Fatty Acid Synthesis Flashcards
Where does fatty acid de novo synthesis occur?
- Mostly in the liver after a CHO-rich meal stimulated by insulin
- The lactating mammary glands also synthesize fatty acids.
What is the purpose of fatty acid de novo synthesis ?
- 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
What is the purpose of fatty acid de novo synthesis in mammary glands?
Milk production and provision of long-chain and medium-chain fatty acids for synthesis of TAGs found in milk
How can liver reduce increase in blood glucose after a meal?
The dietary glucose reaches the liver via the hepatic portal vein and Glucokinase in hepatocytes phosphorylates it to glucose 6-P
In which pathways does insulin favor hepatocytes ?
- Glycogen synthesis
- Glycolysis, PDH complex, TCA cycle
- Fatty acid de novo synthesis and TAG synthesis
- Cholesterol synthesis
- HMP for generation of NADPH
Outline hepatic fatty acid synthesis after a meal by the liver
- 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
Where in the cell does fatty acid de novo synthesis occur in the cell?
- 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
Which enzymes are involved in fatty acid de novo synthesis?
- 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
Why is Acetyl CoA needed for fatty acid synthesis?
Acetyl CoA carboxylase(biotin) converts Acetyl CoA to Malonyl CoA
Malonyl CoA used in fatty acid synthase
Palmitate 16:0 is the end product
Explain Acetyl CoA formation in CoA
- Acetyl CoA formed in mitochondria cannot leave the mitochondria
- 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
- In the cytosol, citrate is cleaved by ATP-citrate lyase to Acetyl CoA and oxaloacetate
What is the regulated enzyme of fatty acid synthesis
Acetyl CoA carboxylase is the regulated enzyme and provides fuel for fatty acid synthase
How can you describe the reaction catalyzed Acetyl CoA carboxylase?
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
Describe the allosteric regulation oh Acetyl CoA carboxylase
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
Why is Acetyl CoA carboxylase allosterically activated by cytosolic citrate
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
Why is Acetyl CoA carboxylase inhibited by accumulation of long-chain fatty acyl CoA and not by palmitate?
- Palmitate is the end product ofFA synthase but shall never accumulate as free palmitate damages the cell.
- The free CoA pool in cytosol is limited
- 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
- 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
Palmitate is the end product of FA synthase but doesn’t inhibit Acetyl CoA carboxylase unlike fatty acyl CoA. Why Is this?
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
Palmitate is the end product of FA synthase but never accumulates. Why is this?
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
How can covalent modification activate a Acetyl CoA carboxylase?
Activation by dephosphorylation
Acetyl CoAvcarboxylase is activated when it its dephosphorylated by protein phosphatase following insulin action
How can Acetyl CoA carboxylase being deactivated via covalent modification?
Acetyl CoA is inhibited by phosphorylation by AMP-kinase
AMPK is activated via:
- allosterically by AMP
- by phosphorylation by AMPK kinases
How is AMPK activated?
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
How does blood glucose level affect fatty acid synthesis?
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
Describe fatty acid synthase in humans
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
Describe fatty acid synthase in bacteria
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
What can form NADPH?
Hexose monophosphate
Hepatic malic enzyme
How does malate enzyme form NADPH?
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
What role does malonyl CoA in fat acid synthesis?
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
How does fatty acid synthesis in the liver inhibit fatty acid degradation in the mitochondria?
- Malonyl CoA formed in cytosol during FA synthesis inhibits the carnitine shuttle
- This ensures that the pathways of fatty acid synthesis and of fatty acid degradation do not take place at the same time
Give the fatty acid synthase reactions in detail
- 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
