Lipid Biosynthesis Flashcards
Name the biological functions of lipids.
- Energy storage (TG)
- Constituents for membranes
- Anchors for membrane proteins (prenyl group, IP2/PIP3)
- Cofactors for enzymes (vitamin K)
- Signaling molecules (eicosanoids, IP3)
- Pigments (retinal); important for vision
- Detergents (bile salts); help the absorption of lipids and fats from the diet
- Transporters
- Antioxidants (vitamin A)
What is the first step in the synthesis of fatty acids? Which enzyme catalyzes this step?
- Formation of Malonyl-CoA from Acetyl-CoA
- Acetyl-CoA carboxylase (ACC)
Does Acetyl-CoA carboxylase (ACC) require energy?
Yes
How is Malonyl-CoA formed?
- CO2 is added to biotin
- Conformational change: biotin shifts from biotin carboxylase to trans carboxylase
- CO2 is added to Acetyl-CoA, converting it to Malonyl-CoA
What is the second step in the synthesis of fatty acids? Which enzyme catalyzes this step?
- Addition of 2-carbons to fatty acyl chains
- Fatty acid synthase
Which reactions occur on fatty acid synthase (in order)?
1) Condensation
2) Reduction
3) Dehydration
3) Reduction
How does Malonyl-CoA attach to fatty acid synthase?
By a thiol (SH) group, attached to Lysine in the ACP moiety
To which domain on the fatty acid synthase does Malonyl-CoA attach itself?
ALWAYS attaches on the ACP domain
What is on the KS domain of fatty acid synthase? What happens to it?
- Acetyl-CoA
- Structure is brought to ACP to get elongated
Where does the elongated FA chain go?
Brought BACK to the KS domain
Where does elongation occur?
- OCCURS in the ACP domain
- Brought back to the KS domain AFTER
What does the reduction reaction do in fatty acid synthase?
Adds hydrogens to the carbons through NADPH
- In the second reduction, it creates a CH2-CH2 bond
At which residue does the growth of the fatty acid chain occur?
On the lysine
What fatty acid does fatty acid synthase typically synthesize?
Palmitate (16:0)
Where are long fatty acid chains produced?
- In the ER
- In the mitochondria
What is the precursor for longer FA chains?
Palmitate
What is the precursor for unsaturated fatty acids?
Palmitate and stearate
How are palmitate and stearate desaturated?
- By Fatty acyl-CoA desaturase
- Adds double bonds by an oxidative reaction (removes hydrogens)
Where are the double bonds on palmitoleate? What about oleate? How many carbons do they have?
- Palmitoleate (16:1)
- Oleate (18:1)
- Double bonds are at C9-C10
Which fatty acid cannot be synthesized in mammals?
- Linoleate (18:2)
- Double bonds at 9 and 12
- It is essential, must be eaten
What is arachidonate synthesized from?
Linoleate
Can arachidonate be synthesized by mammals?
Yes, but it requires linoleate (which can’t)
What is the rate-limiting enzyme in the biosynthesis of fatty acids?
Acetyl-CoA carboxylase
What is Acetyl-CoA carboxylase inhibited by?
Phosphorylation, which is regulated by the hormones epinephrine and glucagon
What is the feedback inhibitor of Acetyl-CoA carboxylase?
Palmitoyl-CoA
What is an activator of Acetyl-CoA carboxylase?
Citrate
What does catabolism of fatty acids produce? Where does it occur?
- Produces Acetyl-CoA and electron donors (NADH)
- Takes place in the mitochondria
What does anabolism of fatty acids produce? Where does it occur?
- Requires Acetyl-CoA, Malonyl-CoA, and electron donors (NADPH)
- Takes place in the cytosol
What makes Acetyl-CoA be destined for B-oxidation?
When it is brought back into the mitochondria through carnitation
What makes Acetyl-CoA be destined for fatty acid synthesis?
When it is converted to Malonyl-CoA
_____________ inhibits all reactions towards B-oxidation.
Malonyl-CoA
How does high levels of glucose regulate fatty acid synthesis/breakdown?
- Sufficient energy; release of glucose
- Signals to hormone-dependent phosphatase to remove a phosphate group of ACC
- Activates ACC and FA synthesis
How does low levels of glucose regulate fatty acid synthesis/breakdown?
- Glucagon (GPCR) leads to the activation of PKA through cyclic AMP
- PKA phosphorylates ACC, which inactivates it
- Inactivation of FA synthesis
What is the source of Acetyl-CoA for the synthesis of fatty acids?
- NOT B-oxidation
- Pyruvate carboxylation
- AA catabolism
How does Acetyl-CoA escape from the matrix of the mitochondria?
- Acetyl-CoA is added to Oxaloacetate
- Citrate synthase in the TCA cycle makes citrate out of it
- Transporter for citrate transports it from the matrix to the cytoplasm
- Citrate lyase in the cytoplasm converts it to Acetyl-CoA and oxaloacetate
What happens to the oxaloacetate in the cytoplasm produced by citrate lyase?
- Oxaloacetate gets converted to Malate by Malate dehydrogenase
- Malate is transported to the matrix through the malate-a-ketoglutarate transporter
- Or, malate is converted to pyruvate in the cytoplasm
- Pyruvate can go into the mitochondria easily through transporters
What are the two steps to the biosynthesis of triacylglycerols?
1) Glycerol-3-phosphate to phosphatidic acid
2) Phosphatidic acid to TG
Which enzyme catalyzes glycerol-3-phosphate to phosphatidic acid?
Acyl transferase
What does acyl transferase do?
- Transfers two fatty acid chains (acyl chains)
- One phosphate still remains, which makes it phosphatidic acid
What can phosphatidic acid become? (2)
1) Synthesized to a glycerophospholipid by adding a head group
2) Phosphate is removed, and one more acyl group is added to form a TG
Which enzymes catalyze phosphatidic acid to TG?
1) Phosphatidic acid phosphatase (removes phosphate)
2) Acyl transferase (adds a FA)
What promotes the synthesis of TG? How?
- Insulin
- Activation of acyl transferase
Where does the biosynthesis of cholesterol occur?
- In the cytoplasm/microsomes
What are the steps of the biosynthesis of cholesterol?
1) Condensation
2) Phosphorylation
3) Polymerization
4) Cyclization
In the biosynthesis of cholesterol, what are the intermediates produced following condensation?
- Converts acetate to HMG-CoA by HMG-CoA synthase
- Converts HMG-CoA to Mevalonate by HMG-CoA reductase
Where is HMG-COA synthase present? What is it used for?
1) Mitochondria: ketone body synthesis
2) Cytoplasm: biosynthesis of cholesterol
What happens during polymerization and cyclization in the biosynthesis of cholesterol?
Polymerization: straight chains
Cyclization: straight chains –> cyclic rings
What is the rate-limiting enzyme in cholesterol synthesis?
HMG-CoA reductase
How does AMP-dependent protein kinase affect cholesterol synthesis?
- When AMP rises, kinase phosphorylates the enzyme
- Decreases cholesterol synthesis
How do glucagon and epinephrine affect cholesterol synthesis?
- Cascades lead to phosphorylation
- Decreases cholesterol synthesis
How does insulin affect cholesterol synthesis?
- Cascades lead to dephosphorylation
- Increases cholesterol synthesis
What does Insig mean? What is its function in cholesterol synthesis?
- Insulin-Induced Gene Protein
- Senses cholesterol levels
What does Insig trigger when cholesterol levels are high?
- Triggers ubiquination of HMG-CoA reductase
- Ubiquination triggers protein degradation
- Decreases cholesterol synthesis
