The common message of constraint-based optimization approaches: overflow metabolism is caused by two growth-limiting constraints

Groot, Daan H. de; Lischke, Julia; Muolo, Riccardo; Planquè, Robert; Bruggeman, Frank J.; Teusink, Bas

doi:10.1007/s00018-019-03380-2

Cited by 66 publications

(58 citation statements)

References 45 publications

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“…Concurrently, we introduced a revised mechanism for carbon storage, effectively treating glycogen as an independent component of biomass. This configuration makes it possible for glycogen to be accumulated and depleted at variable rates (Figure 1), aligning with the overflow metabolism hypothesis (Szul et al, 2019; de Groot et al, 2020). Other key modifications induced by the ReFill algorithm and subsequent manual curation (see Methods) include the completion of the Entner-Doudoroff (ED) pathway, recently discovered in cyanobacteria (Chen et al, 2016) and proposed as the primary Prochlorococcus glucose metabolism pathway under mixotrophic conditions (Biller et al, 2018).…”

Section: Resultssupporting

confidence: 79%

Dynamic allocation of carbon storage and nutrient-dependent exudation in a revised genome-scale model ofProchlorococcus

Ofaim

Sulheim

Almaas

et al. 2020

Preprint

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Microbial life in the oceans impacts the entire marine ecosystem, global biogeochemistry and climate. The marine cyanobacterium Prochlorococcus, an abundant component of this ecosystem, releases a significant fraction of the carbon fixed through photosynthesis, but the amount, timing and molecular composition of released carbon are still poorly understood. These depend on several factors, including nutrient availability, light intensity and glycogen storage. Here we combine multiple computational approaches to provide insight into carbon storage and exudation in Prochlorococcus. First, with the aid of a new algorithm for recursive filling of metabolic gaps (ReFill), and through substantial manual curation, we extended an existing genome-scale metabolic model of Prochlorococcus MED4. In this revised model (iSO595), we decoupled glycogen biosynthesis/degradation from growth, thus enabling dynamic allocation of carbon storage. In contrast to standard implementations of flux balance modeling, we made use of forced influx of carbon and light into the cell, to recapitulate overflow metabolism due to the decoupling of photosynthesis and carbon fixation from growth during nutrient limitation. By using random sampling in the ensuing flux space, we found that storage of glycogen or exudation of organic acids are favored when the growth is nitrogen limited, while exudation of amino acids becomes more likely when phosphate is the limiting resource. We next used COMETS to simulate day-night cycles and found that the model displays dynamic glycogen allocation and exudation of organic acids. The switch from photosynthesis and glycogen storage to glycogen depletion is associated with a redistribution of fluxes from the Entner-Doudoroff to the Pentose Phosphate pathway. Finally, we show that specific gene knockouts in iSO595 exhibit dynamic anomalies compatible with experimental observations, further demonstrating the value of this model as a tool to probe the metabolic dynamic of Prochlorococcus.

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Section: Resultssupporting

confidence: 79%

Dynamic allocation of carbon storage and nutrient-dependent exudation in a revised genome-scale model ofProchlorococcus

Ofaim

Sulheim

Almaas

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Concurrently, we introduced a revised mechanism for carbon storage, effectively treating glycogen as an independent component of biomass. This dynamic implementation of glycogen storage, introduced here in dFBA, makes it possible for glycogen to be accumulated and depleted at variable rates ( Figure 1 ), aligning with the overflow metabolism hypothesis ( Szul et al, 2019 ; de Groot et al, 2020 ). Other key modifications induced by the ReFill algorithm and subsequent manual curation (see section Materials and Methods) include the completion of the Entner–Doudoroff (ED) pathway, recently discovered in cyanobacteria ( Chen et al, 2016 ) and proposed as the primary Prochlorococcus glucose metabolism pathway under mixotrophic conditions ( Biller et al, 2018 ; Muñoz-Marín et al, 2020 ).…”

