Fatty Acid Metabolism II

Question 1

What is fatty acid oxidation (β-oxidation)?

Answer 1

Mechanism through which cells utilize energy stored in fatty acids
Fatty acids —> Acetyl-CoA
2 carbons = removed

Question 2

Where does β-oxidation take place?

Answer 2

The mitochondrial matrix

Question 3

What happens to fatty acids immediately after they are taken up by a cell?

Answer 3

ACS (enzyme) attaches coenzyme A to the fatty acid to form Acyl-CoA

Question 4

Does β-oxidation require energy?

Answer 4

• Yes!
• This reaction breaks 2 high energy phosphodiester bonds
• Requires 2 ATP

Question 5

How are long chain fatty acids transported into the mitochondria?

Answer 5

• Primary fatty acids from our diet are not permeable to the mitochondrial membrane
• 2 enzymes allow fatty acids to cross the membrane (CPTI and CPTII)

Question 6

Describe the function of CPTI

Answer 6

• Transfers fatty acid from CoA to carnitine to form acyl-carnitine
• Acyl-carnitine is permeable to the outer mitochondrial membrane
• A transporter will transport acyl-carnitine into the mitochondrial matrix

Question 7

Describe the function of CPTII

Answer 7

• Performs the opposite reaction as CPTI
• Takes fatty acid from acyl-carnitine to form an acyl-CoA inside the mitochondrial matrix

Question 8

What happens to Acyl-CoA once it is inside the mitochondrial matrix?

Answer 8

4 reactions take place to transform acyl-CoA to acetyl-CoA

Question 9

What carbon does all of the reactions take place on?

Answer 9

The β-carbon

Question 10

What are the products of each round of β-oxidation?

Answer 10

• 1 FADH2
• 2 NADH
• 1 Acetyl-CoA

Question 11

Describe reaction 1 of β-oxidation?

Answer 11

Formation of a trans α,β double bond through dehydration (2 H’s leave) of acyl-CoA by acyl-CoA dehydrogenase
FADH2 = formed

Question 12

Describe reaction 2 of β-oxidation

Answer 12

• Enoyl-CoA Hydratase hydrates the trans α,β double bond
• OH = on β-carbon
  No energy is generated

Question 13

Describe reaction 3 of β-oxidation

Answer 13

• Another dehydration reaction takes place
• NAD+ -dependent dehydrogenase transfers e- from NAD to NADH
• Ketone = formed on β-carbon
  Energy is generated

Question 14

Describe reaction 4 of β-oxidation

Answer 14

• Thiolysis reaction cleaves the bond between the alpha and beta carbons (new CoA comes in and attacks β-carbon liberating acetyl-CoA)
• Result = fatty acyl-CoA (2 carbon atoms shorter) + acetyl-CoA
• The cycle then starts from the beginning

Question 15

What is the problem with β-oxidation of Unsaturated Fatty Acids?

Answer 15

• Enol-CoA Hydratase is intolerant to deviations from its favorite substrate (double bond must be between the α and β carbons)

Question 16

Describe the β-oxidation of an unsaturated fatty acid

Answer 16

• If the double bond is not between the α and β carbons, Enol-CoA Hydratase (EH) is not happy
• Enoyl-CoA Isomerase shifts the double bond so that it is between the α and β carbons (EH is happy now)
• BUT…there is another double bond that EH does not like
• 2 enzymes take care if the second double bond
• 1. 2,4-dienoyl CoA reductase: reduces double bonds into a single double bond (between carbons 2 and 3)
• 2. Enoyl-CoA Isomerase shifts the single double bond so that it is between the α and β carbons
• Now EH is finally happy and regular β-oxidation can take place!

Question 17

Can fatty acids diffuse into the brain?

Answer 17

• No!
• The blood brain barrier
  Why is this a problem

Question 18

What alternate source is needed to transfer energy stored in fatty acids to the brain?

Answer 18

Ketone bodies

Question 19

Ketone bodies

Answer 19

• Released by the liver into the bloodstream
• Used for energy during fasting/low blood sugar
• Can diffuse into the brain
• Provided the bulk of acetyl-CoA to the brain

Question 20

When do ketone body levels increase?

Answer 20

When blood fatty acid concentrations are high

Question 21

What will your body do during a fasting state in order to ensure that the brain has enough energy?

Answer 21

Your liver and muscles will shift to fatty acid metabolism in order to preserve glucose for the brain (the energy requirements for the brain can be supplemented by ketone bodies BUT cannot exclusively power the brain)

Question 22

Describe the production of ketone bodies (ketogenesis)

Answer 22

• Start with 2 acetyl-CoA
• Thiolase combine the 2 acetyl-CoA to form 1 4 carbon unit (acetoacetyl-CoA)
• HMG-CoA synthase (Hydroxymethyglutaryl-CoA synthase) takes acetoacetyl-CoA and combines it with another acetyl-CoA (6 carbon unit)
• HMG-CoA lyase (Hydroxymethyglutaryl-CoA lyase) cleave bond to form a 4 carbon acetoacetate + Acetyl-CoA

Question 23

Why can ketone body synthesis only take place in the liver?

Answer 23

HMG-CoA lyase (Hydroxymethyglutaryl-CoA lyase) is only found in the liver

Question 24

What are some of the advantages of ketone bodies?

Answer 24

• Provide energy to other tissues
• Lower the demand of glucose by the brain during starvation
• Reduce the amount of protein that must be broken down for gluconeogenesis

Question 25

What can happen to a person if they have an excess of ketones?

Answer 25

1. Diabetic ketoacidosis
2. Alcoholic ketoacidosis

Question 26

Why do diabetics have high levels of ketone bodies present in their urine?

Answer 26

You have high levels of blood glucose BUT.. it cannot be taken up by your cells (your cells are starving) therefore, they will start to metabolize fatty acids

Question 27

Describe a GLUT1 deficiency and the ketogenic diet

Answer 27

• GLUT1 is a glucose transporter at the blood brain barrier
• If you have two mutations in this gene (homozygous)…you die
• If you have one mutation you will have frequent seizures (due to the brain having a lack of energy)
• A ketogenic diet will reduce seizures in these patients (increases energy supply to the brain)