Sheridan Fletcher

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What are the different steps of glycolysis that are regulated and how they are regulated?

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Asked 9 months ago

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A newborn baby presented with yellow skin and eyes. Lab test revealed

Decreased red blood cell count
Increased unconjugated bilirubin
Increased reticulocyte count
Decreased haptoglobin
Decreased hemoglobin
Elevated LDH.

Blood smear revealed echinocytes “burr bodies”. Ultrasound revealed an enlarged liver and spleen.

Based on the tests and signs, what is the diagnosis, and which enzyme is deficient?

What are the steps of glycolysis? What is the difference between hexokinase and glucokinase and how they are regulated? What are the characteristics of glucokinase? How phosphofructokinase-1 is regulated? What is the result of arsenic poisoning on glyceraldehyde-3-phosphate dehydrogenase?

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Khalid Michael

9 months ago

Diagnosis:

Nonspherocytic hemolytic anemia.

Enzyme deficiency:

The enzyme deficient is pyruvate kinase.

In the absence of pyruvate kinase, which causes the substrate-level phosphorylation and allows the production of ATP, no ATP is produced. There is no other source of ATP in red blood cells except glycolysis. The red blood cells cannot perform their functions and the cell membrane of red blood cells become less flexible because of the very low energy level and turn into echinocytes. This allows the macrophages to phagocytize the red blood cells. There is increased hemolysis of red blood cells. Also, there is an increased concentration of 2, 3-bisphosphoglycerate as a compensatory mechanism. This shifts the oxygen dissociation curve to the right and increases the oxygen release to the tissues (which mitigates symptoms of anemia).

Glycolysis:

It is a process that does not require oxygen and in which glucose is converted into two molecules of pyruvate. It occurs in the cytoplasm of the cell. There are 10 reactions of glycolysis. The first five reactions correspond to the energy-investment phase and the last five reactions correspond to the energy-generation phase.

The seven reactions of glycolysis are reversible and are not regulated and the three reactions are irreversible that are regulated by various activators, repressors, and covalent modifications.

1.Glucose phosphorylation:

Hexokinase phosphorylates glucose and converts it into glucose-6-phosphate. This is carried out by the enzyme hexokinase. There are four forms (four isozymes) of this enzyme. Glucose is converted into glucose-6-phosphate by using ATP.

Hexokinase I to III:

It is present in most of the tissues can carry the first step of glycolysis.

Low Km:The characteristics of these enzymes are that it has low Km that means that these enzymes have a high affinity for glucose. This enables the efficient phosphorylation of glucose.
Low Vmax:These enzymes also have low Vmax which means that reaction is slow.

These enzymes can also bind fructose and galactose.

Regulation:

Glucose-6- phosphate can inhibit hexokinase. (Product inhibition).

Km is the affinity constant that shows the affinity of the enzyme to substrate.

Vmax shows the maximal velocity of the reaction (how fast the reaction proceeds).

Hexokinase IV:

It is also called glucokinase. It is present in the liver and pancreas. It has the following characteristics;

High Km:High Km shows low affinity which means a lot of glucose is required to activate glucokinase.
High Vmax:High Vmax shows it phosphorylates the glucose quickly and the reaction is speed is high.

Glucokinase is the sensor of glucose. After a carbohydrate-rich meal, it transfers glucose into the liver where it is phosphorylated and is trapped. Glucose-6-phosphate can not cross the cell membrane.

In the liver, it prevents hyperglycemia after a carbohydrate-rich meal by trapping glucose-6-phosphate.

In the pancreas, it helps in the secretion of insulin after carbohydrate-rich meals.

It acts as a glucose-sensor in the hypothalamus.

Regulation:

Glucokinase is inhibited indirectly by fructose-6-phosphate.

It is activated by glucose.

There is a protein called glucokinase regulatory binding protein GKRB which binds glucokinase (GK) and is in the nucleus. When there is excess fructose-6-phosphate, it causes the binding of GK to GKRB which inactivates glucokinase. In the presence of excess glucose, the GK-GKRB complex release glucokinase (GK) and is activated.

2.Glucose-6-phosphate isomerization:

This step is carried out by the phosphoglucose isomerase enzyme. The product formed is fructose-6-phosphate.

3.Fructose-6-phosphate phosphorylation:

This reaction is catalyzed by the enzyme phosphofructokinase-1 (PFK-1) and the fructose is converted into fructose 1, 6-bisphosphate.

It is the most important regulatory point in glycolysis.

Regulation of PFK-1:

PFK-1 is regulated allosterically by the ATP and citrate levels that inhibit PFK-1. (High energy level)

Whereas AMP acts as an activator of PFK-1. (Low energy level).

The most potent regulation of PFK-1 is done by fructose 2, 6-bisphosphate.

Fructose 2, 6-bisphosphate:

It is formed by the enzyme phosphofructokinase-2. PFK-2 is a bifunctional enzyme. It has phosphatase activity as well as kinase activity.

During a well-fed state, there is a decreased level of glucagon and an increased level of insulin. This causes the bi-functional enzyme to be dephosphorylated and active. PFK-2 is active while phosphatase is inactive. This leads to the formation of fructose 2, 6-bisphosphate which is the activator of PFK-1 and hence glycolysis continues.
During the fasting stage, there is decreased insulin and increased glucagon, which causes phosphorylation of the bifunctional enzyme and makes the PFK-2 inactive (phosphorylated) and phosphatase active. This lowers fructose 2, 6-bisphosphate and hence PFK-1 is not activated.

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