Lipid Synthesis Lecture Spe 3 Flashcards
What is the main storage form of fatty acids in the body?
Triagylglycerols (TG)
Where are fatty acids synthesized? From what? When?
Fatty acids are synthesized from acetyl CoA in liver cells whenever ingested calories exceed the requirement for energy.
During conditions of excess energy, what key enzyme is inhibited by the high NADH/NAD+ ratio to drive citrate towards fatty acid synthesis?
Isocitrate dehydrogenase.
In order for fatty acid synthesis to occur, what two reactions acting on pyruvate need to occur?
- You need pyruvate converted to acetyl CoA through PDH.
- You need pyruvate to be converted by pyruvate carboxylase to form oxaloacetate.
Both acetyl CoA and oxaloacetate are needed for fatty acid synthesis because they are both necessary to form citrate, which is an important intermediate in fatty acid synthesis.
In order for fatty acid synthesis to occur, acetyl CoA has to leave the mitochondria and ente rthe cytoplasm. How does this happen?
THe “acetyl CoA” carbons leave on citrate.
Once citrate is in the cytosol, **citrate lyase ** will take 2 carboncs off of citrate and esterify then to CoASH, yielding acetyl CoA in the cytosol
THe byproduct of this is oxaloacetate in the cytosol
In the cytosol, which enzyme cleaves 2 carbons off citrate and puts them on CoA for form acetyl CoA in the cytosol, with the other product being oxaloacetate?
citrate lyase
When the body is in the fed state and wanting to undergo fatty acid synthesis, where does the NAD+ which is necessary for glycolysis come from since we’re not using the NADH dehydrogenase in the electron transport chain?
The NAD+ is regenerated by the enzyme malate dehydrogenase which converts the oxaloacetate in the cytosol (the product from citrate lyase) to malate, oxidizine NADH to NAD+ which can then beused to keep glycolysis going.
Remember, we need glycolysis to continue because we need pyruvate to be turned into citrate for fatty acid synthesis.
In the fed state when the body wants to undergo fatty acid synthesis, what enzyme reaction will regenerate the NADPH to drive the biosyntthetic reactions of Fatty Acid Synthase (FAS)?
Malate (from oxaloacetate) is converted back to pyruvate by malic enzyme , regenerated NADPH to be used by FAS.
What enzyme converts malate back to pyruvate in the pyruvate/malate cycle?
malic enzyme, using NADP as a cofactor
What enzyme converts oxaloacetate to malate?
malate dehydrogenase, using NADH as a cofactor
The pyruvate/malate cycle has two function in lipogenesis (fatty acid synthesis). What are they?
- Transport acetyl CoA from the mitochodnria to the cytosol.
- Malic enzyme generates NADPH to power fatty acid synthesis. Malate dehydrogenase regenerates NAD+ to keep glycolysis going so citrate can still be produced.
THe first step in fatty acid synthesis (once acetyl CoA is in the cytosol) is also the rate limiting step.
What is it?
Cytoplasmic Acetyl CoA is carboxylated to form malonyl CoA using the acetyl CoA carboxylase (ACC) enzyme.
Biotin is the cofactor–remember it’s putting more carbon onto acetyl CoA to form malonyl CoA, which is a 4 carbon molecule.
Acetyl CoA carboxylase catalyzes the conversion of acetyl CoA to malonyl CoA in fatty acid synthesis.
How is it activated? (4 ways)
Which ways are quicker?
Which ways are longer lasting?
Citrate (remember it’s a precursor for acetyl CoA–the substrate)will allosterically activate (this is feed forward).
Insulin will increase transcription of ACC.
Xylulose 5-phosphate increases transcription of ACC
Insulin stimulate dephosphorylation, activating ACC.
The two options that alter transcription will be slower, but will last longer.
Acetyl CoA Carbosylase is the rate limiting step in fatty acid synthesis. How is is inhibited?
Palmitoyl CoA allosterically inhibits (this is the main product of fatty acid synthesis, so this is product inhibition)
Phosphorylation by AMP-K will inhibit (remember that the AMP:ATP ratio is a good way to sense the general energy balance intracellularly. if the AMP:ATP ratio is too high you get activation of AMPK, which phosphorylates ACC so you don’t get synthesis of fatty acids, you get oxidization of fatty acids).
Glucagon (a hunger hormone) will increase levels of cAMP, which will activate PKA, which will phorphorylate ACC similarly to AMP-K, and cause inhibition.
How does malonyl CoA inhibit beta oxidation of newly synthesized fatty acids?
Why is this a good thing during fatty acid synthesis?
Malonyl CoA inbhitirs carnitine palmitoyl transferase 1 (CMPT1) so that the fatty acyl CoA can’t enter the mitochondria and therefore can’t undergo beta-oxidation.
