Fatty Acid Synthesis Flashcards
Where does fatty acid synthesis occur?
the cytosol
How is citrate made for lipogenesis?
pyruvate enters the mitochondria and is broken down into 1 OAA (by pyruvate carboxylate) and 1 acetyl CoA (by pyruvate dehydrogenase). The OAA and Acytl CoA then combine via citrate synthase to make citrate.
Citrate (a branch point of the TCA) then exits the mitochondria via a carrier)
What happens to citrate when it leaves the mitochondria?
It is acted upon by citrate lyase (through addition of ATP) and re-forms OAA and Acetyl CoA
Where does the newly formed OAA go?
the citrate shuttle
What are the steps of the citrate cycle?
1) pyruvate enters the mitochondria and forms OAA and Acetyl CoA
2) OAA and Acetyl CoA combine via citrate synthase to form citrate
3) citrate exits the mitochondria via carrier
4) citrate re-forms OAA and Acetyl CoA via ATP addition to citrate lyase
5) OAA becomes malate via addition of NADH to malate dehydrogenase
6) Malate becomes pyruvate again via MALIC ENZYME and *producing NADPH (important step). This step gives off Co2
7) pyruvate reenters the mitochondria to restart the cycle
What happens to the Acetyl CoA released from citrate when it moves to the cytosol to reform OAA and Acetyl CoA (via citrate lyase)?
It enters into lipogenesis
Outline the steps of lipogenesis from Acetyl CoA re-formation from citrate into the cytosol
1) acetyl CoA becomes malonyl CoA via acetyl CoA dehydrogenase
2) malonyl CoA is acted upon by FATTY ACID SYNTHASE via NADPH (from where?) to form palmitate
3) Palmitate becomes fatty acyl CoA
4) fatty acyl CoA combines with glycerol-3-p (from DHAP) to form TAG
5) Apo-proteins (B48) and other lipids are added to TAG to form VLDL
6) VLDL are secreted from the liver
7) VLDL is broken down by LPL and FAs are absorbed into tissue and glycerol is recycled to the liver
What are the sources of NADPH for fatty acid synthase?
1) Formation of NADPH during conversion of malate to pyruvate via malic enzyme
2) NADPH from the pentose-phosphate pathway
What is the committed step of FA synthesis?
conversion of cytosolic acetyl CoA to malonyl CoA
Like any other committed step, this is highly regulated
What is needed for the conversion of Acetyl CoA to malonyl CoA?
Enzyme?
bioton, Co2 and ATP
acetyl CoA carboxylase
NOTE: Synthesis of a 16-carbon palmitate molecule requires 8 acetyl CoA molecules. 7 of these acetyl CoA’s must first be converted to malonyl CoA. This is accomplished by acetyl CoA carboxylase in the first committed step of fatty acid synthesis
How is the conversion of Acetyl CoA to malonyl CoA regulated?
Its regulation includes allosteric mechanisms, hormone-dependent phosphorylation, and induction ( i.e., the amount of enzyme synthesized is increased by a high-calorie diet and decreased by a low calorie diet)
Is phosphorylated acyl CoA carboxylase active or inactive?
inactive
What activates acyl CoA carboxylase? Any other promotors of this enzyme?
insulin stimulates a phosphatase to dephosphorylate it
A high-calorie diet increases the rate of transcription of the gene for acetyl CoA carboxylase (whereas a low-calorie diet reduces transcription of this gene)
What causes acyl CoA carboxylase to phosphorylated? Any other inhibitors of this enzyme?
Low energy levels, via activation of an AMP-dependent protein kinase, cause the enzyme to be phosphorylated and inactivated
palmityl CoA, a derivative of palmitate, also cause inhibition of the enzyme
Malonyl CoA, an intermediate of lipogenesis, inhibits what part of fatty acid breakdown (lipolysis)?
it inhibits CPT1, which converts fatty acyl CoA to fatty acyl translocase. This mechanism prevents newly synthesized fatty acids from undergoing immediate oxidation.
What is the 5 steps of FA Synthase?
Step 1. Transfer of malonyl to FA Synthase
Step 2. Condensation of malonyl and an acyl groups
Step 3. Reduction of b-ketoacyl group with NADPH
Step 4. Dehydration forms double bond
Step 5. Reduction of double bond with NADPH
These steps are repeated. 2 C add with each repeat. For a new FA chain to start, an AcCoA is required to be the acceptor of the malonyl transfer. Must make malonylCoA from AcCoA.
Stoichiometry of Palmitate synthesis Beginning w/ Acetyl- and Malonyl CoA
Acetyl CoA + 7 Malonyl CoA (converted from acetyl CoA) + 14 NADPH ->
Palmitate + 7 CO2 + 14 NADP+ + 8 CoA
Stoichiometry of Palmitate synthesis Beginning w/ Acetyl CoA, need ATP to add *CO2
8 Acetyl CoA + 7 ATP + 14 NADPH ->
Palmitate + 7 ADP + 14 NADP+ + 8 CoA
Where does elongation of FA occur?
in the endoplasmic reticulum
How does elongase work?
The reaction sequence is similar to that of palmitate synthesis, i.e., the 2-carbon donor is malonyl CoA, and the reduction reactions use NADPH. A difference between the “elongase” in the endoplasmic reticulum and the fatty acid synthase in the cytosol is that elongation occurs while the fatty acid is bound to CoA, rather than to ACP.
This elongase (and a different one in mitochondria) can modify pre-existing saturated or unsaturated fatty acids, creating very long chain fatty acids, although the most common elongation reaction is the synthesis of stearate from palmitate.
Fatty acids with 22-24 carbons are common where?
in the brain, and fatty acids with more than 30 carbons have been demonstrated.
Where does desaturation of Fatty Acids occur?
in the ER
What enzyme does desaturation? How does it work?
Desaturase is an oxidase located in the ER..
Inserts a double bond at the 9th carbon from carboxyl group, Δ9
Makes palmitoleate from palmitate, and oleate from stearate
