Glycolysis: Definition, Steps, Significance and Regulation

Glycolysis is a metabolic pathway that plays a critical role in the metabolism of glucose, one of the most important sources of energy for living organisms. The pathway consists of a series of chemical reactions that convert glucose (C₆H₁₂O₆) into energy in the form of ATP (adenosine triphosphate) and other useful products. The Embden–Meyerhof–Parnas Pathway is another name.

The metabolic pathway occurs in the cytoplasm of cells and does not require oxygen, making it an important metabolic pathway for cells that do not have access to oxygen. It is the first step in the breakdown of glucose, and it is followed by the Krebs cycle and oxidative phosphorylation, which occur in the mitochondria and require oxygen.

The overall chemical equation for glycolysis can be written as:

Glucose + 2 ATP + 2 NAD+ + 2 H2O –> 2 ATP + 2 NADH + 2 H⁺ + 2 pyruvate

As you can see, the net yield of ATP from glycolysis is 2 ATP per molecule of glucose. However, the overall process is not very efficient, as a lot of energy is lost as heat.

Let’s talk about the steps of glycolysis, the enzymes and hormones that control it, how it affects health and disease, and how it’s used in biotechnology and industry.

We will explore the difference between aerobic and anaerobic glycolysis and its relationship with the pentose phosphate pathway. We will also cover some of the frequently asked questions about glycolysis. Stay tuned for our next post for a more in-depth understanding of this important metabolic pathway!

Preparatory Phase

Glycolysis is a metabolic pathway that converts glucose into energy in the form of ATP and other useful products. This phase focuses on the energy-investment phase, also known as the preparatory phase. 

This phase involves a series of chemical reactions that convert glucose into glyceraldehyde-3-phosphate (G3P), which is used in the energy-payoff phase to produce ATP, NADH, and pyruvate.

The preparatory phase of glycolysis is also known as the energy-investment phase. It involves the following steps:

Step 1:  Conversion of glucose into glucose-6-phosphate

In this step, the glucose (C₆H₁₂O₆) is converted into glucose-6-phosphate (G6P) through the action of the enzyme hexokinase.

This reaction is driven by the hydrolysis of ATP:

Glucose + ATP –> Glucose-6-phosphate + ADP

Step 2: Conversion of glucose-6-phosphate into fructose-6-phosphate

This steps involves the conversion of glucose-6-phosphate into fructose-6-phosphate, which is catalyzed by the enzyme phosphoglucose isomerase. This reaction does not require any energy input:

Glucose-6-phosphate –> Fructose-6-phosphate

Step 3: Conversion of fructose-6-phosphate into fructose-1,6-bisphosphate

This step explains the conversion of fructose-6-phosphate into fructose-1,6-bisphosphate, which is catalyzed by the enzyme aldolase. This reaction is also driven by the hydrolysis of ATP:

Fructose-6-phosphate + ATP –> Fructose-1,6-bisphosphate + ADP

Step 4: Splitting of fructose-1,6-bisphosphate into G3P and DHAP

The fourth step of glycolysis involves the splitting of fructose-1,6-bisphosphate into Glyceraldehyde-3-Phospahate (G-3-P) and Dihydroxyacetone Phosphate molecules (DHAP), which is catalyzed by the enzyme Fructose bisphosphate aldolase.

Fructose-1,6-Phosphate –> Glyceraldehyde-3-P + DHAP

Step 5: Isomerization of DHAP to G3P

The second molecule of the before step DHAP is isomerizes into Glyceraldehyde-3-P by the enzyme triose phosphate isomerase. This is a reversible reaction and energy is not required to complete this step.

DHAP <–> Glyceraldehyde-3-P

The preparatory phase of glycolysis requires a total of 2 ATP per molecule of glucose. These ATP molecules are used to drive the conversion of one glucose molecule into two molecules of G3P. The G3P are further oxidized to produce ATP, NADH, and pyruvate.

