The Escherichia coli FadR transcription factor: Too much of a good thing?

Abstract

Escherichia coli FadR is a transcription factor regulated by acyl‐CoA thioester binding that optimizes fatty acid (FA) metabolism in response to environmental FAs. FadR represses the fad genes of FA degradation (β‐oxidation) and activates the fab genes of FA synthesis thereby allowing E. coli to have its cake (acyl chains for phospholipid synthesis) and eat it (degrade acyl chains to acetyl‐CoA). Acyl‐CoA binding of FadR derepresses the transcription of the fad genes and cancels fab gene transcriptional activation. Activation of fab genes was thought restricted to the fabA and fabB genes of unsaturated FA synthesis, but FadR overproduction markedly increases yields of all FA acyl chains. Subsequently, almost all of the remaining fab genes were shown to be transcriptionally activated by FadR binding, but binding was very weak. Why are the low‐affinity sites retained? What effects on cell physiology would result from their conversion to high‐affinity sites (thereby mimicking FadR overproduction)? Investigations of E. coli cell size determinants showed that FA synthesis primarily determines E. coli cell size. Upon modest induction of FadR, cell size increases, but at the cost of growth rate and accumulation of intracellular membranes. Greater induction resulted in further growth rate decreases and abnormal cells. Hence, too much FadR is bad. FadR is extraordinarily conserved in γ‐proteobacteria but has migrated. Mycobacterium tuberculosis encodes FadR orthologs one of which is functional in E. coli. Strikingly, the FadR theme of acyl‐CoA‐dependent transcriptional regulation is found in a different transcription factor family where two Bacillus species plus bacterial and archaeal thermophiles contain related proteins of similar function.

FabR senses long‐chain unsaturated fatty acids to control virulence in pathogen Edwardsiella piscicida

“…Bacteria have evolved sophisticated mechanisms to tightly control the expression of the genes responsible for the metabolism of FAs by using the canonical FA regulators FabR and FadR (Fujita et al, 2007;Zhu et al, 2009). FadR, a GntR/TetR family regulator, represses the FA degradation pathway by directly repressing fadA, fadB, fadD, and fadE and activates the FA biosynthesis pathway by directly activating fabA, fabB, fabF, and fabG (van Aalten et al, 2000;Cronan, 2021;Yeo et al, 2017;Zhang et al, 2015). In contrast, FabR, a TetR family repressor, was first discovered by McCue et al (2001) to impair UFA biosynthesis by directly repressing the expression of fabA and fabB, which are essential for FA biosynthesis (Feng & Cronan, 2011;Zhang, 2002).…”

Determination of Mutational Timing of Colistin-Resistance Genes through Klebsiella pneumoniae Evolution

“…A mutation in fatty-acid metabolism transcriptional regulator FadR was observed on days 24 and 36, which corresponded to 256- and 1024-fold increases in MIC from baseline. This gene activates fatty-acid synthesis while repressing fatty-acid degradation in response to environmental fatty-acid levels and may influence bacterial cell size [ 41 ]. A mutation in acyl carrier protein ACP was generated and fixed after day 24 and aligned with a 246–1024-fold increase in MIC ( Table 4 ).…”

Combinatorial Metabolic Engineering Strategies for the Enhanced Production of Free Fatty Acids in Escherichia coli

“…To improve the production of FFAs by applying multiple genetic modifications, we first evaluated the effect of FadR overexpression along with our previously reported efficient mutant thioesterase ‘TesA R64C on FFA production. The reason for choosing FadR as the first candidate for the study was the ability of FadR to globally regulate the expression levels of many genes involved in the FA metabolism to optimal levels. , The FadR overexpression increased the FFA production by 2.1-fold in SBF40 compared to its counterpart (WT) (Figure ). Strain SBF41 expressing FadR and ‘TesA R64C produced around 5.6 ± 0.2 g/L of FFAs, which was 2.2-fold higher than that produced by SBF08 (expressing ‘TesA R64C alone) (Figure ).…”