Fatty Acid Biosynthesis Flashcards
Fatty acid synthesis takes place in the
- Liver (hepatocytes)
- Adipose tissues (adipocytes)
Fatty acid synthesis is the reversal of β-oxidation
Exam Question: Name 4 differences between beta oxidation and fatty acid synthesis
O = Beta-oxidation; S = Synthesis
1) Location:
Mitochondria (O)
Cytosol (S)
2) Acyl carrier:
CoA (O)
ACP (S)
3) Coenzyme:
NAD+ and FAD (O)
NADPH (S)
4) Basic units:
Acetyl-CoA (O)
Malonyl-CoA (and one acetyl-CoA (S)
3 Characteristics of compartmentalization with fatty acid synthesis
FA synthesis occurs in the cytoplasm of the cell:
1) The inner membrane of the mitochondria is impermeable to acetyl-CoA.
2) Tricarboxylate transporter allows translocation of acetyl-CoA out of mitochondria in the form of citrate.
T or F: When we have a surplus of fatty acids, the TCA cycle is running fast
False, it is running slowly
Tricarboxylate Transport System
Summary of transporting acetyl-CoA from the mitochondria to the cytosol
- Tricarboxylate transport system facilitates directional transport
- Citrate synthase catalyzes the formation of citrate within the mitochondrial matrix
3)ATP-citrate lyase catalyzes the reverse reaction in the cytosol to release acetyl-CoA
How many carbons are added to each round of fatty acid synthesis
2 carbons (so will only synthesize even numbered carbon chains):
- Precursor - Acetyl-CoA (red)
- C2 donor – Malonyl-CoA (blue-green)
What enzyme is the rate-limiting enzyme that is used to form malonyl-CoA
Acetyl-CoA Carboxylase (ACC)
What is Acetyl-CoA Carboxylase (ACC)?
In eukaryotic cells, ACC is a multi-domain, multi-functional enzyme with a biotin carboxylase and the carboxyltransferase activities
What are the 3 functional domains of ACC?
biotin carboxylase domain
biotin carrier protein
transcarboxylase domain
Formation of malonyl-CoA Step 1
This is a carboxylation reaction where a bicarbonate ion is loaded on the biotin prosthetic group attached to ACC (biotin carrier protein)
- catalyzed by the biotin carboxylase activity of ACC and is driven by ATP hydrolysis
-Needs an investment of 2 ATP (need to be in surplus of ATP to occur)
Formation of malonyl-CoA Step 2
The second reaction is a transcarboxylation where the carboxyl group located on the prosthetic biotin is transferred to an acetyl-CoA using the transcarboxylase activity of ACC to produce malonyl-CoA
What enzyme catalyzes all the reactions of fatty acid synthesis
All of these reactions are catalyzed by one multidomain and multifunction enzyme called the Fatty Acid Synthase (FAS).
What type fatty acid synthase do we use
Megasynthase
What type fatty acid synthase do we use
Megasynthase (mammalian FAS)
Characteristics of megasynthase
- 272-kDa polypeptide chain (very large)
-Each subunit of the dimeric mammalian FAS (homodimer) is folded into seven distinct domains, and each domain carry out a specific function in the reaction sequence.
-Homodimer
Why cant we see ACP or TE domain on this image of megasynthase
Don’t see ACP and TE because these are the swinging arms and are always moving so cannot see
T or F: The immediate substrates for FA synthesis are attached to ACP not CoA
True
What bond binds ACP (Acyl Carrier protein) to Acetyl-CoA
thioester bond using the phosphoantetheine group
FA substrate synthesis: Conversion of acetyl-CoA into acetyl-ACP (Step 1a)
Formation of acetyl-ACP is catalyzed by the Malonyl/Acetyl CoA-ACP Transacylase (MAT)
FA substrate synthesis: Loading of the acetyl-ACP onto FAS (Step 1b)
The resulting acetyl-ACP is anchored onto KS domain of FAS by the β-Ketoacyl-ACP Synthase (KS)
FA substrate synthesis: Conversion of malonyl-CoA into malonyl-ACP (Step 2)
Formation of malonyl-ACP is catalyzed by the Malonyl/Acetyl CoA-ACP transacylase (MAT)
FA synthesis: Loading of the substrates onto FAS
T or F: After substrates (Malonyl-CoA and Acetyl-CoA) are loaded to form Malonyl-ACP and Acetyl-KS, fatty acid synthesis can begin
True
How many reactions does each round of fatty acid synthesis undergo
6
FA synthesis: Step 1 of the synthesis
-Decarboxylation and condensation to form C-C bond
-Catalyzed by KS
-Formation of β-ketobutyryl-ACP
Where is the acetyl group in the picture
Always the farthest away from the carboxyl group
FA synthesis: Step 2 of the synthesis
-β-carbon modification
-Reduction of β-keto group by Ketoacyl-ACP Reductase (KR)
FA synthesis: Step 3 of the synthesis
-β-carbon modification
-Dehydration β-hydroxybutyryl-ACP by Hydroacyl-ACP Dehydrase (DH)
FA synthesis: Step 4 of the synthesis
-β-carbon modification
-Reduction of the double bond by Enoyl-ACP Reductase (ER)
FA synthesis: Step 5 of the synthesis
-Translocation
-Translocation of butyryl group to Cysteine on β-Ketoacyl- ACP Synthase (KS)
NOTE: All of the process occurs on ACP and in order to load another malonyl coa it must be transferred to KS (restarts process)
FA synthesis: First Round
FA Synthesis: Second Round
-Recharging of ACP with another Malonyl group by the MAT domain
-Condensation by the KS domain
How many rounds of fatty acid synthesis are required?
7 rounds, 4 carbons produced at first then each other round produces 2 more carbons added
How many rounds of fatty acid synthesis are required?
7 rounds, 4 carbons produced at first then each other round produces 2 more carbons added
FA synthesis: Step 6 of the synthesis
-Hydrolysis
-TE (ThioEsterase) cleaves the thioester bond
FA synthesis: Step 6 of the synthesis
-Hydrolysis
-TE (ThioEsterase) cleaves the thioester bond
