Why are metabolic pathways regulated

The list below, illustrated in the following figure, gives common ways to regulate enzyme activity. Extracellular regulated kinase 2 ERK2 , also known as mitogen activate protein kinase 2 MAPK2 is a protein the plays a vital role in cell signaling across the cell membrane. Phosphoryation of ERK2 on Threonine Thr and Tyrosine Tyr leads to a structural change in the protein and the regulation of its activity.

Jmol: Erk2 - Structural Comparison of phosphorylated and dephosphorylated enzyme. However, this increase is counterbalanced by the accumulation of G6P. This in turn causes the accumulation of G6P, and then causes the degradation of mRNA of ptsG , while causes the activation of the oxidative PP pathway. The accumulation of PEP and the activation of PP pathway for the production of E4P both activate the aromatic amino acid biosynthetic pathways Kedar et al.

In fact, it has been reported that shikimic acid could be implemented by pyk gene knockout in the PTS - background Escalante et al.

The effect of pyk gene knockout in the lysine producing C. If either the ppc or pckA gene, which code for the anaplerotic and gluconeogenic pathway enzymes, respectively, was knocked out, the OAA concentration decreases, which in turn activates another anaplerotic pathway such as glyoxylate pathway Figure 3 Laporte and Koshland, ; Yang et al.

The activation of glyoxylate pathway causes less production of acetate and CO 2 , resulting in the increase in the cell yield with lower cell growth rate as compared to wild type strain Yang et al. The metabolic regulation mechanisms for these mutants seem to be similar. Note that although Pyk activity increased, the Pfk activity decreased, which may be due to the inhibition caused by the increase in PEP concentration.

The metabolic flux analysis of lpdA gene knockout mutant indicates that glyoxylate pathway was activated, while glycolysis, the oxidative PP pathway, and the TCA cycle activities were down-regulated Li et al. In the case of lpdA gene knockout, pyruvate PYR accumulates and in turn glycolysis intermediates accumulate, and thus the glucose consumption rate decreases. As a result, pflA , B gene knockout caused overproduction of lactate Zhu and Shimizu, , This causes the activation of pfkA and pykF gene expressions, and thus the glucose uptake rate was increased Zhu and Shimizu, If ldhA gene was knocked out, the fluxes toward the production of acetate, formate, and ethanol were increased as expected Kabir et al.

The above explanation is for E. The metabolisms of other microorganisms have also been investigated by Fuhrer et al. The above analysis is mainly made based on 13 C-metabolic flux distributions, where the changes in the metabolic flux distributions are caused by the regulation of enzymes and the intracellular metabolite concentrations. In addition to allosteric regulation, the enzyme activities are controlled by their corresponding gene expressions. Since gene expressions are under control of global regulators or transcription factors, it is quite important to understand how these control the metabolism for metabolic engineering Matsuoka and Shimizu, Note that Table 1 gives the relationship between transcription factor and the regulated main metabolic pathway genes, where this gives part of the whole regulation system Gama-Castro et al.

Although most of the metabolic pathway engineering practices have focused on the modulation of the metabolic pathways of interest, the present analysis indicates the importance of understanding the overall main metabolic regulation in response the specific pathway mutation for the efficient metabolic engineering. It may be also considered to modulate transcription factors for the significant strain improvement.

National Center for Biotechnology Information , U. Comput Struct Biotechnol J. Published online Jan Author information Article notes Copyright and License information Disclaimer. E-mail address : pj. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly cited.

This article has been cited by other articles in PMC. Abstract Recent metabolic engineering practice was briefly reviewed in particular for the useful metabolite production such as natural products and biofuel productions. Introduction The concept of metabolic engineering has been proposed back in Bailey, ; Stephanopoulos and Vallino, Systems biology approach The important approach for metabolic engineering is the systems biology approach, where large genome-scale models have been developed Palsson, ; Feist and Palsson, ; Herrgard et al.

Importance of modulating the main metabolism The cell's metabolism comprises thousands of reactions that are involved in the degradation of available nutrient sources for biosynthesis of cellular constituents such as proteins, lipids, carbohydrates, DNA and RNA etc. Open in a separate window.

Figure 1. Main metabolic pathways of E. Figure 2. Table 1 Regulation of global regulators on the metabolic pathway gene. IclR : Repressor of glyoxylate pathway genes.

FadR : Regulator of fatty acid metabolism. Effect of the specific pathway mutation on the metabolic regulation of the main metabolism The proper understanding of the metabolic regulation of the central carbon metabolism is critical for the efficient metabolic engineering.

