Fatty Acid Synthesis

Question 1

describe the characteristics of fatty acids

Answer 1

• amphipathic; both hydrophobic and hydrophilic
• free fatty acids (unsterified) are transported with albumin
• free fatty acids have a detergent character and are esterified in TAGs, cholesteryl ester or polar membrane lipids

Question 2

contrast saturated vs unsaturated fatty acids

Answer 2

• unsaturated fatty acids have double bonds
  
  • in the cis-configuration that has kinks
• saturated fatty acids do not have double bonds

Question 3

what are the sites of biosynthesis of fatty acids and the purpose?

Answer 3

takes place in the cytosol of the cells!

• major: liver, lactating mammary gland
  
  • the liver reduces high blood glucose levels, form palmitate and TAGs which are then released into the blood for eventual storage in fat cells
  • mammary gland: to provide FA for milk
• minor: adipose tissue

Question 4

what are the 2 sources of NADPH for FA synthesis?

Answer 4

1. PPP
   
   • major pathway
2. Malic enzyme
   
   • NADP+ dependent malate dehydrogenase

Question 5

describe the reaction that malic enzyme catalyzes

Answer 5

Question 6

describe the production of cytosolic acetyl CoA

Answer 6

• acetyl CoA formed in the mitochondria cannot cross the mt membrane into the cytosol
  
  • therefore, acetyl CoA has to be converted to citrate
• at very high citrate levels, citrate leaves into the cytosol
• citrate lyase (in the cytosol) uses citrate to form acetyl CoA and oxaloacetate

Question 7

describe the major steps of de novo synthesis of FAs

Answer 7

1. formation of malonyl CoA by acetyl CoA carboxylase
2. synthesis of palmitate by fatty acid synthase (FAS)
   
   • palmitate is a 16C saturated FA
3. elongation of palmitate by elongases
4. desaturation by desaturases

Question 8

describe the carboxylation of acetyl CoA to form malonyl CoA

Answer 8

• the first committed step of FA biosynthesis is catalyzed by acetyl CoA carboxylase (ACC)
  
  • ACC is the rate-limiting enzyme for FA synthesis
  • the enzyme contains biotin and adds a CO2 to the methyl end of acetyl CoA
  • the rxn requires 1 ATP per malonyl CoA formed

Question 9

describe fatty acid synthase (FAS)

Answer 9

• the enzyme complex can exist as a dimer in humans
• each monomer has 7 different enzyme activities and contains an acyl-carrier domain (ACP) and a temporary holding domain with a cysteine residue
• the multifunctional FAS enzyme catalyzes the rxns whereby 2 carbon units from malonyl CoA are linked together to form palmitoyl CoA
• insulin upregulates the amount of enzyme expressed

Question 10

describe the first 2 steps of fatty acid synthase

Answer 10

• the acyl-carrier protein domain (ACP-SH) binds the acetyl group of acetyl CoA
• malonyl CoA (used for chain elongation) but it can only react with the free ACP-SH
• therefore, to open up the ACP domain, the acetyl group is transferred to the SH group of the holding domain and now malonyl ACP can be formed from malonyl CoA

Question 11

describe the next 2 steps of fatty acid synthase

Answer 11

• the decarboxylation of the carboxyl-group of malonyl-ACP allows condensation with the group bound to the holding proein
  
  • a 3-ketoacy-ACP is formed
• NADPH is used to reduce it to 3-hydroxy-acyl ACP

Question 12

describe the final 2 steps of the fatty acid synthase cycle

Answer 12

• after hydrolysis, a double bond is formed and a 2nd NADPH is used to form a fatty-acyl-ACP group
• this fatty acyl group is transferred to the SH of the holding domain and another malonyl CoA can interact with ACP-SH and continue the process of elongation of the growing fatty acyl chain until palmitate is formed and released from FAS

Question 13

what are the activator and inhibitors of fatty acid synthesis?

Answer 13

• activator: citrate
• inhibitor: long-chain fatty acyl CoA (inhibits acetyl CoA carboxylase)

Question 14

describe the modifications of palmitate

Answer 14

• modifications may also include:
  
  • chain elongation to produce longer FAs
  • desaturation, producing unsaturated FAs

Question 15

describe the chain elongation process of FAs

Answer 15

• elongation occurs primarily in membranes of the ER
  
  • done with the enzyme elongase
• palmitate can be further elongated by addition of 2C units (from malonyl CoA) to the carboxylate end
• NADPH provides the reducing equivalents
• the brain can produce VLCFAs (DHA) required for synthesis of brain lipids

Question 16

describe the fatty acid desaturation system

Answer 16

• fatty acyl-CoA desaturases introduce double bonds in positions 5, 6 or 9
• the fatty acid desaturase system is an electron transport system in the ER that involves cytochrome b5, desaturase and NADPH-cytochrome b5 reductase
• since linoleic acid and alpha-linolenic acid have double bonds beyond position 9, they are dietary essential FAs

Question 17

describe the derivatives of essential FAs

Answer 17

Question 18

describe the production of glycerol 3-phosphate in liver and adipose tissue

Answer 18

Question 19

describe the synthesis of TAGs in liver and adipose tissue

Answer 19

Question 20

describe the synthesis of TAGs in intestinal mucosal cells

Answer 20

the MAG pathway: assembly and secretion of chylomicrons by intestinal mucosal cells