Modulation of Gene Expression in Actinobacteria by Translational Modification of Transcriptional Factors and Secondary Metabolite Biosynthetic Enzymes

Abstract

Different types of post-translational modifications are present in bacteria that play essential roles in bacterial metabolism modulation. Nevertheless, limited information is available on these types of modifications in actinobacteria, particularly on their effects on secondary metabolite biosynthesis. Recently, phosphorylation, acetylation, or phosphopantetheneylation of transcriptional factors and key enzymes involved in secondary metabolite biosynthesis have been reported. There are two types of phosphorylations involved in the control of transcriptional factors: (1) phosphorylation of sensor kinases and transfer of the phosphate group to the receiver domain of response regulators, which alters the expression of regulator target genes. (2) Phosphorylation systems involving promiscuous serine/threonine/tyrosine kinases that modify proteins at several amino acid residues, e.g., the phosphorylation of the global nitrogen regulator GlnR. Another post-translational modification is the acetylation at the epsilon amino group of lysine residues. The protein acetylation/deacetylation controls the activity of many short and long-chain acyl-CoA synthetases, transcriptional factors, key proteins of bacterial metabolism, and enzymes for the biosynthesis of non-ribosomal peptides, desferrioxamine, streptomycin, or phosphinic acid-derived antibiotics. Acetyltransferases catalyze acetylation reactions showing different specificity for the acyl-CoA donor. Although it functions as acetyltransferase, there are examples of malonylation, crotonylation, succinylation, or in a few cases acylation activities using bulky acyl-CoA derivatives. Substrates activation by nucleoside triphosphates is one of the central reactions inhibited by lysine acetyltransferases. Phosphorylation/dephosphorylation or acylation/deacylation reactions on global regulators like PhoP, GlnR, AfsR, and the carbon catabolite regulator glucokinase strongly affects the expression of genes controlled by these regulators. Finally, a different type of post-translational protein modification is the phosphopantetheinylation, catalized by phosphopantetheinyl transferases (PPTases). This reaction is essential to modify those enzymes requiring phosphopantetheine groups like non-ribosomal peptide synthetases, polyketide synthases, and fatty acid synthases. Up to five PPTases are present in S. tsukubaensis and S. avermitilis. Different PPTases modify substrate proteins in the PCP or ACP domains of tacrolimus biosynthetic enzymes. Directed mutations of genes encoding enzymes involved in the post-translational modification is a promising tool to enhance the production of bioactive metabolites.

Flaviolin-Like Gene Cluster Deletion Optimized the Butenyl-Spinosyn Biosynthesis Route in Saccharopolyspora pogona

“…After the BLAST alignment analysis of genes in clu13 (), six regulatory factors, four transport-related proteins, and a two-component system protein were investigated (Data S1), and they were likely to affect secondary metabolism. − However, the transcriptional abundance of these genes in the clu13 cluster was low, which suggested that they were unlikely to affect the butenyl-spinosyn biosynthesis. However, a hypothetical protein, Sp1764, with high transcriptional abundance attracted our attention (Data S1; Figure A).…”

Dissecting the role of the two Streptomyces peucetius var. caesius glucokinases in the sensitivity to carbon catabolite repression

“…In S. coelicolor , even though the ATP-Glk also lacks DNA-binding motifs, the enzyme specifically affects the expression of 43 genes by a mechanism that awaits to be defined (Romero-Rodríguez et al, 2016 ). Recently, the report of Glk crotonylation by an acyltransferase opened a plausible mechanism to explain how the modified ATP-Glk may interact with its corresponding transcriptional factors (Martín et al, 2021 ; Sun et al, 2020 ).…”

The roles of SARP family regulators involved in secondary metabolism in Streptomyces

“…SAM activates actinorhodin biosynthesis by increasing the autophosphorylation of AfsK ( Lee et al, 2007 ; Jin et al, 2011 ). Moreover, two other serine/threonine kinases, AfsL and PkaG, that can phosphorylate AfsR in vitro have been identified ( Sawai et al, 2004 ; Liu et al, 2013 ; Martín et al, 2021 ). This finding suggested that AfsR works as a signal integrator of signals that are sensed by multiple serine/threonine kinases ( Horinouchi, 2003 ).…”