Oxidation of Fatty Acids

Question 1

What type of fuel does the brain utilize during periods of starvation? Where are these molecules synthesized? Which disease impairs this function?

Answer 1

ketone bodies

produced in the liver (but cannot use)

Ketogenesis is impaired in hepatic steatosis (fatty liver disease)

Question 2

What is the route of fatty acid metabolism dependent on?

List the 4 characterizations.

Answer 2

chain length

• very-long chain fatty acids (C>20)
• long chain fatty acids (C12-C20, most abundant)
• medium chain fatty acids (C6-C12)
• short chain fatty acids (C4)

Question 3

What is the function of albumin with relation to fatty acids?

Answer 3

Due to the low solubility of fatty acids in aqueous solutions, it requires binding proteins, the major one beign albumin

Question 4

Describe the basic steps of mirochondrial long-chain fatty acid (LCFA) metabolism for saturated even chain fatty acids, and monounsaturated even chain fatty acids.

Answer 4

1. LCFA-albumin enters the plasma membrane
2. Using 2 ATP, Fatty Acyl CoA synthetase swaps the binding proteins for CoA, producing Fatty acyl CoA
3. Fatty acyl CoA enters the outer mitochondrial membrane
4. The CoA is swapped out for carnitine
5. The fatty acid carnitine compound cross the inner mitochondrial membrane
6. Inside the matrix, the carnitine is swapped for a CoA producing Fatty acyl CoA, again
7. Fatty acyl CoA undergoes Beta oxidaion, which produces FADH2 and NADH, resulting in acetyl CoA
8. Acetyl CoA can enter the TCA cycle, or it can leave to the liver to produce ketone bodies (acetoacetate, beta-hydroxybutyrate)

Question 5

What is the name of fatty acids C16, C18, and C18:1

Answer 5

• C16
  
  • palmitate
• C18
  
  • stearate
• C18:1
  
  • oleate

Question 6

Explain the activation of fatty acid by fatty acyl-CoA synthetase. Why is this step necessary?

Answer 6

The fatty acid needs to be activated fatty acyl-CoA synthetase in order to cross through the outer mitochondria membrane and participate in beta-oxidation

• Fatty acyl CoA synthetase acts on a Fatty acid (C12-C20) and ATP to form the transient intermediate Fatty acyl AMP
• The AMP leaves, and fatty acyl CoA remains
• Since an ATP is converted to an AMP, this reacting requires the equivalent of 2 ATP

Question 7

What are the three fates for fatty acyl CoA?

Answer 7

1. Endoplasmic reticulum (storage)
   
   1. triacylglycerol synthesis
2. peroxisomes (membrane lipids)
   
   1. plasmalogen (membrane glycerophospholipid) synthesis
3. mitochondria (energy)
   
   1. beta-oxidation and ketogenesis

Question 8

Explain how Fatty acyl CoA is transported across the inner mitochondrial membrane.

Answer 8

• Carnitine palmitoyltransferase I (CPTI) transfers long chan-fatty acyl groups from CoA to carnitine (located on the outer mitochondrial membrane)
• fatty acylcarnitine crosses the inner mitochondrial membrane, transferred by the Carnitine: acylcarnitine translocase, into the matrix
• Carnitine palmitoyltansferase II (CPTII) transfers the fatty acyl group back to a CoA
• the carnitine released is transferred back to the intermembrane space, again by Carnitine: acylcarnitine translocase

Question 9

What end of the fatty acid is cleaved at the start of fatty acid oxidation? What size segments are subsequently cleaved?

Answer 9

beta-oxidation begins with the carboxyl end attached to CoA, cleaving the fatty acyl group into two-carbon acetyl-CoA units

this pattern continues, with the fatty acid being 2 carbons shorter each round, until the final cleavage yields 2 acetyl CoAs

Question 10

What are the four steps of beta oxidation?

