Lipid Synthesis Lecture Spe 3 Flashcards Preview

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Flashcards in Lipid Synthesis Lecture Spe 3 Deck (69):
1

 

 

What is the main storage form of fatty acids in the body?

 

Triagylglycerols (TG)

2

 

 

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.

3

 

 

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.

4

 

In order for fatty acid synthesis to occur, what two reactions acting on pyruvate need to occur?

1. You need pyruvate converted to acetyl CoA through PDH.

2. 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.

5

 

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

6

 

 

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

7

 

 

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.

8

 

 

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.

9

 

 

What enzyme converts malate back to pyruvate in the pyruvate/malate cycle?

malic enzyme, using NADP as a cofactor

10

 

What enzyme converts oxaloacetate to malate?

malate dehydrogenase, using NADH as a cofactor

11

 

 

The pyruvate/malate cycle has two function in lipogenesis (fatty acid synthesis). What are they?

 

1. Transport acetyl CoA from the mitochodnria to the cytosol.

2. Malic enzyme generates NADPH to power fatty acid synthesis. Malate dehydrogenase regenerates NAD+ to keep glycolysis going so citrate can still be produced.

12

 

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.

13

 

 

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.

14

 

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.

15

 

 

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.

 

 

16

 

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

17

 

 

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.

18

 

 

Fatty acid synthase is a large enzyme with multiple acitvities. It has two important binding sites involving sulfer. WHat are they?

 

1. A sulfur from a phosphopantetheinyl group covalently linked to a serine residue on the acyl carrier protein subunit of FAS.

2. A sulfur from a cystein side chain on another protein subunit of FAS

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19

 

Going beyond bond formation, reduction, dehydration, and reduction....

what are the steps of fatty acid synthesis?


1. 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

2. Then the keto gruop is reduced to an alcohol, with NADPH oxidation powering the reaction.

3. In the third step, a dehydration reaction removes water and introduces a C-C double bond

4. finally, the carbon carbon double bond is reduced using NADPH again, resulting in a fully saturated C-C bond.

5. 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.

6. THis continues until 16 carbons have been added to the chain and you get palmitate.

20

 

 

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.)

21

 

 

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(

22

 

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.

23

 

 

What is the final product of FAS?

An acyl chain that is 16 carbons long--palmitate

24

 

 

After being synthesized by FAS, palmitate can undergo 2 more forms of processing. WHat are they?

 

 

Elongation

 

Unsaturation

25

 

 

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.

26

 

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.

27

 

 

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.

28

 

 

What enzyme introduces unsaturated double bonds into fatty acid tails?

 

Fatty acyl CoA desaturase

29

 

 

Fatty acyl CoA desaturate intoruces C-C double bonds in fatty acid tails. What is the eventual electron acceptor in this oxidation reaction?

 

Where does the energy from this reaction come from? aka....what's the cofactor?

 

Molecular oxygen.

 

THe energy to do this comes from NADH, which drives a complex including different cytochrome proteins that transfer the electrons ultimately to fatty acyl CoA desaturase, which will then place them on O2.

30

 

What do we use linoleic and linolenic acid to make in the body?

 

What is it used for in the body?

 

We use linolenic acid consumed in the diet to make arachidonic acid.

 

Arachidonic acid is a precursor for prostaglandins, which are important hormones.

31

 

 

How do we convert linolenic acid to arachidonic acid?

 

Arachidonic acid has 4 double bonds, and linoleic acid has 2, so we just need to introduce 2 more. Remember that we wont be able to add them to the omega side, we'll have to add them to the alpha side.

The body takes linolenic acid, esterifies it to a handle to form linoleoyl CoA.

Linoleoyl CoA is oxidized by a desaturase, which adds a third double bond in.

Then an elongation step occur, with malonyl CoA adding 2 more carbons to the alpha end...

And then the now longer lineleoyl CoA is oxidized again by a second desaturase, to form arachidonyl CoA that has 4 unsaturated CC double bonds.

 

NADH provides the energy for both oxidation steps.

32

 

 

What has to happen to the fatty acids after they're synthesized in the liver?

Why?

They need to be packaged because they're hydrophobic and therefore insoluble.

33

 

 

What are the four types of "globules" we use to package fatty acids that were synthesized in the liver?

 

Triacylglycerides

glycerophospholipids

ether phospholipids

sphingolipids

34

 

 

What makes up triacylglycerol?

What is the source of the backbone?

TG is made up of three fatty acyl chains linked to a glycerol backbone.

