Glycolysis is a fundamental metabolic pathway that is essential for the production of energy in the body. Glycolysis is the process of breaking down glucose to produce energy in the form of ATP. In this article, we are going to take a look at the biochemical reactions in glycolysis, its regulation, and some clinical applications of it.

Glucose Transporters

The absorption of this monosaccharide from the lumen of the intestine is primarily via Sodium (Na) dependent glucose co-transporters. . Glucose enters cells via facilitative glucose transporters called GLUT 1, 2, 3, and 4. These transporters are part of a family of facilitative glucose transporters that transport glucose in and out of cells. The most important of these is GLUT 4, which is insulin dependent and found in key tissues such as the skeletal muscle, heart, adipose tissue, and brain.

Reactions

Glycolysis is a series of 10 reactions that occur in the cytosol of cells. Lets divide it into 2 phases for ease of understanding:

• Preparatory Phase: This phase consists of reactions 1-5 and uses 2 ATP molecules. We invest in 2 ATP to get a gigger return in the next phase.
• Payoff Phase: This phase consists of reactions 6-10, which generate 4 ATP molecules by substrate-level phosphorylation and 2 NADH molecules. We get our return for the invested ATP with a 100% profit!

The 10 steps are as follows:

1. Enzymes hexokinase and glucokinase facilitate the phosphorylation of glucose, marking the first step of glycolysis.
2. Isomerase converts glucose-6-phosphate to fructose-6-phosphate.
3. Phosphofructokinase-1 (PFK-1) converts fructose-6-phosphate to fructose-1,6-bisphosphate, which is the rate-limiting step of glycolysis and an irreversible reaction, regulating the entire process.
4. Aldolase breaks down fructose-1,6-bisphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate.
5. Glyceraldehyde-3-phosphate dehydrogenase reduces glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate and donates a hydrogen atom to NAD+ to form NADH.
6. Phosphoglycerate kinase converts 1,3-bisphosphoglycerate to 3-phosphoglycerate, utilizing a phosphate to form ATP, demonstrating substrate-level phosphorylation.
7. Phosphoglycerate mutase converts 3-phosphoglycerate to 2-phosphoglycerate.
8. Enolase converts 2-phosphoglycerate to phosphoenolpyruvate, resulting in the formation of NADH.
9. Pyruvate kinase converts phosphoenolpyruvate to pyruvate and utilizes a phosphate to form ATP, marking the final step of glycolysis.

Regulation of Glycolysis

The reaction pathway is regulated by 3 key regulatory steps. All the regulatory steps are always irreversible reactions. Which means the enzyme only catalyses the forward reaction

Reaction 1: Phosphorylation of Glucose

Hexokinase (HK) mediates the phosphorylation of glucose. It exhibits a high affinity for glucose and serves as the primary enzyme of glycolysis, being widely expressed in various tissues. However, the accumulation of glucose-6-phosphate negatively regulates its activity

Glucokinase (GK) also plays a role in the phosphorylation of glucose. It has a lower affinity for glucose and is insensitive to glucose-6-phosphate. GK is primarily expressed in glucose-sensing cells.

Reaction 3: Phosphofructokinase 1 (PFK-1)

High levels of ATP, citrate, and a high insulin to glucagon ratio inhibit PFK-1. Conversely, PFK-1 is activated by high levels of AMP, G6P, and a low insulin to glucagon ratio, as well as the presence of fructose-2,6-bisphosphate (via PFK-2).

PFK-2 catalyzes the conversion of fructose-6-phosphate into fructose-2,6-bisphosphate in small amounts. The reverse reaction is catalyzed by the enzyme fructose-2,6-bisphosphatase.

Reaction 10: Pyruvate Kinase

Fructose 1,6-bisphosphate acts as a positive regulator of pyruvate kinase, while ATP serves as a negative regulator

Clinical Applications

There are several genetic deficiencies that can affect glycolysis. The most common is pyruvate kinase deficiency in red blood cells, which leads to haemolysis (anaemia and jaundice) due to insufficient ATP production. Other rare deficiencies include PFK-1 deficiency in muscles, causing exercise intolerance.

To inhibit glycolysis for blood sample collection, one can lower the temperature and introduce fluoride ions. These ions effectively inhibit enolase, thereby halting the glycolytic process.

Pyruvate Kinase Deficiency

Pyruvate kinase deficiency manifests with haemolysis and anaemia because of diminished ATP production in red blood cells, resulting in impaired ion transport. Additionally, it can induce jaundice due to heightened bilirubin production stemming from haemolysis. Echinocytes (spiky red blood cells) may also appear in a blood smear.

Cancer cells

This characteristic can be used to monitor and detect cancer using a radiolabeled sugar analogue called FDG and PET scanning method.

It is important to note that while glycolysis is an essential process in the body, its regulation and balance with other metabolic pathways is critical for proper cell function and overall health. Deficiencies or imbalances in glycolysis can have significant effects on the body, as described above. Therefore, understanding and studying glycolysis is important for both basic research and clinical applications.

Quiz:

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