Fatty Acid Metabolism II Flashcards
"Fasting State"
What is fatty acid oxidation (β-oxidation)?
Mechanism through which cells utilize energy stored in fatty acids
Fatty acids —> Acetyl-CoA
2 carbons = removed
Where does β-oxidation take place?
The mitochondrial matrix
What happens to fatty acids immediately after they are taken up by a cell?
ACS (enzyme) attaches coenzyme A to the fatty acid to form Acyl-CoA
Does β-oxidation require energy?
- Yes!
- This reaction breaks 2 high energy phosphodiester bonds
- Requires 2 ATP
How are long chain fatty acids transported into the mitochondria?
- 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)
Describe the function of CPTI
- 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
Describe the function of CPTII
- Performs the opposite reaction as CPTI
- Takes fatty acid from acyl-carnitine to form an acyl-CoA inside the mitochondrial matrix
What happens to Acyl-CoA once it is inside the mitochondrial matrix?
4 reactions take place to transform acyl-CoA to acetyl-CoA
What carbon does all of the reactions take place on?
The β-carbon
What are the products of each round of β-oxidation?
- 1 FADH2
- 2 NADH
- 1 Acetyl-CoA
Describe reaction 1 of β-oxidation?
Formation of a trans α,β double bond through dehydration (2 H’s leave) of acyl-CoA by acyl-CoA dehydrogenase
FADH2 = formed
Describe reaction 2 of β-oxidation
- Enoyl-CoA Hydratase hydrates the trans α,β double bond
- OH = on β-carbon
No energy is generated
Describe reaction 3 of β-oxidation
- Another dehydration reaction takes place
- NAD+ -dependent dehydrogenase transfers e- from NAD to NADH
- Ketone = formed on β-carbon
Energy is generated
Describe reaction 4 of β-oxidation
- 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
What is the problem with β-oxidation of Unsaturated Fatty Acids?
- Enol-CoA Hydratase is intolerant to deviations from its favorite substrate (double bond must be between the α and β carbons)
Describe the β-oxidation of an unsaturated fatty acid
- 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
- 2,4-dienoyl CoA reductase: reduces double bonds into a single double bond (between carbons 2 and 3)
- 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!
Can fatty acids diffuse into the brain?
- No!
- The blood brain barrier
Why is this a problem
What alternate source is needed to transfer energy stored in fatty acids to the brain?
Ketone bodies
Ketone bodies
- 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
When do ketone body levels increase?
When blood fatty acid concentrations are high
What will your body do during a fasting state in order to ensure that the brain has enough energy?
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)
Describe the production of ketone bodies (ketogenesis)
- 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
Why can ketone body synthesis only take place in the liver?
HMG-CoA lyase (Hydroxymethyglutaryl-CoA lyase) is only found in the liver
What are some of the advantages of ketone bodies?
- 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
What can happen to a person if they have an excess of ketones?
- Diabetic ketoacidosis
- Alcoholic ketoacidosis
Why do diabetics have high levels of ketone bodies present in their urine?
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
Describe a GLUT1 deficiency and the ketogenic diet
- 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)
