13C-Metabolic Flux Analysis: An Accurate Approach to Demystify Microbial Metabolism for Biochemical Production
Abstract
:1. Introduction
2. Techniques of 13C Metabolic Flux Analysis
3. Integrating 13C Metabolic Flux Analysis and Metabolic Engineering for Different Industrial Microorganisms
Name | Capabilities | Labeled Pattern | Key Solver (Algorithm) | Platform | Developer |
---|---|---|---|---|---|
13CFLUX2 [66] | Steady-state 13C-MFA | EMU [67] d | IPOPT | UNIX/Linux | Wiechert’s group |
Metran [67] | Steady-state 13C-MFA | EMU | fmincon | MATLAB | Antoniewicz’s group |
FIA [177] | Steady-state 13C-MFA | Fluxomer | SNOPT [178] | UNIX/Linux | Young’s group |
influx_s [179] | Steady-state 13C-MFA | Cumomer | NLSIC [179] | UNIX/Linux | Portais’s group |
C13 [180] | Steady-state 13C-MFA | SFL [181] e | fmincon | MATLAB | Nielsen’s group |
OpenFLUX2 [65] | Steady-state 13C-MFA with PLEs a | EMU | fmincon | MATLAB | Mashko’s group |
FiatFLUX [69] | METAFoRA b, steady-state 13C-MFA | MDV f | fmincon | MATLAB | Sauer’s group |
INCA [68] | Steady-state 13C-MFA and INST-13C-MFA c | EMU | Customized Differential Equation Solver [71] | MATLAB | Young’s group |
OpenMebius [182] | Steady-state 13C-MFA and INST-13C-MFA c | EMU | Levenberg-Marquardt method [183] | MATLAB | Shimizu’s group |
Organism | Key Issues in Metabolic Engineering | Final Product (Objective) | Major Results of 13C-MFA | Strategies of Metabolic Engineering | Results of Metabolic Engineering |
---|---|---|---|---|---|
S. cerevisiae | Bottleneck step: Cytosolic acetyl-CoA supply | n-Butanol |
|
| |
Bottleneck step: Cytosolic acetyl-CoA supply | Isoprenoid-derived drugs [184] |
|
|
| |
Bottleneck step: Cytosolic acetyl-CoA supply | Various industrially relevant products |
|
|
| |
Bottleneck step: Pentose phosphate pathway |
|
|
|
| |
S. cerevisiae | Cofactor imbalance issue | Ethanol (Xylose utilization) [35] |
| ||
S. cerevisiae | High maintenance energy | S-Adenosyl-L-methionine [34] |
|
|
|
High maintenance energy | Xylose utilization [35] |
| |||
S. cerevisiae | Stress response: Furfural [38] | Growth (Survival) |
|
|
|
E. coli | Bottleneck step: Cytosolic acetyl-CoA supply, reduction power supply. | Fatty acid and fatty acid derived chemicals [56,57] |
|
|
|
E. coli [186] | Cofactor imbalance issue | NADPH-dependent compounds [52,93,117] (Lycopene, fatty acid, etc.) |
|
|
|
E. coli | Stress response: Octanoic acid [37] | Growth (Survival) |
|
|
|
Stress response: Super-oxidative (paraquat induced) | Growth (Survival) |
| Suggested strategies: |
| |
| |||||
B. subtilis | Bottleneck step: biosynthesis pathways [126] | Riboflavin | Suggested strategies: |
| |
| |||||
B. subtilis | High maintenance energy [128,129] | Riboflavin |
|
|
|
C. glutamicum | Cofactor imbalance issue | L-lysine |
|
| |
Cofactor imbalance issue | L-valine [53] |
|
|
| |
P. pastoris | High maintenance energy | R. oryzae lipase [185] |
|
| |
A. niger | Cofactor imbalance issues | Fructofuranosidase [151] |
| Suggested strategies: |
|
| |||||
P. chrysogenum | Cofactor imbalance issues[153] | Penicillin-G |
| Suggested strategies: |
|
| |||||
R. palustris | Cofactor imbalance issues [154] | Hydrogen |
| Suggested strategies: |
|
| |||||
B. succiniciproducens | Bottleneck steps in precursor supply [155] | Succinate |
|
|
|
3.1. Saccharomyces Cerevisiae
3.1.1. Bottleneck Steps
3.1.2. Cofactor Imbalance
3.1.3. Metabolic Burden and Microbial Stress
3.2. Escherichia coli
3.2.1. Bottleneck Steps
3.2.2. Cofactor Imbalance
3.2.3. Metabolic Burden and Microbial Stress
3.3. Bacillus Subtilis
3.4. Corynebacterium Glutamicum
3.5. Other Industrial Microorganisms
3.5.1. Pichia Pastoris
3.5.2. Aspergillus Niger
3.5.3. Penicillium Chrysogenum
3.5.4. Rhodopseudomonas Palustris
3.5.5. Basfia Succiniciproducens
4. Perspectives of Integrating 13C Metabolic Flux Analysis with Metabolic Engineering
4.1. Expand 13C-MFA into Genome Scale
4.2. Isotopic Nonstationary 13C-MFA (13C-INST-MFA)
4.3. 13C-Based Dynamic Metabolic Flux Analysis (13C-DMFA)
4.4. Improve Accuracy of 13C-MFA via Parallel Labeling Experiments (PLE)
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Guo, W.; Sheng, J.; Feng, X. 13C-Metabolic Flux Analysis: An Accurate Approach to Demystify Microbial Metabolism for Biochemical Production. Bioengineering 2016, 3, 3. https://doi.org/10.3390/bioengineering3010003
Guo W, Sheng J, Feng X. 13C-Metabolic Flux Analysis: An Accurate Approach to Demystify Microbial Metabolism for Biochemical Production. Bioengineering. 2016; 3(1):3. https://doi.org/10.3390/bioengineering3010003
Chicago/Turabian StyleGuo, Weihua, Jiayuan Sheng, and Xueyang Feng. 2016. "13C-Metabolic Flux Analysis: An Accurate Approach to Demystify Microbial Metabolism for Biochemical Production" Bioengineering 3, no. 1: 3. https://doi.org/10.3390/bioengineering3010003