This is a good thing during fatty acid synthesis because it allows the cell to avoid futile cycling–most cells don’t want to be burning fatty acids and synthesizing fatty acids at the same time–this would be a net energy loss.
THe liver is somewhat special in this because it needs to undergo “futile” cycling occasionally.
What is the general reaction sequence in beta oxiation of fatty acids?
What is the general reaction sequence in fatty acid synthesis?
Beta oxidation:
Oxidation, Hydration, Oxidation, Bond Cleavage
for fatty acid synthesis it’s the opposite:
Bond formation, reduction, dehydration, reduction
There are two key differences between beta oxidation and fatty acid synthesis (besides the general steps of the reactions). What are they?
Location and the enzymes:
Beta oxidation occurs in the mitochondria and there are multiple enzymes involved in each of the 4 steps.
Fatty acid synthesis occurs in the cytosol and only one enzyme (FAS) is sused to carry out all 4 steps.
Fatty acid synthase is a large enzyme with multiple acitvities. It has two important binding sites involving sulfer. WHat are they?
Going beyond bond formation, reduction, dehydration, and reduction….
what are the steps of fatty acid synthesis?
- Two carbon units (the initial 2 carbons are from acetyl CoA, but the subsequent carbons are from malonyl CoA) are first added to the phophopathetheinyl sulfur
- Then the keto gruop is reduced to an alcohol, with NADPH oxidation powering the reaction.
- In the third step, a dehydration reaction removes water and introduces a C-C double bond
- finally, the carbon carbon double bond is reduced using NADPH again, resulting in a fully saturated C-C bond.
- Then these carbons are transferred to the growing acyl chain on the cystein sulfur, and the next malonyl CoA binds to the phosphopantetheinyl sulfur to repeat the process.
- THis continues until 16 carbons have been added to the chain and you get palmitate.
What important cofactor does FAS use?
NADPH (in two steps–the reduction of the keto group to the alcohol, and the reduction of the C-C double bond for form the saturated single bond.)
What bring in the omega carbon for the fatty acid chain?
THe omega carbon comes in on acetyl CoA (remember that the intial carbons come from acetyl CoA, and the subsequent carbons come from malonyl CoA(
For every malonyl CoA that enters FAS, what happens to its omega carbon?
What happens to its alpha carbon?
The omega carbon is lost as carbon dioxide in the first decarboxylation.
The alpha carobn is added to the chain that eventually becomes palmitate.
What is the final product of FAS?
An acyl chain that is 16 carbons long–palmitate
After being synthesized by FAS, palmitate can undergo 2 more forms of processing. WHat are they?
Elongation
Unsaturation
How is palmitate (in the form of palmitoyl CoA) elongated?
Palmitoyl CoA is elongated, 2 carbons at a time, in the ER.
This is a very similar process to the FAS process, only it occurs in the ER and uses different enzymes.
Malonyl CoA donates the two carbons, and the added keto group undergoes the same reduction, dehydration, and reduction to produce a saturated fatty acyl chain.
How can the body unsaturate the carbon carbon bonds in fatty acid chains?
THe body can unsaturate CC bonds if they are AT LEAST 9 CARBONS AWAY from the omega end.
This is because the enzyme that does this binds to the CoA (remember–it’s the big handle) on the alpha carbon. This means it won’t be able to reach the carbons that are within 9 carbons from the omega carbon.
Why is it so important that we get linoleic (18:2 9,12) and linolenic (18:39,12,15) acid in our diet?
Because we need to use them as precursors for the signalling molecules that need those unsaturated bonds that far down the chain–our body can’t introduce unsatrated bonds between carbons that are less than 9 carbons away from the omega end.
What is a glycerophospholipid?
Name 4 common glycerophospholipids
How are ether glycerolipids (plasmalogens) different from glycerolipids?
How can lipid concentrations be used to determine gestational age?
Lung surfactants are made from lipids, including dipalmitoylphosphatidylcholine (the most important one) and sphingomyelin.
The ratio of these two lipids in amniotic fluid is an indicator of gestational progress.
Early on during gestation, dipalmitoylphosphatidylcholine and sphingomyelin are produces at similar levels, but over the course of development, dipalmitoylphosphatidylcholine becomes much more prevalent.
What is the effect of leptin release from adipocytes?
When is it released?
What receptors does it use to alter beheavior?
Leptin is a satiety hormone.
When TG levels are high, leptin secretion increases.
Leptin acts through JAK/STAT receptors in the hypothalamus, leading to the release of anorexigenic factors that depress appetite.
With leptin binding, the Jak receptor is phosphorylated. This phosphotrylates STAT molecules, which dimerize, enter the nucleus and act as transcription factors.
