Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Distribution of Control Coefficients in Absence of Feedback Regulation
3.2. Feedback Inhibitions of PPP and Upper Glycolysis Synergistically Cooperate for Efficient PPP Flux Rerouting
3.3. Ros-Dependent Inhibition of Glycolytic Enzymes Expands NADPH Homeostatic Abilities
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
MCA | Metabolic control analysis |
PPP | Pentose phosphate pathway |
ROS | Reactive oxygen species |
G6P | Glucose-6-phosphate |
F6P | Fructose-6-phosphate |
FBP | Fructose-1,6-bisphosphate |
GAP | Glyceraldehyde-3-phosphate |
6PG | 6-phosphogluconate |
R5P | Ribose 5-phosphate |
PKM2 | Pyruvate kinase muscle isozyme M2 |
PFKFB3 | Phosphofructo-2-kinase fructose-2,6-bisphosphatase-3 |
NH,NADPH | Nicotinamide adenine dinucleotide phosphate hydrogen |
N,NADP | Nicotinamide adenine dinucleotide phosphate |
OX | Oxidative stress |
GR | Glutathione reductase |
HK | Hexokinase |
G6PD | G6P dehydrogenase |
6PGD | 6PG dehydrogenase |
PRP | Phosphoribosyl pyrophosphate |
PGI | Phosphoglucose isomerase |
PFK | Phosphofructokinase (type 1) |
FBPase | Fructose-1,6-bisphosphatase |
ALD | Fructose 1,6 bisphosphate aldolase |
GAPD | GAP dehydrogenase |
TKT | Transketolase |
Appendix A. Kinetic Model
- RPI, RPE, TKT1, TKT2, and TAL are pooled to form a single reaction for the nonoxidative branch of the PPP (S7P, E4P metabolites are not included).
- ALD and TPI are pooled (DHAP metabolite is not included).
- GP and GRX are pooled (GSSG, GSH are not included).
- Catalase reaction degrading H2O2 is neglected.
Appendix B. Matrix Equation for Control Coefficients
Appendix C. Computation of Control Manifolds
Appendix C.1. Control Analysis of Regulatory Crosstalk r1,2,3
- All those asymptotic relations are proportional to , justifying the use of the normalized control coefficient (Figure 3).
- Equation (A11a) shows that a PPP flux control driven by NADPH+ cofactor binding to G6PD (no regulation) has an upper bound of .
- Equation (A11b) expresses that promotes PPP flux control (i) independently on , (ii) especially for small .
- Equation (A11c) defines the complex nonlinear interplay between contributions of , , and .
- Equation (A11d) shows indeed that alone, even very large, cannot increase PPP flux control.
Appendix C.2. Control Analysis of Regulatory Crosstalk r 1,4,5
- Positive values of which is increased by regulation following Equation (A12f), but also regulation .
- The effect of those regulations is enhanced by large directional PGI flux from F6P to G6P.
- The effect of is amplified by large directional PGI flux from G6P to F6P.
- The two items above indicate that efficient regulation of NADPH homeostasis by requires high values of both with an upper bound given by:
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Pfeuty, B.; Hurbain, J.; Thommen, Q. Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis. Metabolites 2023, 13, 485. https://doi.org/10.3390/metabo13040485
Pfeuty B, Hurbain J, Thommen Q. Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis. Metabolites. 2023; 13(4):485. https://doi.org/10.3390/metabo13040485
Chicago/Turabian StylePfeuty, Benjamin, Julien Hurbain, and Quentin Thommen. 2023. "Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis" Metabolites 13, no. 4: 485. https://doi.org/10.3390/metabo13040485