Pay-off Phase

The payoff phase of glycolysis, also known as the energy-payoff phase, consists of the final reactions in the pathway that convert glyceraldehyde-3-phosphate (G3P) into ATP, NADH, and pyruvate. The steps involved in this phase are as follows:

Step 6: Dehydrogenation

The next step is the oxidation of G3P to produce 1,3-bisphosphoglycerate, NADH, and H⁺, which is catalyzed by the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH):

2 G3P + 2 NAD⁺ –> 2 (1,3-bisphosphoglycerate) + 2 NADH + 2 H⁺

Step 7: Phosphorylation

The 1,3-bisphosphoGlycerate is converted into 3-Phosphoglycerate by the enzyme phosphoglycerate kinase. This is an exothermic reaction. the released energy is utilized in the phosphorylation process of ADP. The ADP is converted into ATP.

1,3-bisphosphoglycerate + ADP + Pⁱ–> 3-phosphoglycerate + ATP

Step 8: Isomerization

The two molecules of 3-PG is isomerizes into 2-Phosphoglycerate by shifting phosphate group from third carbon to 2nd carbon of the molecule.

3-Phosphoglycerate –> 2-Phosphoglycerate

Step 9: Hydration

In this step, the 2-PG molecule is converted into Phosphoenole Pyruvate (PEP) in the presence of Enolase. Here one water molecule (H₂O) is released.

2-PhosphoGlycerate –> PhosphoEnolPyruvate + H₂O

Step 10: Phosphorylation

In the final step of the payoff phase, pyruvate is produced by the enzyme Pyruvate Kinase by converting PEP into pyruvate, releasing a molecule of ATP in the process:

PhosphoenolPyruvate + ADP + Pⁱ –> Pyruvate + ATP

The net yield of ATP from glycolysis is 2 ATP per molecule of glucose. However, the overall process is not very efficient, as a lot of energy is lost as heat. 

It is important for the production of energy in cells, particularly in cells that do not have access to oxygen, such as red blood cells and muscle cells during intense exercise. 

Additionally, the byproducts NADH and pyruvate are also important for further metabolism.

In summary, the payoff phase of glycolysis involves four main steps: the cleavage of fructose 1,6-bisphosphate into G3P, the oxidation of G3P, the conversion of 1,3-bisphosphoglycerate into 3-phosphoglycerate, and the production of pyruvate.

These reactions produce 2 ATP, 2 NADH, and 2 pyruvate per molecule of glucose.

Chemical equation of Glycolysis

The chemical reactions of glycolysis can be written as a series of chemical equations, each representing a specific step in the process. 

The overall chemical equation for glycolysis can be written as follows:

2 Glucose + 2 ATP + 2 NAD⁺ + 2 H₂O    –>  2 pyruvate + 2 ATP + 2 NADH + 2 H⁺

This equation represents the sum of all the chemical reactions that occur during glycolysis, including the energy-investment phase (where ATP is used to convert glucose into G3P) and the energy payoff phase (where G3P is further broken down to produce ATP, NADH, and pyruvate).

It is important to note that this equation represents the net yield of ATP from glycolysis, which is 2 ATP per molecule of glucose. 

However, the overall process is not very efficient, as a lot of energy is lost as heat.

Significance of glycolysis

a. Role of glycolysis in energy production for cells: 

Glycolysis plays a crucial role in the production of energy for cells. As we have seen, the net yield of ATP from glycolysis is 2 ATP per molecule of glucose. Although it may not be the most efficient process, it is the first step in the breakdown of glucose and is an important source of energy for cells that do not have access to oxygen.

b. Importance of glycolysis in the production of other compounds 

Glycolysis not only produces energy but also produces other useful compounds. For example, the intermediate products of glycolysis, such as pyruvate and acetyl-CoA, can be used in the production of amino acids, lipids, and nucleotides.

c. Implications of glycolysis in disease

The significance of glycolysis extends beyond the basic metabolism of cells. Several diseases and health problems have been linked to problems with how glycolysis is controlled. For example, cancer cells have a faster rate of glycolysis and use it to fuel their growth. Diabetes is linked to changes in insulin-dependent glucose uptake, and exercise-induced muscle fatigue is linked to higher levels of lactate, which comes from anaerobic glycolysis.

Aerobic and Anaerobic Glycolysis

Glycolysis can occur under both aerobic and anaerobic conditions, which refer to the presence or absence of oxygen, respectively. Aerobic glycolysis is characterized by the presence of oxygen, while anaerobic glycolysis occurs in the absence of oxygen.

