Midterm II: Fatty Acid Synthesis (Ben) Flashcards
In what 3 tissues does fatty acid synthesis occur?
And in what part of the cell?
- Liver
- Adipose Tissue
- Lactating Mammary Gland
- in the cytosol
What enzyme produces fatty acids?
What is special about its structure and function?
Fatty Acid Synthase
- one single polypeptide chain with 7 different active sites for different reactions in separate domains
What is the “committed step” in fatty acid synthesis?
Reactants?
Enzyme + co-factor?
Products?
The first step… carboxylation…
Reactants: Acetyl-CoA + HCO3- + ATP
Enzyme: Acetyl-CoA Carboxylase + Biotin
Products: Malonyl-CoA
How is biotin connected to acetyl-CoA carboxylase?
- covalently bound to a lysine side chain of the enzymes “biotin carrier protein”
Acetyl-CoA Carboxylase is a “multienzyme protein” and performs a 2-step reaction.
What is the first step?
Biotin Carboxylase transfers a carboxyl group from bicarbonate to biotin in the presence of ATP.
Acetyl-CoA Carboxylase is a “multienzyme protein” and performs a 2-step reaction.
What is the second step?
Carboxyl transferase transfers the carboxyl group from biotin to acetyl-CoA, forming malonyl-CoA
How are biotin + its attached carboxyl group moved between the two enzymes within Acetyl-CoA carboxylase?
via biotin carrier protein
What is the protein responsible for fatty acid synthesis?
How many enzymatic actions does it have?
Fatty Acid Synthase
- has 6 enzymes and an acyl carrier protein
What first happens to fatty acid synthase before it can begin building a fatty acid chain?
Acetyl group of acetyl-CoA is transferred from…
ACP-SH to…
Cys-SH of …
β-ketoacyl-ACP synthase part of FA synthase, via…
MAT
On what special part of acyl carrier protein do molecules bind to become involved in fatty acid synthesis?
the -SH group on the vitamin panthothenic acid
(in 4’-phosphopantetheine form)
On which enzyme in the fatty acid synthase complex is the Cys-SH which binds acetyl-CoA found?
β-ketoacyl-ACP synthase
or “KS” part
What happens in fatty acid synthesis after acetyl-CoA binds to Cys-SH?
a Malonyl group is transferred to the ACP-SH by MAT
Once both the malonyl and acetyl groups are connected to fatty acid synthase…
What is the first step of fatty acid synthesis?
Reactants?
Enzyme?
Products?
Condensation…
Reactants: Acetyl + Malonyl groups
Enzyme: β-ketoacyl-ACP Synthase
Product: Acetoacetyl-ACP + CO2
After condensation of the malonyl + acetyl groups…
what is the 2nd step in fatty acid synthesis?
Reactants?
Enzyme?
Products?
Reduction of carbonyl group…
Reactants: Acetoacetyl-ACP + NADPH + H+
Enzyme: β-Ketoacyl-ACP Reductase (KR)
Products: β-Hydroxybutyryl-ACP + NADP+
After reduction of the carbonyl group at C-3…
what is the 3rd step of fatty acid synthesis?
Reactants?
Enzyme?
Product?
Dehydration to form a double bond…
Reactants: β-Hydroxybutyryl-ACP
Enzyme: β-Hydroxybutyryl-ACP Dehydratase (DH)
Product: trans-Δ2-Butenoyl-ACP + H20
After dehydration to form a double bond…
what is the 4th step in fatty acid synthesis?
Reactant?
Enzyme?
Product?
Reduction of the double bond…
Reactant: trans-Δ2-Butenoyl-ACP + NADPH + H+
Enzyme: Enoyl-ACP-Reductase
Product: Butyryl-ACP + NADP+
After reduction of a double bond…
what is the 5th and final step of fatty acid synthesis before the cycle begins again?
Translocaton of Butyryl-ACP to the Cys-SH of β-Ketoacyl-ACP Synthase (KS)
After the formation of a butyryl group, how does each subsequent round of the fatty acid synthase cycle begin?
ACP is recharged with another malonyl group by MAT
How many fatty acid synthase cycles does it take to produce palmitate?
And how is it finally released from the enzyme?
After 7 cycles a 16C palmitate is produced…
…and released by thioesterase enzyme
What is the overall reaction for the seven cycles of fatty acid synthase activity leading to production of one palmitate?
(Including the synthesis of the Malonyl-CoA substrates.)
What condition in lipid synthesizing tissues makes them favorable environments for this process?
High [NADPH]/[NADP+] ratio
(in the cytosol of adipose + liver cells)
Where does most of the NADPH used in FA synthesis come from?
Pentose Phosphate Pathway
and some from Malic Enzyme
How does acetyl-CoA get from the mitochondria to the cytosol for FA synthesis?
it is transported out of the mitochondria as citrate after combining with oxaloacetate via citrate synthase
What happens to citrate after it has left the mitochondria for FA synthesis?
Enzyme + co-factors?
Product?
it is converted back to acetyl-CoA via citrate lyase
- this requires ATP and yields oxaloacetate, ADP + Pi
After oxaloacetate is released from citrate in the cytosol, what happens to it?
It is converted back into malate via malate dehydrogenase using NADH + H+
What 2 things can happen with malate that has been formed from oxaloacetate in the cytosol?
And what byproduct of one of these things contributes directly to fatty acid synthesis?
- re-enters the mitochondria directly
- conversion to pyruvate via malic enzyme + NADP+
- yields NADPH for FA synthase
What are 3 regulatory mechanisms of acetyl-CoA Carboxylase?
- Negative feedback inhibition - via palmitate
- Allosteric Stimulation - via citrate
- Covalent Modification - insulin —> dephosphorylation —> activation
Increased levels of what two citric acid cycle molecules inhibit a key citric acid cycle enzyme?
(which then leads to increased FA synthesis)
Increased acetyl-CoA and ATP inhibit isocitrate dehydrogenase
- this leads to increased citrate + FA synthesis
What is the mechanism for glucagon’s effect on fatty acid synthesis?
- Gs
- Adenylyl Cyclase
- [cAMP] increase
- PKA
- Phosphorylation/deactivation of ACC
How does the presence of Palmitoyl-CoA affect FA synthesis?
(Generally and via what mechanisms?)
It inhibits it, via…
- Ac-CoA Carboxylase inhibition
- Inhibition of citrate movement to cytosol
-
G-6-P Dehydrogenase inhibition
- key pentose phosphate pathway enzyme
- leads to decreased [NADPH]
