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Using a hybrid approach to model central carbon metabolism across - - PowerPoint PPT Presentation

May 22, 2023 278 likes •630 views

Using a hybrid approach to model central carbon metabolism across the cell cycle Ccile Moulin 1 , 2 , Laurent Tournier 2 and Sabine Peres 1 , 2 1 LRI, Universit Paris-Sud, CNRS, Universit Paris-Saclay, France 2 MaIAGE, INRA, Universit

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Using a hybrid approach to model central carbon metabolism across the cell cycle

Cécile Moulin 1,2, Laurent Tournier 2 and Sabine Peres 1,2

1LRI, Université Paris-Sud, CNRS, Université Paris-Saclay, France 2MaIAGE, INRA, Université Paris-Saclay, 78350 Jouy-en-Josas, France

6th April 2019 - HSB 2019

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Metabolism is a production system

Glucose Oxygen ATP Nucleotides Lipids

Metabolism

CO2

Cécile Moulin Hybrid model of metabolism and cell cycle 2 / 21

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Metabolism is a reaction network

Glucose Oxygen ATP Nucleotides Lipids CO2

Cécile Moulin Hybrid model of metabolism and cell cycle 2 / 21

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Metabolism is a huge network

Recon3D:13 543 metabolic reactions, 4 140 unique metabolites (Brunk et al., 2018). Kegg Map (metabolism global view):

Cécile Moulin Hybrid model of metabolism and cell cycle 3 / 21

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Solution: Metabolic Pathways

AKG

Lactate Glucose Nucleotides Lipids Glutamine

Glycolysis Pentose Phosphate Pathway Overflow TCA Cycle Glutaminolysis

Cécile Moulin Hybrid model of metabolism and cell cycle 4 / 21

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SLIDE 6

Metabolic pathways are coupled by currency metabolites

ADP NAD ATP ATP NADH NADP NADPH NADH NAD NADPH NADP ADP ATP NAD NADP ADP NADH NADPH ATP AKG

Lactate Glucose Nucleotides Lipids Glutamine

Glycolysis Pentose Phosphate Pathway Overflow TCA Cycle Glutaminolysis

Cécile Moulin Hybrid model of metabolism and cell cycle 4 / 21

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SLIDE 7

Eukaryotic cell cycle: From one mother cell to two daughter cells G1 S G2 M M i t

  • s

i s I n t e r p h a s e

Cell Cycle

G0

Cécile Moulin Hybrid model of metabolism and cell cycle 5 / 21

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Eukaryotic cell cycle: Divided into 4 phases G1 S G2 M G0

Growth Proteins DNA Duplication

  • f

Growth Membrane Cell Division

Cécile Moulin Hybrid model of metabolism and cell cycle 5 / 21

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SLIDE 9

Eukaryotic cell cycle: Linked to the metabolism G1 S G2 M G0

Growth Proteins DNA Duplication

  • f

Growth Membrane Cell Division Energy Amino Acids Nucleotides Energy Nucle-

  • tides

Lipids

not known

(da Veiga Moreira et al., Theoretical Biology and Medical Modelling, 2015) Cécile Moulin Hybrid model of metabolism and cell cycle 5 / 21

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Goal: Create a model coupling metabolism and cell cycle

Glucose Oxygen ATP Nucleotides Lipids CO2

How do metabolism and cell cycle communicate?

G1 S G2 M G0

Growth Proteins DNA Duplication

  • f

Growth Membrane Cell Division Energy Amino Acids Nucleotides Energy Nucle-

  • tides

Lipids

not known

Cécile Moulin Hybrid model of metabolism and cell cycle 6 / 21

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SLIDE 11

Goal: Create a model coupling metabolism and cell cycle

Glucose Oxygen ATP Nucleotides Lipids CO2

How do metabolism and cell cycle communicate?

G1 S G2 M G0

Growth Proteins DNA Duplication

  • f

Growth Membrane Cell Division Energy Amino Acids Nucleotides Energy Nucle-

  • tides

Lipids

not known

Challenges: Different time scales Which level of knowledge?

Cécile Moulin Hybrid model of metabolism and cell cycle 6 / 21

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“Wherever continuous and discrete dynamics interact, hybrid systems arise.”

(Heemels et al., Handbook of Hybrid Systems Control, 2009) Nucleotides

G1 S G2

? ? ?