Table 2 Effect of the specific gene mutation on the metabolism. Figure 3. Concluding remarks Although most of the metabolic pathway engineering practices have focused on the modulation of the metabolic pathways of interest, the present analysis indicates the importance of understanding the overall main metabolic regulation in response the specific pathway mutation for the efficient metabolic engineering.

Competing Interests The authors have declared that no competing interests exist. References Alper H and Stephanopoulos G Global transcription machinery engineering: a new approach for improving cellular phenotype. Mol Syst Biol 6 : Microb Cell Fact 7 : 8. Mol Syst Biol 7 : Microb Cell Fact 9 : Curr Opin Biotechnol 22 : — [ PubMed ] [ Google Scholar ] Gosset G Improvement of Escherichia coli production strains by modification of the phosphoenolpyruvate: sugar phosphotransferase system.

Microb Cell Fact 4 : Signal processing in hierarchical structured functional units. Many of the molecular transformations that occur within cells require multiple steps to accomplish. Recall, for instance, that cells split one glucose molecule into two pyruvate molecules by way of a ten-step process called glycolysis. This coordinated series of chemical reactions is an example of a metabolic pathway in which the product of one reaction becomes the substrate for the next reaction.

Consequently, the intermediate products of a metabolic pathway may be short-lived Figure 3. Figure 3: Reaction pathway Enzymes can be involved at every step in a reaction pathway. At each step, the molecule is transformed into another form, due to the presence of a specific enzyme. Such a reaciton pathway can create a new molecule biosynthesis , or it can break down a molecule degradation.

Sometimes, the enzymes involved in a particular metabolic pathway are physically connected, allowing the products of one reaction to be efficiently channeled to the next enzyme in the pathway. For example, pyruvate dehydrogenase is a complex of three different enzymes that catalyze the path from pyruvate the end product of glycolysis to acetyl CoA the first substrate in the citric acid cycle. Within this complex, intermediate products are passed directly from one enzyme to the next.

Cells are expert recyclers. They disassemble large molecules into simpler building blocks and then use those building blocks to create the new components they require.

The breaking down of complex organic molecules occurs via catabolic pathways and usually involves the release of energy. Through catabolic pathways, polymers such as proteins, nucleic acids, and polysaccharides are reduced to their constituent parts: amino acids, nucleotides, and sugars, respectively. In contrast, the synthesis of new macromolecules occurs via anabolic pathways that require energy input Figure 4.

Cells must balance their catabolic and anabolic pathways in order to control their levels of critical metabolites — those molecules created by enzymatic activity — and ensure that sufficient energy is available.

For example, if supplies of glucose start to wane, as might happen in the case of starvation, cells will synthesize glucose from other materials or start sending fatty acids into the citric acid cycle to generate ATP. Conversely, in times of plenty, excess glucose is converted into storage forms, such as glycogen, starches, and fats. Figure 4: Catabolic and anabolic pathways in cell metabolism Catabolic pathways involve the breakdown of nutrient molecules Food: A, B, C into usable forms building blocks.

In this process, energy is either stored in energy molecules for later use, or released as heat. Anabolic pathways then build new molecules out of the products of catabolism, and these pathways typically use energy. The new molecules built via anabolic pathways macromolecules are useful for building cell structures and maintaining the cell. Figure 5: Feedback inhibition When there is enough product at the end of a reaction pathway red macromolecule , it can inhibit its own synthesis by interacting with enzymes in the synthesis pathway red arrow.

Figure Detail Not only do cells need to balance catabolic and anabolic pathways, but they must also monitor the needs and surpluses of all their different metabolic pathways. In order to bolster a particular pathway, cells can increase the amount of a necessary rate-limiting enzyme or use activators to convert that enzyme into an active conformation.

Conversely, to slow down or halt a pathway, cells can decrease the amount of an enzyme or use inhibitors to make the enzyme inactive. Such up- and down-regulation of metabolic pathways is often a response to changes in concentrations of key metabolites in the cell. For example, a cell may take stock of its levels of intermediate metabolites and tune the glycolytic pathway and the synthesis of glucose accordingly. In some instances, the products of a metabolic pathway actually serve as inhibitors of their own synthesis, in a process known as feedback inhibition Figure 5.

For example, the first intermediate in glycolysis, glucosephosphate, inhibits the very enzyme that produces it, hexokinase. This page appears in the following eBook.