Fatty Acid Synthesis

Question 1

Where does fatty acid de novo synthesis occur?

Answer 1

• Mostly in the liver after a CHO-rich meal stimulated by insulin
• The lactating mammary glands also synthesize fatty acids.

Question 2

What is the purpose of fatty acid de novo synthesis ?

Answer 2

• Reduction of the normal increase blood glucose levels after a meal.
• Hepatic fatty acid de novo synthesis enables the body to convert surplus of dietary carbohydrates into fatty acids which can be stored as TAGs in fat cells

Question 3

What is the purpose of fatty acid de novo synthesis in mammary glands?

Answer 3

Milk production and provision of long-chain and medium-chain fatty acids for synthesis of TAGs found in milk

Question 4

How can liver reduce increase in blood glucose after a meal?

Answer 4

The dietary glucose reaches the liver via the hepatic portal vein and Glucokinase in hepatocytes phosphorylates it to glucose 6-P

Question 5

In which pathways does insulin favor hepatocytes ?

Answer 5

1. Glycogen synthesis
2. Glycolysis, PDH complex, TCA cycle
3. Fatty acid de novo synthesis and TAG synthesis
4. Cholesterol synthesis
5. HMP for generation of NADPH

Question 6

Outline hepatic fatty acid synthesis after a meal by the liver

Answer 6

• Uptake of dietary Glucose from hepatic portal vein
• Glycolysis and HMP lead to PDH and TCA cycle in the mitochondria
• this increases citrate levels into cytosol for cytosolic fatty acid synthesis
• as well as cholesterol synthesis and TAG synthesis and formation of VLDL
• release of VLDL

Question 7

Where in the cell does fatty acid de novo synthesis occur in the cell?

Answer 7

• The enzymes are in the cytosol however mitochondria are needed to provide citrate which leaves the mitichondria and is transported into the cytosol to provide cytosolic Acetyl CoA for FA synthesis
• NADPH is needed and is formed in cytosol by the HMP and the malic enzyme

Question 8

Which enzymes are involved in fatty acid de novo synthesis?

Answer 8

• The liver uses glycolysis, the oxidative part of HMP, PDH and a part of the TCA cycle for generation of substrates for FA synthesis.
• The specific enzymes used in cytosol for fatty acid synthesis are ATP-citrate lyase, Acetyl-CoA carboxylase and multifunctional fatty acid synthase

Question 9

Why is Acetyl CoA needed for fatty acid synthesis?

Answer 9

Acetyl CoA carboxylase(biotin) converts Acetyl CoA to Malonyl CoA

Malonyl CoA used in fatty acid synthase

Palmitate 16:0 is the end product

Question 10

Explain Acetyl CoA formation in CoA

Answer 10

1. Acetyl CoA formed in mitochondria cannot leave the mitochondria
2. Citrate leaves the mitochondria only at very high citrate levels in mitochondria and is transported into the cytosol.

This prevents predict inhibition of citrate synthase by high mitochondrial citrate levels

3. In the cytosol, citrate is cleaved by ATP-citrate lyase to Acetyl CoA and oxaloacetate

Question 11

What is the regulated enzyme of fatty acid synthesis

Answer 11

Acetyl CoA carboxylase is the regulated enzyme and provides fuel for fatty acid synthase

Question 12

How can you describe the reaction catalyzed Acetyl CoA carboxylase?

Answer 12

acetyl CoA carboxylase (active polymer) contains biotin

Acetyl CoA carboxylase uses cytosolic Acetyl CoA, carbon dioxide and ATP for formation of malonyl CoA

Note: cytosolic Acetyl CoA is available in hepatocytes only after a carbohydrate-rich meal and at high insulin levels. It is formed by citrate levels

Question 13

Describe the allosteric regulation oh Acetyl CoA carboxylase

Answer 13

Cytosolic citrate leads to the active polymer-activates Acetyl CoA active polymer

Accumulation of fatty acyl CoA leads to the inactive protomers
-long chain fatty acyl CoA inhibits Acetyl CoA carboxylase active polymer

Question 14

Why is Acetyl CoA carboxylase allosterically activated by cytosolic citrate

Answer 14

Only at very high mitochondrial levels, citrate leaves into cytosol and is cleaved by citrate lyase to Acetyl CoA which provides substrate for Acetyl CoA carboxylase

Note: cytosoliccitrate shall not accumulate as it would allosterically inhibit PFK-1

Question 15

Why is Acetyl CoA carboxylase inhibited by accumulation of long-chain fatty acyl CoA and not by palmitate?

