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Biochemistry - Metabolism

Enzyme Function and Activation Energy

(Chapter 6 - Enzyme function and activation energy, n.d.)

Induced Fit Model

(Hudon-Miller, Enzymes, 2013)

Why Does Aldolase B Deficiency Lead to HFI?
• Understanding what happens to Glucose and Fructose in the liver is the first step. • Glucose enters the liver cell and Glucokinase is in the cytoplasm and adds a Phosphate (Pi) to make G-6-P to keep the glucose in the liver cell, which then becomes G-1-P and can be stored as glycogen or move onto the Citric Acid Cycle (CAC) to make ATP or fatty acids. • Fructose enters the liver, fructokinase adds a Pi to make F-1-P (the substrate of Aldolase B) to form Aldolase B forming the products DHAP and glyceraldehyde which can then go to glycolysis or onto the (CAC) to make ATP or fatty acids.

• The Lock and Key Model (slide 3) and the Activation Engery Ea (slide 2) will help to explain how Aldolase B is the catalyst to convert F-1-P in the liver.
• The Lock and Key Model shows how an enzyme and substrate attach, the enzyme then converts the substrate to the product and then releases the product. One of the important factors is that the enzyme then continues on without being changed.

• The Ea shows how the substrate on its own requires a certain amount of free energy but with an enzyme the amount of free energy in the Ea is decreased. The enzyme is the catalyst that works to lower the Ea without being used in the reaction. Again the enzyme is unchanged during this process.

Why Does Aldolase B Deficiency Lead to HFI?
• When Blood Sugar (BS) is high:
• Glucokinase is in the cytoplasm. Glycogen is stored. Glucose moves through glycolysis and CAC to make ATP and Fatty Acids.
• F-1-P acts like a signal for the Glucokinase to come out of the nucleus and into the cytoplasm.
• When BS is low:
• Glycogen is broken down, the Pi is taken off and can then be released into the blood to stabilize the BS.
• F-1-P is low and Glucokinase moves into the nucleus of the cell.

Why Does Aldolase B Deficiency Lead to HFI?,

What happens when there is an Aldolase B deficiency?
There are several areas that the deficiency is affecting.
First, in HFI the enzyme Aldolase B has a mutation.
Second, Aldolase B is the enzyme that acts as the catalyst for the substrate F-1-P and converts it into DHAP and glyceraldehyde that can then to go onto glycolysis. As explained previously, with the mutation of Aldolase B, it can not act as it should on F-1-P as explained in the Lock and Key Model. F-1-P can not be attached to Aldolase B, thus making the products DHAP and glyceraldehyde. • Third, the next issue is the amount of free energy F-1-P must use to overcome the reaction in the Ea! that without Aldolase B, F-1-P must use a large amount of free energy as compared to when Aldolase B is present.

• In the process of Fructose coming into the liver and being converted to F-1-P, if there is an Aldolase B deficiency the process slows down.
(Sanders, 2013)

Why Does Aldolase B Deficiency Lead to HFI?,
• F-1-P begins to build up or pool in the liver, Pi starts to become low, the products of Aldolase B DHAP and Glyceraldehyde slowdown in return slowing down the CAC and the ability to make ATP and Fatty Acids.

• Because there is now a buildup of F-1-P and that it acts as a signal for Glucokinase to come out of the nucleus and into the cytoplasm, glucose continues to form G6-P and now backs up the process of gluconeogenesis. • Ultimately leading to a Futile Cycle and cell death.

• Problems:
• With the Pi being used on the F-1-P the Pi can no longer be used in the Electron Transport Chain (ECT) to make ATP (ADP does not have the free Pi to add on to convert to ATP). If the ECT is not efficient and ATP production slows the liver cells become low in energy and cannot survive leading to liver damage/failure. • With the liver unable to use glycogen from storage Glucose can’t be released into the...
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