Flux is defined as the rate at which energy, matter, or particles are interconverted or transferred from one form to another. It is a measure of the rate at which a certain property or quantity is changing over time.
Flow, or metabolic flux is the turnover rate of molecules through a metabolic pathway. Flow is regulated by enzymes involved in a pathway. Within cells, flow regulation is vital for all metabolic pathways to regulate pathway activity under different conditions. Flow is therefore of great interest in modeling metabolic networks, where it is analyzed through flow balance analysis and metabolic control analysis.
In this way, flux is the movement of matter through metabolic networks that are connected by metabolites and cofactorsand is therefore a way of describing the activity of the metabolic network as a whole using a single characteristic.
It is easier to describe the flow of metabolites through a pathway by considering the reaction steps individually. The flux of metabolites through each reaction (J) is the rate of the forward reaction (Vf), less than that of the reverse reaction (Vr):
In equilibrium, there is no flow. Furthermore, it is observed that along a steady-state path, the flux is determined to varying degrees by all steps of the path. The degree of influence is measured by the flow control coefficient.
Control of metabolic flow
Controlling flow through a metabolic pathway requires that
- The degree to which metabolic steps determine metabolic flux varies according to the metabolic needs of organisms.
- The change in flux that occurs due to the above requirement being communicated to the remainder of the metabolic pathway to maintain a steady state.
Flow control in metabolic pathways:
- Flow control is a systemic property, that is, it depends, to varying degrees, on all interactions in the system.
- Flow control is measured by the flow control coefficient
- In a linear chain of reactions, the flow control coefficient will have values between zero and one.
- A step with a flow control coefficient of zero means that that particular step has no influence on steady flow.
- A step in a linear chain with a flow control coefficient of one means that particular step has complete control over the steady-state flow.
- A flow control coefficient can only be measured on the intact system and cannot, for example, be determined by inspecting an isolated enzyme in vitro.
Cellular metabolism is represented by a large number of metabolic reactions involving the conversion of the carbon source (generally glucose) into the building blocks necessary for macromolecular biosynthesis. These reactions form metabolic networks within cells. These networks can then be used to study metabolism within cells.
To allow these networks to interact, a tight connection between them is required. This connection is provided by the use of common cofactors such as ATP, ADP, NADH and NADPH. Furthermore, sharing some metabolites between the different networks further tightens the connections between the different networks.
Control of metabolic networks
Existing metabolic networks control the movement of molecules through their enzymatic steps, regulating enzymes that catalyze irreversible reactions. The movement of molecules through reversible steps is generally not regulated by enzymes, but rather regulated by the concentration of products and reactants. Irreversible reactions in regulated steps of a pathway have a negative change in free energy, thus promoting spontaneous reactions in only one direction. Reversible reactions have no free energy change or are very small. As a result, the movement of molecules through a metabolic network is governed by simple chemical equilibria (in reversible steps), with specific key enzymes being subject to regulation (in irreversible steps). This enzymatic regulation can be indirect, in the case of an enzyme being regulated by some cellular signaling mechanism (such as phosphorylation), or it can be direct, as in the case of allosteric regulationwhere metabolites from a different portion of a metabolic network directly bind and affect the catalytic function of other enzymes in order to maintain homeostasis.
One result that may at first seem counterintuitive is that regulated steps tend to have small flow control coefficients. The reason is that these steps are part of a control system that stabilizes flows, so a disturbance in the activity of a regulated step will inevitably trigger the control system to resist the disturbance, so flow control coefficients will tend to be small. . This explains why, for example, that phosphofructokinase at the glycolysis It has as small coefficient of flow control.
Flows and genotype
Flows and phenotype
The function of the central carbon metabolism (glucose metabolism) has been tuned to exactly meet the needs of the building blocks and Gibbs free energy along with cell growth. There is therefore a strict regulation of fluxes through central carbon metabolism.
The flux in a reaction can be defined based on one of three things
- The activity of the enzyme that catalyzes the reaction
- The enzyme properties
- The concentration of metabolites that affect enzyme activity.
Considering the above, the metabolic fluxes can be described as the final representation of the cell phenotype when expressed under certain conditions.
Roles of metabolic flux in cells
Mammalian cell growth regulation
Research has shown that rapidly growing cells show changes in their metabolism. These changes are observed in relation to glucose metabolism. The changes in metabolism occur because the rate of metabolism controls several signal transduction pathways that coordinate the activation of transcription factors as well as determining cell cycle progress.
Growing cells require the synthesis of new nucleotides, membranes and protein components. These materials can be obtained from carbon metabolism (eg glucose metabolism) or from peripheral metabolism. The increased flux seen in abnormally growing cells is caused by high glucose uptake.
Metabolic flux and more specifically how metabolism is affected due to changes in various pathways has grown in importance since it was observed that tumor cells exhibit increased glucose metabolism compared to normal cells. By studying these changes, it is possible to better understand the mechanisms of cell growth and, where possible, to develop treatments to combat the effects of increased metabolism.
There are several ways to measure flows, but all of them are indirect. Because of this, these methods make a key assumption that all fluxes into a given pool of intracellular metabolites balance all fluxes out of the pool.
This assumption means that, for a given metabolic network, the equilibria around each metabolite impose a series of constraints on the system.
In order to avoid the complexity of data analysis, a simpler method of estimating flow rates has been recently developed, based on unlabeled and uniformly fed together. 13C-labeled glucose. Intermediate metabolic patterns are then analyzed using NMR Spectroscopy. This method can also be used to determine metabolic network topologies.
Source: Flux (metabolism)
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