Sophia maintained a healthy weight
of 132 pounds during the first months of graduate school. Normally, she ran 2 miles every other day and
ate healthy diet with plenty of fruits and veg.
During the December holiday Sophia
was too busy to exercise. There were big
family dinners, relatives cooked special foods, her mother baked. And Sophia ate big breakfasts (pancakes,
omelets), lunches (sandwiches, cookies) and dinners (mashed potatoes, bread
& butter, roasts, pies…).
On January 2, 2007 she weighed 137
1. What was the composition of her weight gain?
2. Does composition of Sophia's December diet matter in terms of promoting weight gain?
3. Each meal resulted in glucose entering --> glycolysis via allosteric and covalent regulation of _____?
4. Transcriptional changes also occurred. What components of her diet do you think would lead to transcriptional diet.
Allosteric and covalent regulation of hexokinase/glucokinase and GLUT 4?
Draw the big picture of how glucose metabolism intersects with fatty acid metabolism. 14 players.
What are the main regulatory steps of FA synthesis? 2
Acetyl CoA carboxylase and FA synthase
When is glucose shunted into FA synthesis ?
This pathway occurs with excess glucose meaning excess pyruvate (due to lots of glycolysis) which shunts glucose into PPP creaing extra NADPH (necessary for FA synthesis).
Pyruvate = primary source of mitochondria acetyl CoA for FA synthesis.
ANABOLIC STATE with lots of NADPH, ATP and PYRUVATE (due to glycolysis; substrate for FAs)
Name the 6 steps of the cytosolic conversion of pyruvate cycle (malate) to produce NADPH
- 1. Mitochondria: PDH - pyruvate --> acetyl CoA
- 2. Citrate synthase: Acetyl CoA + OAA --> citrate
- 3. Citrate is translocated into cytosol
- 4. ATP citrate lyase: citrate + CoA + ATP --> acetyl CoA + OAA + ADP
- 5. Malate dehydrogenase: OAA + NADH --> malate + NAD+
- 6. Malic enzyme: malate + NADP+ --> pyruvate + CO2 + NADPH.
Then NADPH + acetyl CoA from step 4 + ATP forms palmitate.
What regulates production of cytosolic acetyl CoA? 2
- 1. High ATP inhibits isocitrate DH, leading to accumulation of citrate and isocitrate in mitochondria.
- 2. High mitochondrial citrate
How many enzymes are necessary to assemble FAs? What are the two compounds needed for FA Synthesis?
Acetyl CoA and an acyl carrier peptide.
What is the rate-limiting step for FA synthesis? Why? What is the enzyme? What is its inactive form? (2) Active form? (2)
Carboxylation of acetyl CoA --> malonyl CoA (Acetyl CoA Carboxylase)
Bc apart from initial acetyl CoA, all carbons in the FA will have passed through malonyl CoA.
- Inactive: dimer & phosphorylated
- Active: polymer & dephosphorylated.
How are ACC and FA synthesis regulated?
ACC short (activated by 2, inhibited by 2)
long term: activated by 3, inhibited by 2.
ACC: short term: citrate, insulin (via SREBP1); inhibited by LC FA CoA, AMPK (via AMP like mTOR)
Both ACC and FAS are activated transcriptionally/long-term by excess calories, high carb diets/fat free diets and inhibited by fasting/high fat diet.
What are the 4 steps of FA synthesis? What is the final product?
- 1. Glucose --> pyruvate --> Acetyl CoA
- 2. Acetyl CoA (2C) --> Malonyl CoA (3C)
- 3. FAs are built by adding 2 Cs at a time from malonyl CoA
- 4. With each 2-C addition, one CO2 is lost.
Final product: C16:0 palmitic acid.
How does metformin work? (3)
Lowers serum TAG through activation of AMPK resulting in inhibition of ACC activity and inhibition of ACC & FAS expression by downregulating SREBP-1.
Also lowers blood glucose by increasing AMPK-mediated uptake of glucose by muscle.
- 1. Activates AMPK - increasing glucose uptake in muscle & inhibiting ACC.
- 2. Downregulating SREBP to inhibit gene expression of ACC and FAS
What additional things does ACC require to work? (4)
- 1. CO2
- 2. ATP
- 3. B5 (CoA)
- 4. B7 (biotin)
How do glucagon and epinephrine activate AMPK?
Indirectly via adenylate cyclase --> cAMP --> PKA --> AMP kinases --> AMPK.
What are the 2 essential FAs? Common name and 16:0 form. What are they precursors of?
Linoleic acid 18:2 and Linolenic acid 18:3
Linoleic is the precursor for arachidonic acid which is the precursor for prostaglandins.
Linoleic is precursor for other w-3 FAs necessary for growth and development.
What is arachidonic acid a precursor for? What is it derived from?
Arachidonic: precursor of prostaglandins. Derived from linoleic acid (essential fatty acid).
What is the most important domain in FAS? What drives this part of FA synthesis? What binds FA to this domain?
ACP (Acyl carrier protein domain).
The loss of free energy from decarboxylation (release of CO2).
A thioester bond.
What domain is FA built upon? What happens to the FA when a new malonyl CoA comes in? Then what happens? What is released?
ACP. When a new malonyl CoA comes in, the FA is transferred temporarily to the cysteine residue while ACP accepts malonyl CoA.
THEN ACP condenses the two compounds, taking back the FA and releasing CO2.
Where does NADPH for FA synthesis come from? (2) What are sources of Acetyl CoA? (4)
NADPH: PPP and cytosolic conversion of malate to pyruvate.
Acetyl CoA comes from oxidation of pyruvate and catabolism of FAs, ketone bodies, and certain amino acids (ketogenic).
Which amino acids are solely ketogenic? (2) Both ketogenic and glucogenic? (5)
- 1. Leucine & lysine
- 2. Isoleucine, phenylalanine, tryptophan, tyrosine, threonine
Remember: three ties try phat ice
Where does FA synthesis take place? What is the total summary for palmitate? 3 types of substrates and 5 types of products.
Acetyl CoA + 7 malonyl CoA + 14 NADPH>>>>
Palmitate + 8 CoA + 7 CO2 + 6H2O + 14NADP+
What part of FA synthesis requires NADPH? What part requires ATP?
FA synthase requires NADPH, while ACC requires ATP.
What are two ways that insulin regulates ACC?
- 1. Dephosphorylates ACC --> activating it
- 2. Activates transcription of SREBP which increases gene expression of ACC.
In what increments are FAs elongated? What else is required? (2)
2C at a time. Also requires NADPH.
what is the total rxn for synthesizing one 16-C FA?
What is the delta system? Omega system?
For desaturated FAs. Delta system counts from carboxyl end of FA while omega system counds from methyl end.
Which desaturases do mammals have? What is required for desaturation? (2)
delta 4,5,6, and 9. NADH and O2.
What coenzyme is needed for elongation?
What is the C16:0 for linolenic acid? linoleic acid? DHA? EPA? arachidonic acid?
- Linolenic: 18:3w3
- Linoleic: 18:2w6
- DHA: 22:6w3
- EPA: 20:6w3
- Arachidonic acid: 20:4w6