Energy Lipids Cécile Moulin Hybrid model of metabolism and cell cycle 7 / 21

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SLIDE 13

Outline

1

The metabolic model Introduction of the model Test the model with cell cycle inputs

2

The hybrid model Parameters selection Behavior of the hybrid model

Cécile Moulin Hybrid model of metabolism and cell cycle 8 / 21

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Extended mammalian Central Carbon Metabolism model

The original models: Robitaille et al., PLOS ONE, 2015 da Veiga Moreira et al., Scientific Reports, 2019 (CHO) (mice)

Cécile Moulin Hybrid model of metabolism and cell cycle 9 / 21

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Extended mammalian Central Carbon Metabolism model

The original models: Robitaille et al., PLOS ONE, 2015 da Veiga Moreira et al., Scientific Reports, 2019 (CHO) (mice) x(t) =   xI(t) xII(t) xbiomass(t)   16 7 1 S = SI SII

  • ∈ Q23×30

θ ∈ R∼100

+

   ˙ xI = SIνθ(x(t)) − µθ(x(t))xI(t), ˙ xII = SIIνθ(x(t)), ˙ xbiomass = µθ(x(t))xbiomass(t). ATP + G6P + R5P + PALM → X + ADP

Cécile Moulin Hybrid model of metabolism and cell cycle 9 / 21

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Example: production/consumption of fructose 6-phosphate (F6P)

2 2

dF6P dt = νpgi_f (t) − νpgi_b(t) − νpfk(t) + 2νtkt(t) − µ(t)F6P(t).

(Robitaille et al., PLOS ONE, 2015) Cécile Moulin Hybrid model of metabolism and cell cycle 10 / 21

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Example: production/consumption of fructose 6-phosphate (F6P)

2 2

dF6P dt = νpgi_f (t) − νpgi_b(t) − νpfk(t) + 2νtkt(t) − µ(t)F6P(t).

(Robitaille et al., PLOS ONE, 2015) Cécile Moulin Hybrid model of metabolism and cell cycle 10 / 21

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Example: production/consumption of fructose 6-phosphate (F6P)

1 Michaelis-Menten

νmax = kcat[E] νpfk = νmax F6P Km1 + F6P

(Robitaille et al., PLOS ONE, 2015) (Ghorbaniaghdam et al., Bioprocess and Biosystems Engineering, 2013) (Segel, Enzyme kinetics, 1993) Cécile Moulin Hybrid model of metabolism and cell cycle 11 / 21

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Example: production/consumption of fructose 6-phosphate (F6P)

1 Michaelis-Menten

νmax = kcat[E]

2 Currency Metabolites

νpfk = νmax F6P Km1 + F6P

ATP ADP

Km2 + ATP

ADP

(Robitaille et al., PLOS ONE, 2015) (Ghorbaniaghdam et al., Bioprocess and Biosystems Engineering, 2013) (Segel, Enzyme kinetics, 1993) Cécile Moulin Hybrid model of metabolism and cell cycle 11 / 21

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Example: production/consumption of fructose 6-phosphate (F6P)

1 Michaelis-Menten

νmax = kcat[E]

2 Currency Metabolites 3 Non-competitive inhibition

νpfk = νmax F6P Km1 + F6P

ATP ADP

Km2 + ATP

ADP

Ki Ki + CIT

(Robitaille et al., PLOS ONE, 2015) (Ghorbaniaghdam et al., Bioprocess and Biosystems Engineering, 2013) (Segel, Enzyme kinetics, 1993) Cécile Moulin Hybrid model of metabolism and cell cycle 11 / 21

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Example: production/consumption of fructose 6-phosphate (F6P)

1 Michaelis-Menten

νmax = kcat[E]

2 Currency Metabolites 3 Non-competitive inhibition 4 Non-essential activation

νpfk = νmax F6P

  • 1 +

β αK AMP ATP

  • Km1
  • 1 + 1

K AMP ATP

  • + F6P
  • 1 +

1 αK AMP ATP

  • ATP

ADP

Km2 + ATP

ADP

Ki Ki + CIT

(Robitaille et al., PLOS ONE, 2015) (Ghorbaniaghdam et al., Bioprocess and Biosystems Engineering, 2013) (Segel, Enzyme kinetics, 1993) Cécile Moulin Hybrid model of metabolism and cell cycle 11 / 21

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The model reaches a stationary regime

θ ∈ R∼100

+

Cécile Moulin Hybrid model of metabolism and cell cycle 12 / 21

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The model responds correctly to G1 inputs

(Diaz-Moralli et al. 2013)

[...] the accumulation of PFK/FB3 leads to the activation

  • f glycolysis and an increase in lactate production. [...]