 

The glycerol backbone comes from Glycerol 3-phosphate (usually from dihydroxyacetone phosphate (DHAP) which undergoes a reduction to form glycerol 3-phosphate with the enzyme glycerol 3 phosphate dehydrogenase)

35

 

 

Why can the storage of fatty acids in adipose tissue only occur if glycolysis is going on?

Because FA stored in adipose tissue is stored as TG, and the backbone for TG is glycerol provided by glycerol 3-phosphate (which is an intermediate of glycolysis, or produced from DHPA, another intermediate of glycolysis)

36

 

There are two ways to generate the glycerol 3-phosphate to use as the backbone for triacylglycerol. WHat are they?

1. Glycolysis production of DHAP, which can be reduced to form lycerol 3-phosphate.

2. The liver has an enzyme called glycerol kinase which can take old glycerol that has had its fatty acid tails removed during lipolysis, and rephosphorylate it to produce glycerol 3 phosphate.

37

 

 

The liver has the capacity to use recycled glycerol to form triacylglycerols because it has glycerol kinase (which phosphorylates glycerol to make glycerol 3-phosphate).

What does this mean in terms of futile cycling for the liver?

 

The liver has the capacity for futile cycling because it does not need glycolysis to occur in order to undergo fatty acid synthesis. It needs fatty acid tails being cleaved off the glycerol backbone.

This means it is often underoing fatty acid oxidation and fatty acid synthesis at the same time.

This would be a bad thing for all the cells in our body to do, but it's actually necessary for the liver at times because the liver has important biosynthesis functions (such as making fatty acid signalling molecules like arachidonic acid for prostaglandins) regardless of whether the body is in the fed or fasted state.

38

 

 

How is TG synthesized?

1. Two molecules of pamitoyl CoA are esterified to the 2 hydroxyl groups on glycerol 3-phosphate to make phosphatidic acid (releasing 2 CoASH)

2. A phosphatase then removes the phosphate group as Pi, resulting in the formation of a third hydroxyl group on the glycerol, giving us diacylglycerol

3. A third molecule of pamitoyl COA attacks the hydroxyl on diacylglycerol, to form triacylglycerol

39

 

 

What happens to TG synthesized in the liver?

 

In other words, how does TG synthesized in the liver get transported to other tissues, either for oxidation or storage?

 

 

In the Golgi of hepatocytes, the newly synthesized TGs are packaged with apoprotein B-100 to become very low density lipoproteins (VLDL).

These form secretory vesicles which fuse with the plasma membrane and release the VLDL into the blood.

VLDLs will circulate in the blood and then react with lopoprotein lipase (LPL) at the lumen of the capillary endothelial cells.

LPL cleaves off the fatty acid, which then enter the cells--either for beta oxidatoin in working cells or for storage in adipocytes.

40

 

 

In the golgi of hepatocytes, TGs are packaged with what?

 

They're packaged with apoprotein B-100 to form VLDL, so that the TG can leave the liver and enter the blood to go to other cells.

41

 

 

How do muscle cells and adipocytes get fatty acids from TG (synthesized in the liver) inside their cytosol?

They have lipoprotein lipases (LPL) on the exterior, which will cleave the fatty acids off of VLDL, transport them into the cell.

In the muscle cells the FA will undergo oxidation for fuel.

In adipocytes, the FA will be reesterified to glycerol 3=phosphate to make TG for storage.

42

 

 

After lipoprotein lipase (LPL) cleaves the fatty acids off VLDL-TG, what happens to the glycerol that's leftover?

 

It can be receyled in the liver and either phosphorylated to make new glycerol #-phosphate or it can be used for gluconeogenesis. Or it can be oxidized in glycolysis to make pyruvate.

43

 

How are dietary fatty acids handled differently than stored fatty acids?

DIetary fatty acids don't go to the liver initially.  THey're packaged in particles called chylomicroms, which then brings the fatty acids from the gut epithelial cells through the lymphatic vessel before they get dumped into the blood. This bypasses the liver.

After that, chylomicrons do the same thing as VLDL-TG--they travel through the blood to various tissues where they deliver their fatty acids and then get recycled.

44

 

 

When the TG is consumed off a chylomicron, what is left over?

Where does it go to be receycled?

 

A remnant.

It goes to the liver to be recycled.

45


WHat happens to VLDL after it's TG is removed by LPL?

 

 

It becomes an intermediate density lipoprotein, then it's converted to a low density lipoprotein that can be recycled int he liver.

46

 

What is a glycerophospholipid?

 

 

A phospholipid that is similar to TG, but with a head group attached to the first carbon with a phosphate bond.

