The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

Abstract

Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and thus represent potential targets for antibacterial strategies. Here we focused on the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. The involvement of the PPP in the intracellular life cycle of Francisella was first demonstrated by studying PPP inactivating mutants. Indeed, we observed that inactivation of the tktA, rpiA or rpe genes severely impaired intramacrophage multiplication during the first 24 hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular multiplication. To better understand the links between PPP and other metabolic networks in the bacterium, we also performed an extensive proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections to glycolysis, the tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Altogether our study highlights how PPP plays a key role in the pathogenesis and growth of Francisella in its intracellular niche.

Comparative Genome Analysis of a Novel Alkaliphilic Actinobacterial Species Nesterenkonia haasae

“…The pentose phosphate pathway is composed of two branches, an oxidative and a non-oxidative branch (Zheng et al 2017;Rytter et al 2021). In addition to glucose catabolism, the pentose phosphate pathway also contributes to bacterial metabolic adaptation (Zheng et al 2017;Rytter et al 2021). The oxidative pentose phosphate pathway was reported to provide essential material for synthesizing osmolytes like glycerol.…”

The protein carboxymethyltransferase–dependent aspartate salvage pathway plays a crucial role in the intricate metabolic network of Escherichia coli

“…The supernatants were collected and analyzed by LC-MS using SeQuant ZIC-pHilic column (Millipore) for the LC separation. The peak areas, corresponding to relative measurements of different metabolites, were determined ( 70 , 71 ). For each time point, three biological replicates were performed.…”

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“…Importantly, the oxidative branch of the PPP provides, in contrast to the Embden-Meyerhof-Parnas (EMP) pathway, nicotinamide adenine dinucleotide phosphate (NADPH), which can be used as reducing equivalents [103]. This electron donor is necessary for the de novo synthesis of biomolecules, especially during persistence in nutrient-poor niches such as the Brucella-containing vacuole, and for the protection against oxidative stress as described for Francisella [104]. The reductive branch of the PPP feeds trioses into the lower, well-conserved part of the EMP pathway, and subsequently fuels the active and complete tricarboxylic acid (TCA) cycle of Brucella, generating NADH (Figure 4) [100].…”