4F- Oxidation of Fatty Acids and Ketones

Question 1

How are long-chain fatty acids transported into the mitochondria?

Answer 1

carnitine serves as the carrier that transported the activated long-chain fatty acyl groups across the inner mitochondrial membrane

Question 2

How does malonyl-coa regulate the transport of long-chain FA’s into the mitcohrondria?

Answer 2

Malonyl CoA inhibits fatty acids from associating with carnitine by regulating the enzyme carnitine acyltransferase, thereby preventing them from entering the mitochondria where fatty acid oxidation and degradation occur.

Question 3

What is the process of beta-oxidation?

Answer 3

Question 4

where does beta-oxidation take place?

Answer 4

within the mitochrondial matrix

Question 5

What is the total ATP yield of the beta oxidation of palitate (c16)?

Answer 5

yields:

7 FADH2 (x1.5)

7 NADH (x2.5)

8 acetyl-CoA (x10)

Total = 108 - 2 ATP for activation = 106 ATP

Question 6

4. Compare the hormonal and allosteric controls over fatty acid oxidation during the fed and fasted states and how energy need regulates this process

Answer 6

a. Fatty acids are used mainly when they are released from the adipose tissue in response to signals indicating that the body is fasting. However, the process of β-oxidation is mainly regulated by the cells requirements for energy.
b. The demand for tissues is illustrated by the malonyl-CoA inhibiton of carnitine palmitoyltransferase I:
i. During exercise AMP levels rise  AMP-dependent protein kinase phosphorylates acetyl CoA carboxylase (which makes malonyl-CoA in many tissues)  inactivates it  malonyl-CoA levels decrease  CAT is activates  β-oxidation of fatty acids can restore ATP homeostasis.
ii. This is why we get skinny when we work out!

Question 7

How do we breah down unsaturated fatty acids?

Answer 7

i. The double bond in unsaturated fatty acids creates a problem: β-oxidation must convert the double bond to the right form to continue
ii. When a cis double bond arrives, it is isomerized to a trans double bond, which is in the proper configuration for the normal enzymes to act.
iii. Furthermore, such as in the case of linoleolyl-CoA, if there are 2 double bonds next to each other, the further one gets saturated by NADH + H+.

Question 8

How do we break down odd-chain fatty acids?

Answer 8

i. Fatty acids with odd chains undergo β-oxidation normally until they arrive at the last part, when 3 carbons remain. The remaining propionyl CoA undergoes this synthesis:
ii. The conversion of propionyl CoA to Succinyl CoA is so that succinyl CoA can be used as an intermediate in the TCA cycle.

Question 9

How do we break down very long chain fatty acids?

Answer 9

i. Fatty acids of 24-26 carbons are oxidized exclusively in peroxisomes. This reaction is similar to β-oxidation in mitochondria, since it yields acetyl CoA and NADH. However, the process stops when they chain reaches 4-6 carbons in length.
ii. Furthermore, the first step produces hydrogen peroxide instead of FADH2:

Question 10

How do we break down branched-chain fatty acids?

Answer 10

i. The 2 most common branches cahin fatty acids are phytanic acid and pristanic acid, which are from vegetables.
ii. Phytanic acid, which is multimethylated, is oxidized to pristanic acid using the α-oxidation pathway. A hydroxylase introduces a hydroxyl group at the α-carbon  oxidized to a carboxyl group  release of CO2
iii. By shortening the fatty acid by releasing CO2, the methyl groups will appear on the α-carbon rather than the β-carbon, and β-oxidation in the pweroxisome can proceed normally.

Question 11

What is the process of omega-oxidation?

Answer 11

a. Fatty acids may be oxidized by the ω-carbon of the chain (which is the terminal methyl group) by enzymes in the endoplasmic reticulum.
b. Process:
i. The ω-methyl group is oxidized to an alcohol that uses NADPH  dehygdrogenases convert the alcohol into a carboxylic acid  the dicarboxyclic acids produced can undergo β-oxidation  forms compounds 6-8 carbons  enter blood  oxidized as medium chain fatty acids

Question 12

What tissues can use ketone bodies as fuels?

Answer 12

they are synthesized from excess acetyl-CoA

SkM, brain, kidney, intestinal mucosa

Question 13

What is MCAD?

Answer 13

1. There are separate β-oxidative enzymes for long chain, medium chain, and short chain fatty acids. MCAD deficiency is a defect in the medium chain enzymes only. However, since long chains eventually become medium chain during their metabolism, it affects most beta- oxidation of fatty acids.
2. MCAD deficiency occurs in 1/4,000 Northern Europeans and between 1/13,000 and 1/26,000 of the general public.
3. This autosomal recessive genetic disease shows up in children at the first prolonged fast (usually an illness), when they experience a non-ketotic hypoglycemia.
   a. The hypoglycemia results because after fasting has depleted the glycogen in the liver, the liver depends on ATP generated by fatty acid oxidation to provide the energy for gluconeogenesis. Therefore no beta oxidation. No gluconeogenesis with resulting severe hypoglycemia.
4. Some cases of SIDS (Sudden Infant Death Syndrome or Crib Death) can be attributed to this MCAD deficiency.