In aerobic glycolysis, the final product pyruvate, which is produced during the energy-payoff phase, is further oxidized in the mitochondria to produce more ATP via the citric acid cycle and the electron transport chain.

In anaerobic glycolysis, pyruvate is not fully oxidized, but is instead converted into lactate by lactate dehydrogenase. This occurs in the absence of oxygen and leads to a lower energy yield of 2 ATP per glucose molecule as compared to 38 ATP in aerobic glycolysis.

The role of oxygen in the process of glycolysis is critical for its efficiency. Aerobic glycolysis works better than anaerobic glycolysis because oxygen is the last electron acceptor in the electron transport chain. This means that more ATP can be made.

Aerobic glycolysis is the normal mode of glucose metabolism in most cells, while anaerobic glycolysis is usually seen in short bursts of activity, such as muscle activity, where oxygen demand exceeds the supply.

Aerobic Glycolysis	Anaerobic Glycolysis
Presence of Oxygen	Absence of Oxygen
Pyruvate is fully oxidized in the mitochondria	Pyruvate is converted into lactate
Energy yield of 38 ATP per glucose molecule	Energyenergy yield of 2 ATP per glucose molecule
Normal mode of glucose metabolism in most cells	Occurs in short bursts of activity such as muscle activity

The implications of aerobic and anaerobic glycolysis extend beyond the basic metabolism of cells. For example, it has been found that some cancer cells switch to anaerobic metabolism to grow and that exercise-induced muscle fatigue is linked to higher levels of lactate, which is a byproduct of anaerobic glycolysis.

Regulations of Glycolysis

Glycolysis is a tightly regulated process that is controlled by various enzymes, hormones, and other signaling molecules. 

Some of the key regulators of glycolysis include:

a. Enzyme regulation

The enzymes that catalyze the reactions of glycolysis are regulated by various mechanisms, including covalent modification, allosteric regulation, and protein-protein interactions. For example, the activity of hexokinase, the enzyme that catalyzes the first step of glycolysis, is inhibited by its product glucose-6-phosphate.

b. Hormonal regulation

Hormones such as insulin and glucagon play a crucial role in regulating glycolysis. Insulin promotes the uptake and utilization of glucose, while glucagon increases glucose production and release.

c. Metabolic feedback

The products of glycolysis such as glucose-6-phosphate, pyruvate, and NADH can act as feedback inhibitors to regulate the pathway. This ensures that the rate of glycolysis is in proportion to the energy demands of the cell.

d. Gene expression

The expression of genes that encode enzymes involved in glycolysis is regulated by transcription factors. For example, the transcription factor HIF1-alpha (hypoxia-inducible factor 1-alpha) plays a role in regulating the genes encoding the enzymes of the glycolytic pathway under hypoxia.

e. Signaling molecules

Various signaling molecules, such as AMP-activated protein kinase (AMPK) and mTOR (mammalian target of rapamycin), play a role in regulating glycolysis in response to changes in cellular energy levels. For example, AMPK is activated in response to low energy levels and promotes energy conservation by inhibiting anabolic pathways such as glycolysis, while mTOR is activated in response to high energy levels and promotes anabolic pathways such as glycolysis.

f. Cytosolic pH

The pH of the cytosol also plays a role in the regulation of glycolysis. A decrease in pH can inhibit the activity of certain enzymes involved in the pathway, such as phosphofructokinase, and thus slow down the rate of glycolysis.

g. Metabolite sensing

Some enzymes involved in glycolysis are also able to sense changes in the levels of other metabolites such as citrate, and act accordingly.

h. Immunological & Inflammatory signals

Some Immune/Inflammatory signaling pathways such as NF-kB, STAT3, and IL-6 signaling can induce the expression of genes involved in the glycolysis pathway, thus the rate of glycolysis can be increased in response to those signals.

The regulation of glycolysis is a complex process that involves a balance of multiple signaling pathways and enzymes that respond to the energy needs of the cell and its environment. The way these signals intersect and how they are integrated can ultimately determine the rate of glycolysis, as well as the cell’s fate.

Frequently Asked Questions (FAQs)

Referance:

• Biochemistry, Glycolysis
• The Embden–Meyerhof–Parnas Pathway
• Glycolysis inhibition for anticancer treatment