M3: Fatty Acid Synthesis L20 Flashcards
What is the output of b-oxidation? A. Acetyl-CoA B. FADH2 C. NADH D. NADPH E. CPT1
A. Acetyl-CoA
B. FADH2
C. NADH
When does ketogenesis occur? A. To initiate cell division B. Glycogen stores are exhausted in liver C. After a fat-rich meal D. After a glucose-rich meal E. When blood [glucose] is low
B. Glycogen stores are exhausted in liver
E. When blood [glucose] is low
Explain what happens when blood glucose is running low in terms of production of ketone bodies.
Low blood glucose:
- Glucose is exported from liver to blood which decreases the pool of glucose in the liver.
- Glycogen breakdown replenishes glucose to be exported to blood.
- When pool of glycogen is exhausted you begin gluconeogenesis which is further stimulated by the presence of glucagon that will speed up breakdown of glycogen and synthesis of glucose from oxaloacetate.
- Problem: How can the CAC run if oxaloacetate is being depleted to make glucose?
- Solution: There is an accumulation of acetyl-CoA from triacylglycerol being lipolysed to Fatty acids and the fatty acids being broken down via B-oxidation to acetyl-CoA. Since Acetyl-CoA can’t enter the CAC due to the depletion of oxaloacetate, it can be converted to ketone bodies that can be exported out through the blood to the brain and heart to feed them.
- Once they reach the heart and the brain, they do the opposite reactions to make acetyl-CoA and produce energy through the CAC.
Which of the following metabolic circumstances require(s) to synthesize fatty acids? A. To initiate cell division B. After a fat-rich meal C. After a glucose-rich meal D. After a fructose-containing meal E. Exhausted glycogen stores in muscle
A. To initiate cell division (If u need to make more cells you need to make more FAs in the form of phospholipids)
C. After a glucose-rich meal (The surplus of glucose will be converted to FAs, which is why when you eat too much sugar you get fat)
D. After a fructose-containing meal
Where does Fatty Acid synthesis occur? What is significant about this?
FA synthesis happens in the cytosol.
This means that you need to export acetyl-CoA from the mitochondria to the cytosol.
What happens in liver metabolism in a fed state?
- In a fed state, liver is an ANABOLIC organ => generates glycogen until glycogen stores are full.
- Excess glucose that can’t be stored as glycogen + insulin (Insulin is required to stimulate the fatty acid pathway from fructose or glucose. You get insulin stimulation after a meal) => Your excess glucose needs to be converted all the way to acetyl-CoA in the liver and then the acetyl CoA can go to make fatty acids for VLDL production.
- Fructose bypasses PFK control in anabolic liver and is rather converted to FA
- Inhibition of CAC: in the presence of high ATP and NADH, isocitrate accumulates because isocitrate dehydrogenase is inhibited, the isocitrate to citrate reaction is reversible and will make more citrate. Citrate will be exported out of the mitochondria to the cytoplasm to make acetyl-CoA and make fatty acids
How is acetyl-CoA transported out of the mitochondria?
- Oxaloacetate + Acetyl-CoA make citrate via citrate synthase in the CAC.
- Citrate is shuttled to the cytosol via the citrate shuttle
- Citrate is degraded by citrate lyase to form acetyl-CoA and oxaloactetate
- Acetyl CoA goes on to make FAs
- Oxaloacetate turns into malate by malate dehydrogenase
- Malate to pyruvate via malic enzyme
- Pyruvate goes back to the mitochondria
- Pyruvate to oxaloacetate via pyruvate carboxylase
What are the 3 main steps for the synthesis of palmitate?
- Synthesis of Malonyl-CoA by ACC
- Coupling to ACP by MAT
- Elongation
Describe the first step of Palmitate synthesis.
Acetyl-CoA Carboxylase (ACC): Converts Acetyl-CoA (2 carbons) to Malonyl-CoA (3 carbons)
- Irreversible, rate-limiting step of the synthesis of fatty acids
- ATP breakdown provides the energy for the whole process to be exergonic
- One enzyme, two activities (i.e. two steps)
Overall reaction:
A biotin transfers a CO2 onto acetyl-CoA because it is a very good CO2 donor. This forms Malonyl-CoA.
Describe the second step of Palmitate synthesis.
The MAT (Malonyl/Acetyl-CoA Transacylase) couples acetyl-CoA and Malonyl-CoA with ACP. ACP is the acyl carrier protein, which when coupled, keeps acetyl and malonyl “activated” and prevents leakage to other compartments. Overall reaction: 1. Acetyl-CoA to Acetyl-ACP Via MAT. Acetyl-ACP to Acetyl-KS (high energy intermediate) via Beta-KS-Synthase. 2. Malonyl-CoA to Malonyl-ACP (high energy intermediate) via MAT.
Which of the reactions below is an “activation” step in FA synthesis? A. Adding CPT1 to acetyl-CoA B. Adding CPT1 to malonyl-CoA C. Adding ACP to acetyl-CoA D. Adding ACP to malonyl-CoA E. Adding ACP to citrate
C. Adding ACP to acetyl-CoA
D. Adding ACP to malonyl-CoA
To describe the 3rd step of FA Palmitate synthesis, refer to L20 S32.
L20 S32. Elongation.
Describe fatty acyl synthase.
- Very large protein, many domains, all catalytic activities on one monomer
- Two domains make thio-ester bonds (KS and ACP). ACP is the main one
- 2 homodimers organized in upside-down orientation
- Domains interact with each other
- VERY FAST (less than one second from Acetyl-CoA to palmitate)
- ACP, MAT, and KS are all part of the fatty acyl synthase enzyme therefore steps 2 and 3 of palmitate synthesis happen due to fatty acyl synthase.
Learn the synthesis of palmitate reaction. L20 S36.
L20 S36.
What is the overall stoichiometry for palmitate biosynthesis?
8 Acetyl-CoA + 14 NADPH + 7 ATP to palmitate + 14 NADP+ 8 CoA + 6 H2O + 7 ADP + 7 Pi