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47

Name 4 common glycerophospholipids

phosphatidylcholine

phosphatidylethanolamin

phosphatidylserine

phosphatidylinositol biophosphate

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48

 

Where are glycerophospholipids typically used in the body?

THeir primary role is in cell membranes, but they are also contituents of the lipoproteins, bile, and lung surfactant.

49

 

How are glycerophospholipids synthesized?

Similar to TG synthesis....

It starts with fatty acids being esterified to the two palmitoyl CoA molecules on glycerol 3-phosphate, giving phosphatidic acid.

Then, instead of having the phosphatases remove the phosphate group to make a third hydrosyl, you get the addition of a head group onto the phosphate group.

50

 

 

What do glycerophospholipids used as a backgone?

glycerol

51

 

How is the head group added onto the phosphate group to make a glycerophospholipid?

 

1. THe head group is first activated by linking it to a cytosine diphosphate, releasing Pi

For example: choline + CTP -----> CDP-choline

2, The CDP-choline can use the energy from its bond to esterify onto the phosphate group on the diacylglycerol backbone, yielding the glycerophospholipid

example: diacylglycerol + CDP-choline ----> phosphatidylcholine

52


Phosphatidylethanolamin (with CH2-Ch2-N+H3 on the phosphate group) can be modified to form phosphatidylcholine and phosphatidylserine. How?

Phosphatidylethanolamine can be converted to phosphatidylcholine through the addition of 3 SAM

 

It can be converted to phsophatidylserine by kicking off the ethanolamine with a serine AA.

53

 

 

How is cardiolipin formed?

What membrane is it a component of?

 

Cardiolipin is formed by linking phosphaidyl glycerol (which is a glycerophosphate with a glycero head group) with CDP-diacylglycerol.

This essentially gives a higher order structure invovling not 1, but 3 glycerol backbones with their associated fatty acids.

 

It is a major component of the inner mitochodnrial membrane, and is responsible for giving its impermeability

54


How is phosphatidyllinositol synthesized? it's slightly different than the other glycerophospholipid synthesis and more like cardiolipin synthesis.

It's different than the other glycerophospholipid synthesis because it starts with a CDP-diacylglycerol, which is then added to an inositol to form phosphatidylinositol

This is the difference: for the others, it's the head group that's put on CDP, not the backbone.

55

 

 

What enzyme cleaves phosphatidlylinositol to produce the second messengers DAG and PI3?

 

Phospholipase C

56

 

How are ether glycerolipids (plasmalogens) different from glycerolipids?

They have an ether linkage to the number 1 carbon of the glycerol backbone

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57

 

WHere does the ether linke come from in ether glycerolipids?

From DHAP, a glycolysis intermediate.

58

 

Name 2 important ether glycerolipids (plasmalogens)

1. Ethanolamine Plasmalogen is a component of the myelin sheath of neurons

1. Platelet activating factor is a plasmalogen with choline as a head group, and mediates allergic responses

59

 

Sphingolipids have a special backbone. WHat is it?

Ceramide instead of glycerol.

Ceramide is derived from serine and palmitoyl CoA, synthesized in the ER and exported to the golgi for sphingolipid synthesis.

60

 

 

What is the most important sphingolipid in the body? WHa tis is used for?

Sphingomyelin

 

It's present in the myelin sheath of nerve fibers. The head group is choline.

61

 

Cerebrosides are sphingolipids with ceramide as the backbone. What is the head group?

 

Glucose or galactose attached to the hydroxymethyl group

62

 

What is the head group of the sphingolipid gangliosides?

They have oligosaccharides plus saliacic acid (NANA)

63

 

 

What make globosides special among the sphingolipids?

 

 

They have two or more sugars

64


What lipid makes up the most abundant lung surfactant?

Dipalmitoylphosphatidylcholine

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65

 

 

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.

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66

 

What two hormones related to appetite and metabolism are released from acipocytes?

leptin

adiponectin

67

 

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.

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68

 

What is the effect of adiponectin release from adipocytes?

It's complementary to leptin, but acts in a different way.

Adiponectin signals to cells through ADIPOR1 and ADIPOR2 receptors. When these receptors are activated, they activate AMP-K and PPAR, both of which can inhibit ACC, leading to suppression of fatty acid synthesis and increased fatty acid oxidation.

 

So when you have excess TG floating around, you want to supress synthesis and increase fatty acid oxidation.

 

69

 

What satiety hormone is decreased in Obesity?

What does this lead to?

Adiponectin is decreased.

 

This means you lose the satiety signal from adiponectin and you continue to store fat even though you already have abundant fatty acid stores.