Answer 15

1. Palmitate is the end product ofFA synthase but shall never accumulate as free palmitate damages the cell.
2. The free CoA pool in cytosol is limited
3. An accumulation of long-chain fatty acyl CoAs indicates a slow turnover of FA-CoAs and that soon free CoA may not be available for newly synthesized FA
4. That is why fatty acid synthesis is not inhibited by its end product free palmitate but instead inhibited by high levels of long-chain fatty acyl CoAs

Question 16

Palmitate is the end product of FA synthase but doesn’t inhibit Acetyl CoA carboxylase unlike fatty acyl CoA. Why Is this?

Answer 16

The free CoA pool in cytosol is limited. Usually, free CoA is used for fatty acid activation to fatty acyl CoA and this bound CoA is released again as free CoA during synthesis of TAGs or phospholipids

Question 17

Palmitate is the end product of FA synthase but never accumulates. Why is this?

Answer 17

Palmitate is the end product FA synthase but shall never accumulate as free palmitate damages the cell. The fatty acid needs to be activated by the separate enzyme fatty acyl CoA synthetase to palmitoyl CoA which is then used for synthesis

Question 18

How can covalent modification activate a Acetyl CoA carboxylase?

Answer 18

Activation by dephosphorylation

Acetyl CoAvcarboxylase is activated when it its dephosphorylated by protein phosphatase following insulin action

Question 19

How can Acetyl CoA carboxylase being deactivated via covalent modification?

Answer 19

Acetyl CoA is inhibited by phosphorylation by AMP-kinase

AMPK is activated via:

• allosterically by AMP
• by phosphorylation by AMPK kinases

Question 20

How is AMPK activated?

Answer 20

AMPK is activated via:

• allosterically by AMP
• by phosphorylation by AMPK kinases

The AMPK kinases are activated following glucagon and epinephrine actions using the cAMP messenger system and PKA

Question 21

How does blood glucose level affect fatty acid synthesis?

Answer 21

High blood glucose level: insulin stimulates hepatic fatty acid synthesis. This uses glucose and reduces the increased blood glucose after a meal

Low blood glucose: glucagon and epinephrine inhibits hepatic fatty acid synthesis

The liver stops fatty acid synthesis and can focus on gluconeogenesis and the release of glucose into the blood

Question 22

Describe fatty acid synthase in humans

Answer 22

Multifunctional dimeric enzyme:

Two identical subunits with several enzyme domains and work together “head to tail” and synthesize two fatty acids at the same time. Mostly free palmitate is released, double bonds are not formed fatty acid synthase

Question 23

Describe fatty acid synthase in bacteria

Answer 23

Multienzyme complex

Each reaction is catalyzed by a discrete mono- functional enzyme. A double bond can be added when the fatty acyl-group reaches 10 carbons

Question 24

What can form NADPH?

Answer 24

Hexose monophosphate

Hepatic malic enzyme

Question 25

How does malate enzyme form NADPH?

Answer 25

ATP-citrate lyase cleaves cytosolic citrate to Acetyl CoA and oxaloacetate

Oxaloacetate is used by malate DH to form malate

The hepatic malic enzyme catalyzes an irreversible reaction: malate is decarboxylase day to Pyruvate and NADPH is formed by the process

Question 26

What role does malonyl CoA in fat acid synthesis?

Answer 26

During fatty acid synthesis, the malonyl-group which has 3 carbons, is decarboxylated and the CO2 that was linked to Acetyl CoA by Acetyl CoA carboxylase is released

The growing fatty acyl chains will be elongated by the 2 carbons from the original Acetyl group

Question 27

How does fatty acid synthesis in the liver inhibit fatty acid degradation in the mitochondria?

Answer 27

1. Malonyl CoA formed in cytosol during FA synthesis inhibits the carnitine shuttle
2. This ensures that the pathways of fatty acid synthesis and of fatty acid degradation do not take place at the same time

Question 28

Give the fatty acid synthase reactions in detail

Answer 28

• the growing fatty acyl group is transferred from ACP to the SH group of the holding domain and now ACP(Acyl-carrier protein) is free again
• the malonyl group of malonyl CoA is bound to ACP
• DECARBOXYLATION of the carboxyl-group of malonyl-ACP generates energy and allows CONDENSATION with the group that was bound so far to the holding domain
• REDUCTION using NADPH, DEHYDRATION and another REDUCTION using NADPH are used to form a fatty acyl group that now is 2 carbons longer