Section: Resultsmentioning

confidence: 58%

Dynamic Allocation of Carbon Storage and Nutrient-Dependent Exudation in a Revised Genome-Scale Model of Prochlorococcus

et al. 2021

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Microbial life in the oceans impacts the entire marine ecosystem, global biogeochemistry and climate. The marine cyanobacterium Prochlorococcus, an abundant component of this ecosystem, releases a significant fraction of the carbon fixed through photosynthesis, but the amount, timing and molecular composition of released carbon are still poorly understood. These depend on several factors, including nutrient availability, light intensity and glycogen storage. Here we combine multiple computational approaches to provide insight into carbon storage and exudation in Prochlorococcus. First, with the aid of a new algorithm for recursive filling of metabolic gaps (ReFill), and through substantial manual curation, we extended an existing genome-scale metabolic model of Prochlorococcus MED4. In this revised model (iSO595), we decoupled glycogen biosynthesis/degradation from growth, thus enabling dynamic allocation of carbon storage. In contrast to standard implementations of flux balance modeling, we made use of forced influx of carbon and light into the cell, to recapitulate overflow metabolism due to the decoupling of photosynthesis and carbon fixation from growth during nutrient limitation. By using random sampling in the ensuing flux space, we found that storage of glycogen or exudation of organic acids are favored when the growth is nitrogen limited, while exudation of amino acids becomes more likely when phosphate is the limiting resource. We next used COMETS to simulate day-night cycles and found that the model displays dynamic glycogen allocation and exudation of organic acids. The switch from photosynthesis and glycogen storage to glycogen depletion is associated with a redistribution of fluxes from the Entner–Doudoroff to the Pentose Phosphate pathway. Finally, we show that specific gene knockouts in iSO595 exhibit dynamic anomalies compatible with experimental observations, further demonstrating the value of this model as a tool to probe the metabolic dynamic of Prochlorococcus.

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“…Nutrient-dependent regulation membrane permeability to antibiotics ( Figure 3E) can be a result of different metabolic pathways. It has been observed that E.coli cells have different metabolic pathways for nutrients depending on the growth conditions [53]. Furthermore, if the cells are subjected to a nutrient downshift, the proteome reallocates such that a larger fraction of proteins is allocated to the sector responsible for carbon catabolism which in turn reduces the available proteome fraction for other sectors [54,55].…”

Section: Mechanistic Origin Of Ribosomal Tradeoff Between Growth and mentioning

confidence: 99%

Nutrient-dependent trade-offs between ribosomes and division protein synthesis control bacterial cell size and growth

Serbanescu

Ojkic

Banerjee

2020

Preprint

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Cell size control emerges from a regulated balance between the rates of cell growth and division. In bacteria, simple quantitative laws connect cellular growth rate to ribosome abundance. However, it remains poorly understood how translation regulates bacterial cell size and shapes under growth perturbations. Here we develop a whole-cell model for growth dynamics in rod-shaped bacteria that links ribosomal abundance with cell geometry, division control, and the extracellular environment.Our study reveals that cell shape maintenance under nutrient perturbations requires a balanced trade-off between ribosomes and division protein synthesis. Deviations from this trade-off relationship is predicted under translational perturbations, leading to distinct modes of cell morphological changes, in agreement with single-cell experimental data on Escherichia coli. Furthermore, by calibrating our model with experimental data, we predict how combinations of nutrient-, translational-and shape perturbations can be chosen to optimize bacterial growth fitness and drug resistance.

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The common message of constraint-based optimization approaches: overflow metabolism is caused by two growth-limiting constraints

Cited by 66 publications

References 45 publications

Dynamic allocation of carbon storage and nutrient-dependent exudation in a revised genome-scale model ofProchlorococcus

Dynamic allocation of carbon storage and nutrient-dependent exudation in a revised genome-scale model ofProchlorococcus

Dynamic Allocation of Carbon Storage and Nutrient-Dependent Exudation in a Revised Genome-Scale Model of Prochlorococcus

Nutrient-dependent trade-offs between ribosomes and division protein synthesis control bacterial cell size and growth

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