Answer 10

1. Oxidation
   
   1. a double bond is formed between the beta and alpha carbon by an acyl-CoA dehydrogenase
   2. electrons are transferred to FAD, producing FADH2
2. Hydration
   
   1. -OH from water is added to the beta-carbon, and an -H from water is added to the alpha carbon by enol CoA hydratase
3. Oxidation
   
   1. the hydroxyl group on the beta carbon is oxidized to a ketone by beta-hydroxy acyl CoA dehydrogenase
   2. during this process, electrons are transferred to NAD+, production NADH
4. Cleavage
   
   1. bond between the beta and alpha carbon is cleaved by a reacion that attaches CoASH (coenzyme A) to the beta carbon, and acetyl-CoA is released

Question 11

How many rounds of oxidation spirals occur per fatty acid?

How many FADH2, NADH, and Acetyl-CoA are produced each round?

How many ATP do FADH2, NADH, and Acetyl Co-A produce?

Answer 11

To find the number of spirals, divide the number of carbons by 2 and subtract 1. (C16–> 7 spirals)

1 FADH2 is produced per round (1.5 ATP)

1 NADH is produced per round (2.5 ATP)

1 Acetyl Co-A is produced per round, + 1 for final cleavage (10 ATP)

Question 12

Describe beta oxidation of unsaturated fatty acids.

Answer 12

• Beta oxidation proceeds regularly until it reaches a double bond
• The doulbe bond in the cis configuration is converted to trans double bond between the second and third carbon by Enoyl CoA isomerase
• One spiral and the first step of the second spiral complete, but the cis adjacent cis double bond prevents the second spiral from completing
• 2,4 Dienoyl CoA reductase reduces the two double bonds to a single double bond in the 3,4 position, taking those electrons to an NADPH oxidizing it to NADP+
• Then enol CoA isomerase switches the double bond from the 3,4 position to the 2,3 position, allowing beta oxidation spiral to continue

Question 13

What is different about the beta-oxidation of odd numbered fatty acids?

Answer 13

beta oxidation occurs regularly until the last spiral when 5 cabons remain on the fatty acyl-CoA

Cleavage by thiolase produces acetyl-CoA and a 3-carbon farry acid, propionyl-CoA

Question 14

What substance is uniquely produced by peroxisomal oxidation? What types of fatty acids undergo peroxisomal oxidation? How long does it continue?

Answer 14

Hydrogen peroxide

very long chain fatty acids (C24-26)

The spirals continue until a medium chain acyl-CoA is produced, at which point carnithin is added and they go to the mitochondria

Question 15

What type of oxidation do branched fatty acids undergo? What are key steps in this process? What are the 2 most common branched fatty acids?

Answer 15

alpha- oxidation

phytanic acid and pristanic acid (degradation products of chlorophyl)

It is called alpha-oxidation because a hydroxyl group is introduced onto the alpha carbon by an alpha-hydroxylase, which is then oxidized to a carboxyl group as the original carboxyl group is released as CO2

Now, the methyl goup is on the alpha carbon, and beta-oxidation can continue its spiral, producing a propionyl-CoA rather than an acetyl CoA

Question 16

What is the product of omega-oxidation? Describe their properties.

Answer 16

the omega-methy group is oxidized to an alcohol, at which point dehydrogenases converts the alcohol group to a carboxylic acid, producing a dicarboxylic acid

The dicarboxylic acid is more soluble in water, and can either undergo beta-oxidation or be excreted in the urine

It becomes a major process in individuals who have conditions that interfere with beta-oxidation

Question 17

Describe the process of synthesizing ketone bodies in the liver mitochondrai.

Answer 17

1. 2 Acetyl CoA are converted to acetoacetyl CoA by thiolase (releasing Co- ASH)
2. HMG CoA synthase converts the acetoacetyl CoA and an additional CoA to 3-Hydroxy-3-methyl glutaryl CoA (HMG CoA), releaseing Co-ASH in the process
3. HMG CoA lyase then acts on HMG CoA to produce acetoacetate, releasing an acetyl CoA in the process
4. The acetoacetate can then be converted to D-beta-hydroxybutyrate or, it can spontaneously convert to acetone

acetoacetate can enter the blood directly, or enter the blood as D-beta-hydroxybutyrate, generally the ratio of D-beta-hydroxybutyrate to acetoacetate is 3:1 in the blood

acetone is expired bye the lungs