Moreover cyclin D1 is able to downregulate the expression

  • f lipogenic enzymes [...] preventing pyruvate consumption

in lipogenesis and contributing to lactate formation. (Diaz-Moralli et al. Pharmacology & Therapeutics, 2013) Cécile Moulin Hybrid model of metabolism and cell cycle 13 / 21

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The model responds correctly to G1 inputs

(Diaz-Moralli et al. 2013)

[...] the accumulation of PFK/FB3 leads to the activation

  • f glycolysis and an increase in lactate production. [...]

Moreover cyclin D1 is able to downregulate the expression

  • f lipogenic enzymes [...] preventing pyruvate consumption

in lipogenesis and contributing to lactate formation. (Diaz-Moralli et al. Pharmacology & Therapeutics, 2013) Cécile Moulin Hybrid model of metabolism and cell cycle 13 / 21

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The model responds correctly to S inputs

(Diaz-Moralli et al. 2013)

[...] proliferating cells increase G6PD activity during late G1- and S-phases [...]. Moreover, during S-phase the activation of the SCF ubiquitin ligase [...] allows [the proteasome degradation of ] PFKFB3. [...] Through these mechanisms cells redirect the glucose flux from the direct glycolytic pathway to the PPP [...] (Diaz-Moralli et al. Pharmacology & Therapeutics, 2013) Cécile Moulin Hybrid model of metabolism and cell cycle 14 / 21

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The model responds correctly to G2 inputs

(Diaz-Moralli et al. 2013)

[...]transketolase activity showed an acute increase in late

  • S. This shift allows [...] recycling the excess of R5P back

to glycolysis in late S- and G2-phases, when lipid synthesis [... is highly demanded]. Moreover, [...] the activation of transcription of lipogenic enzymes [contributes] to this process [...]. (Diaz-Moralli et al. Pharmacology & Therapeutics, 2013) Cécile Moulin Hybrid model of metabolism and cell cycle 15 / 21

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Creation of the three sub-models: G1, S, G2

G1 ր PFK: ր glycolysis G1 ց VPALM: ր LAC S ց PFK: ր PPP S ր G6PDH: ր PPP G2 ր TKT: ր end of PPP G2 ր VPALM: ր PALM

G1 S G2 PFK +

  • G6PDH
  • +

+ TKT

  • +

VPALM

  • +

Cécile Moulin Hybrid model of metabolism and cell cycle 16 / 21

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Validation of the sub-models

G1: High Glycolysis activity and Lactate production S: High beginning of Pentose Phosphate Pathway activity G2: High Pentose Phosphate Pathway activity and Lipids production

Cécile Moulin Hybrid model of metabolism and cell cycle 17 / 21

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Hybrid model: transition between phases

Nucleotides

G1 S G2

? ? ?

Energy Lipids

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Hybrid model: transition between phases

Nucleotides

G1 S G2

c e l l s i z e c e l l s i z e c e l l s i z e

Energy Lipids

Rules

G1 ends when: xbiomass(t) := (1 + α)x0

b

S ends when: xbiomass(t) := (1 + β)x0

b

G2 ends when: xbiomass(t) := (1 + γ)x0

b

New parameters:

α, β, γ := 1

Cécile Moulin Hybrid model of metabolism and cell cycle 18 / 21

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Validation of the hybrid model

Duration of phases × G1: High Glycolysis activity S: High beginning of Pentose Phosphate Pathway activity G2: High Pentose Phosphate Pathway activity and Lipids production x0

b = 1.1 · 10−4L, α = 0.3, β = 0.4 Cécile Moulin Hybrid model of metabolism and cell cycle 19 / 21

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Comparison with experimental data

NAD/NADH variations × NADP/NADPH decrease in S ATP variations

ATP NADP/NADPH NAD/NADH

pH (da Veiga Moreira et al., Metabolites, 2016)

Cécile Moulin Hybrid model of metabolism and cell cycle 20 / 21

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Conclusion and Perspectives

From a metabolic model to a hybrid model, representing metabolism through cell cycle. Succession of phases: G1: Glycolysis activity S: Nucleotides production G2: Lipids production Toward the understanding of the interconnections between cell cycle and metabolism Are these changes minimum ? Other areas of the Central Carbon Metabolism (Amino-Acids) Change biomass function (supply and demand) Adaptations to cancer metabolism

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