Fatty Acid Metabolism III

Question 1

Where does fatty acid biosynthesis take place?

Answer 1

In the cytosol
Where does fatty acid metabolism take place

Question 2

When is the only time that fatty acid biosynthesis will occur?

Answer 2

Only during aa high energy state because …ATP is required

Question 3

How does acetyl-CoA makes its way to the cytoplasm (remember, acetyl-CoA is NOT permeable to the mitochondrial membrane)?

Answer 3

It gets converted to citrate (citrate has a transporter on the mitochondrial membrane)

Question 4

What transports citrate from the mitochondrial matrix to the cytosol?

Answer 4

Tricarboxylate transport system

Question 5

What initiates fatty acid biosynthesis?

Answer 5

Increases in citrate concentration (this is indicative of a high energy state)

Question 6

Where does the NADH used in fatty acid biosynthesis come from?

Answer 6

Once in the cytosol, citrate is converted to oxaloacetate which produces the NADH needed for fatty acid biosynthesis

Question 7

Where does fatty acid biosynthesis primarily occur?

Answer 7

The liver

Question 8

What are the key enzymes in fatty acid biosynthesis?

Answer 8

1. Acetyl-CoA carboxylase (ACC): takes acetyl-CoA and converts it to malonyl-CoA
2. Fatty acid synthase (FAS/FASN): takes malonyl-CoA and converts it to palmitate

Question 9

Describe the biosynthesis of malonyl-CoA

Answer 9

• This is the committed step of fatty acid biosynthesis
• ATP is required
• ATP is utilized to convert 2 carbon acetyl group into 3 carbon malonyl group

Question 10

How is ACC activated?

Answer 10

• ACC is activated by cytosolic citrate
• Citrate induces polymerization of ACC

Question 11

How do cells ensure that
β-oxidation and fatty acid biosynthesis do not occur at the same time?

Answer 11

• Malonyl CoA (product of ACC activation) inhibits CPTI
  Remember, CPTI facilitates the transport of fatty acids into the matrix (fatty acid metabolism must take place inside the mitochondrial matrix)

Question 12

Describe fatty acid synthase

Answer 12

• Multifunctional enzyme
• Main enzyme that synthesizes fatty acids
  *The goal is to form palmitate (Acetyl-CoA —> malonyl-CoA—> palmitate)

Question 13

What is ACP?

Answer 13

• ACP or acyl-carrier protein is a cofactor located on fatty acid synthase
• ACP never leaves the enzyme
• All intermediates in fatty acid synthesis will be attached via ACP

Question 14

Describe the role of Fatty acid synthase and ACP in fatty acid synthesis

Answer 14

• Site 1 (MAT site): acetyl is transferred from CoA to ACP
• Site 2 (KS site): acetyl group is transferred from ACP to the enzyme itself
• ACP goes back to site 1 (MAT site) to pick up a malonyl group
• Malonyl-ACP then gets transferred back to site 2 (KS site) where it undergoes a condensation reaction (with the acetyl group that is already in site 2) to form acetoacetyl-ACP
• The end product of this first cycle butyryl-ACP is formed in site 2
• After the formation of butyryl-ACP, ACP is released and goes back to site 1 where it can grab another malonyl group
• These cycles are repeated until palmitate is produced

Question 15

What are the important intermediates that you should know in the formation of palmitate by fatty acid synthase (and cofactor ACP)?

Answer 15

1. Acetyl-CoA (start)
2. Acetyl-ACP
3. Acetyl-Enzyme
4. Malonyl-ACP
5. Acetoacetyl-ACP
6. Butyryl-ACP

Question 16

How is palmitate released from fatty acid synthase?

Answer 16

Palmitoyl Thioesterase

Question 17

What happens to triglycerides and cholesterol esters once they have been synthesized in the liver?

Answer 17

Triglycerides and cholesterol esters are incorporated into VLDL (very low density lipoprotein) which then get released into the bloodstream

Question 18

Describe the structure of VLDL

Answer 18

• Structurally similar to chylomicrons
• Inner core = triglycerides + cholesterol esters (hydrophobic)
• Cholesterol = confined to the phospholipid monolayer

Question 19

How are triglycerides released from VLDL?

Answer 19

• Lipoprotein lipase cleaves triglycerides in VLDL (similar to how it cleaves triglycerides in chylomicrons)
• The fatty acids then get taken back up by adipose tissue

Question 20

How is fatty acid biosynthesis regulated?

Answer 20

By regulation of ACC (acetyl-CoA Carboxylase)

Question 21

How is ACC regulated?

Answer 21

• Phosphorylation
• Glucagon inhibits ACC activity by enhancing its phosphorylation (no malonyl-CoA and no CPTI activity)
• Insulin stimulates ACC by enhancing its dephosphorylation

Question 22

How is ACC regulated by AMPK (AMP-Activated Protein Kinase)

Answer 22

• AMPK = activated by AMP signaling a low energy state
• AMPK phosphorylates and inactivates ACC
• Fatty acid biosynthesis will only occur under a high energy state (therefore, AMPK must be inactivated)

Question 23

Why is phosphorylation of ACC important in its inactivation

Answer 23

Phosphorylation will reduce polymerization
Remember, polymerization is needed for ACC to function properly

Question 24

What are some diseases linked to fatty acid biosynthesis?

Answer 24

• Certain cancers
• FAS/FASN expression is elevated in cancer cells
• Fatty acids promote cancer cell proliferation