Glycolysis/gluconeogenesis specialization in microbes is driven by biochemical constraints of flux sensing

Abstract

Central carbon metabolism is highly conserved across microbial species, but can catalyze very different pathways depending on the organism and their ecological niche. Here, we study the dynamic reorganization of central metabolism after switches between the two major opposing pathway configurations of central carbon metabolism, glycolysis, and gluconeogenesis in Escherichia coli , Pseudomonas aeruginosa , and Pseudomonas putida . We combined growth dynamics and dynamic changes in intracellular metabolite levels with a coarse‐grained model that integrates fluxes, regulation, protein synthesis, and growth and uncovered fundamental limitations of the regulatory network: After nutrient shifts, metabolite concentrations collapse to their equilibrium, rendering the cell unable to sense which direction the flux is supposed to flow through the metabolic network. The cell can partially alleviate this by picking a preferred direction of regulation at the expense of increasing lag times in the opposite direction. Moreover, decreasing both lag times simultaneously comes at the cost of reduced growth rate or higher futile cycling between metabolic enzymes. These three trade‐offs can explain why microorganisms specialize for either glycolytic or gluconeogenic substrates and can help elucidate the complex growth patterns exhibited by different microbial species.

Dynamic fluctuations in a bacterial metabolic network

“…The first interaction is the feedforward activation of pyruvate kinase (PYK) by fructose-1,6-bisphosphate (FBP), which plays an important role for glycolysis flux regulation in E. coli 61 . The other two interactions represent negative feedbacks from phosphoenolpyruvate (PEP) to the interconversion of hexose-phosphate and FBP, by respectively inhibiting phosphofructokinase (PFK) and activating fructose-1,6-bisphosphatase (FBPase), which together regulate the PFK-FBPase cycle 62 .

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Degradation and bioconversion of complex municipal solid waste streams into human biotherapeutics and biopolymers

“…This post-transcriptional regulation has evident physicochemical advantages, which allow for an extremely rapid and sensitive response to substrate availability. In P. putida, this mechanism confers a preference for gluconeogenic substrates 33,56,57 , although studies have previously demonstrated that in nutritionally complex environments, glycolytic and gluconeogenic co-utilisation can coexist 45,[58][59][60] . In this current work, we showed that lactic acid is preferentially consumed, and C5 sugars and aromatics were least favoured.…”

“…Pseudomonas putida is a soil dwelling bacterium that displays high solvent tolerance and is considered to be a robust host for bioproduction and bioremediation applications 31,32 . It possesses remarkably flexible non-archetypal metabolism that can accept divergent carbon substrates with no overflow metabolism and rapid shift/adaptation to nutrient availability without a long lag-phase 33 .…”

The Pareto principle: To what extent does it apply to resource acquisition in stable microbial communities and thereby steer their geno−/ecotype compositions and interactions between their members?

“…Since the Pelz et al (1999) publication, there have been a number of studies that indicate that the Pareto principle may apply widely to stable microbial communities, often in the context of metabolic trade‐offs (e.g., De Vrieze & Verstraete, 2016; Fuentes et al, 2021; Marzorati et al, 2008; Mertens et al, 2005; Schink et al, 2022), but also in terms of the relationship between cell morphology and function (Schuech et al, 2019; Sheftel et al, 2013; Shoval et al, 2012), the composition of human microbiome communities (Heinken & Thiele, 2015a, 2015b), and the biotechnological use of microbes for the production of chemicals (Amaradio et al, 2022).…”