Quantitative modeling of pentose phosphate pathway response to oxidative stress reveals a cooperative regulatory strategy

Hurbain, Julien; Thommen, Quentin; Anquez, François; Pfeuty, Benjamin

doi:10.1016/j.isci.2022.104681

Cited by 16 publications

(15 citation statements)

References 69 publications

(128 reference statements)

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“…This result is consistent with that of a previous report, which showed that the expression of G6PD in Mortierella alpina improved NADPH level [ 32 ]. The activity of G6PD was regulated by the NADPH/NADP + ratio, and when the ratio decreased, the enzyme activity of G6PD increased and promoted NADPH synthesis [ 33 ]. This conclusion was verified in the present study, where the NADPH/NADP + ratio at 72 h was lowest, but the G6PD activity was enhanced by 46.9%.…”

Section: Resultsmentioning

confidence: 99%

Construction of Glucose-6-Phosphate Dehydrogenase Overexpression Strain of Schizochytrium sp. H016 to Improve Docosahexaenoic Acid Production

et al. 2022

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Docosahexaenoic acid (DHA) is an important omega-3 polyunsaturated fatty acid (PUFA) that plays a critical physiological role in human health. Schizochytrium sp. is considered an excellent strain for DHA production, but the synthesis of DHA is limited by the availability of nicotinamide adenine dinucleotide phosphate (NADPH). In this study, the endogenous glucose-6-phosphate dehydrogenase (G6PD) gene was overexpressed in Schizochytrium sp. H016. Results demonstrated that G6PD overexpression increased the availability of NADPH, which ultimately altered the fatty acid profile, resulting in a 1.91-fold increase in DHA yield (8.81 g/L) and increased carbon flux by shifting it from carbohydrate and protein synthesis to lipid production. Thus, G6PD played a vital role in primary metabolism. In addition, G6PD significantly increased DHA content and lipid accumulation by 31.47% and 40.29%, respectively. The fed-batch fermentation experiment results showed that DHA production reached 17.01 g/L in the overexpressing G6PD strain. These results elucidated the beneficial effects of NADPH on the synthesis of PUFA in Schizochytrium sp. H016, which may be a potential target for metabolic engineering. Furthermore, this study provides a promising regulatory strategy for the large-scale production of DHA in Schizochytrium sp.

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Section: Resultsmentioning

confidence: 99%

Construction of Glucose-6-Phosphate Dehydrogenase Overexpression Strain of Schizochytrium sp. H016 to Improve Docosahexaenoic Acid Production

et al. 2022

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“…Upstream, nucleotide synthesis depends on the pentose phosphate pathway (PPP), which shares multiple intermediate metabolites with glycolysis and amino acid metabolism. The trade-off between glycolytic and PPP flux has been implied to influence the relationships between growth rate, yield, and oxidative stress (Christodoulou et al 2018;Cheng et al 2019;Hurbain et al 2022). A coarse-grained model that includes both protein and nucleotide synthesis must account for the coordination between the two carbon metabolic pathways (Chubukov et al 2014), considerably increasing its complexity versus the model presented in this study.…”

Section: Non-protein Biomassmentioning

confidence: 99%

A coarse-grained resource allocation model of carbon and nitrogen metabolism in unicellular microbes

Kleijn

Marguerat

Shahrezaei

2023

Preprint

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Coarse-grained resource allocation models (C-GRAMs) are simple mathematical models of whole cell physiology, where large components of the macromolecular composition are abstracted into single entities. The dynamics and steady-state behaviour of such models provides insights on optimal allocation of cellular resources and have explained experimentally observed cellular growth laws. Here, we formulate a minimal C-GRAM with nitrogen and carbon pathways converging on biomass production, with parameterizations accounting for respirofermentative and purely respiratory growth. The model describes the effects of the uptake of sugars, ammonium, and/or compound nutrients such as amino acids on the translational resource allocation towards proteome sectors that maximised the growth rate. It robustly recovers cellular growth laws including the Monod law and the ribosomal growth law. Furthermore, we show how the growth-maximizing balance between carbon uptake, recycling, and excretion depends on the nutrient environment. Lastly, we find a robust linear correlation between the ribosome fraction and the abundance of amino acid equivalents in the optimal cell, which supports the view that simple regulation of translational gene expression can enable cells to achieve an approximately optimal growth state.

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“…Ordinary differential equation (ODE) models are widely used to describe the dynamics of biochemical processes such as signalling [1][2][3], metabolism [4,5] or gene regulation [6,7]. These models can capture the mechanistic details of interactions between biochemical species, aggregate current knowledge and integrate heterogeneous data types.…”

Section: Introductionmentioning

confidence: 99%

Efficient computation of adjoint sensitivities at steady-state in ODE models of biochemical reaction networks

et al. 2023

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Dynamical models in the form of systems of ordinary differential equations have become a standard tool in systems biology. Many parameters of such models are usually unknown and have to be inferred from experimental data. Gradient-based optimization has proven to be effective for parameter estimation. However, computing gradients becomes increasingly costly for larger models, which are required for capturing the complex interactions of multiple biochemical pathways. Adjoint sensitivity analysis has been pivotal for working with such large models, but methods tailored for steady-state data are currently not available. We propose a new adjoint method for computing gradients, which is applicable if the experimental data include steady-state measurements. The method is based on a reformulation of the backward integration problem to a system of linear algebraic equations. The evaluation of the proposed method using real-world problems shows a speedup of total simulation time by a factor of up to 4.4. Our results demonstrate that the proposed approach can achieve a substantial improvement in computation time, in particular for large-scale models, where computational efficiency is critical.

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Quantitative modeling of pentose phosphate pathway response to oxidative stress reveals a cooperative regulatory strategy

Cited by 16 publications

References 69 publications

Construction of Glucose-6-Phosphate Dehydrogenase Overexpression Strain of Schizochytrium sp. H016 to Improve Docosahexaenoic Acid Production

Construction of Glucose-6-Phosphate Dehydrogenase Overexpression Strain of Schizochytrium sp. H016 to Improve Docosahexaenoic Acid Production

A coarse-grained resource allocation model of carbon and nitrogen metabolism in unicellular microbes

Efficient computation of adjoint sensitivities at steady-state in ODE models of biochemical reaction networks

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