terminal end (αN-acetylation) or at the ε-amino group (εN-acetylation) of an internal lysine residue. GNAT members have been classified into different groups on the basis of their substrate specificity, and in spite of a very low primary sequence identity, GNAT proteins display a common and conserved fold. This Current Topic reviews the different classes of bacterial GNAT proteins, their functions, their structural characteristics, and their mechanism of action.

Quantitative N-Terminal Footprinting of Pathogenic Mycobacteria Reveals Differential Protein Acetylation

“…Given the crucial role of acyl donors in physiology and virulence, targeting NTA pathways may provide additional avenues to combat mycobacterial disease. 31,32 …”

“…31 Moreover, NAT activity is essential for the formation of mycothiol, a glutathione-like molecule produced by mycobacteria that maintains redox state in the cytosol and detoxifies cells during oxidative stress. 32,33 We and others have reported NTA of virulence factors secreted by ESX systems, 30,34–41 which promote the survival of the bacteria within host macrophages. 42–46 …”

Structure and Catalytic Mechanism of a Bacterial Friedel–Crafts Acylase

“…The most abundant group of acyltransferases mostly require acyl‐CoA derivatives as donor substrates, catalyzing various reactions involved in primary and secondary metabolism . In bacteria, CoA‐dependent O‐ and N‐acylation play a key role in detoxification of antibiotics such as chloramphenicol, aminoglycosides, streptothricin, and phosphinothricin . Acyltransferases are also involved in numerous biosynthetic pathways, especially in the biosynthesis of membrane phospholipids, of wax esters and triacylglycerols, and of polyketides, and also play a role in lysozyme resistance …”

GNAT toxins of bacterial toxin–antitoxin systems: acetylation of charged tRNAs to inhibit translation

“…GNAT toxins: a newly discovered member of type II TA toxins with a unique mechanism of translation inhibition Novel type II TA systems were recently discovered in several bacterial species with the toxins exhibiting a GNAT-fold (GCN5-related N-acetyltransferases) and their cognate antitoxins having a ribbon-helix-helix (RHH) fold (Van Acker et al, 2014;Iqbal et al, 2015;Lobato-M arquez et al, 2015;Cheverton et al, 2016;McVicker and Tang, 2016;Jur _ enas et al, 2017a). GNAT represents a large family of enzymes in prokaryotes and eukaryotes that mainly utilizes acetyl-CoA as the acetyl donor in acetylation reactions, with the term GNAT first derived from the yeast GCN5 (general control nonrepressible 5), which is a histone acetyltransferase (Favrot et al, 2016;Ud-Din et al, 2016). The GNAT family is involved in the acetylation of a vast variety of substrates ranging from proteins to small metabolites and antibiotics such as aminoglycosides (where aminoglycoside N-acetyltransferases that confers resistance to aminoglycosides were the first GNAT family to be identified).…”