Lipid Synthesis - General Flashcards

1
Q

Triacylglycerol and phospholipids both have a _____ backbone, to which several _____ are linked. What is the difference between the connections?

A

Glycerol, fatty acids.

  1. Triacylglycerol: three fatty acids are linked to each of the three carbon atoms of glycerol.
  2. Phospholipids: two fatty acids linked to carbons 1 and 2 of glycerol, while a phosphate group and one of several different head groups are linked to carbon 3.
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2
Q

_____ is a common precursor for both classes of lipids. What can it be derived from?

A

Glycerol-3-P. It can be derived either from glycerol released from adipose when triacylglycerol is degraded (in liver only), or from the conversion of dihydroxyacetone phosphate (in liver and other tissues).

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3
Q

Where in the body does triacylglycerol synthesis occur? Where does phospholipid synthesis occur?

A

Triacylglycerol synthesis only occurs in liver and adipose, whereas phospholipid synthesis occurs in all cells since they are major components of membranes.

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4
Q

A molecule called _____ is the precursor for both triacylglycerol and phospholipids, and is synthesized from glycerol-3-P.

A

Phosphatidate.

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5
Q

How is phosphatidate synthesized?

A

The synthesis of phosphatidate from glycerol-3-P consists of two consecutive additions of a fatty acid (using an acyl-CoA derivative) to carbon 1 and then to carbon 2, via ester linkages.

  • A saturated fatty acid is usually linked to carbon 1.
  • An unsaturated fatty acid is usually linked to carbon 2.
  • Carbon 3 has the phosphate group attached to it, which will facilitate the addition of different head groups to form different phospholipids
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6
Q

Synthesis of triacylglycerol from phosphatidate is a two-step process. What enzyme catalyzes this reaction? Where is it located in the cell? What are the two steps?

A

Triacylglycerol synthetase complex that is located on the ER membrane.

  1. In the first step, the phosphate group is cleaved off to form diacylglycerol,
  2. In a second step the third fatty acid is linked to carbon 3 to form triacylglycerol.
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7
Q

Under normal condtions, where is most of the triacylglycerol that is synthesized in the liver sent to (2)? What purpose does it serve in these tissues?

A

Either the muscle to be used as fuel or the adipose to be stored for future needs.

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8
Q

Common membrane phospholipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol, are all very similar in structure, but differ from each other in what way?

A

Differ in the head group attached to the phosphate group on carbon 3 of the glycerol backbone.

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9
Q

Phospholipids are _____ molecules, having a very non-polar region due to the two fatty acid chains and a highly polar head group.

A

Amphiphilic

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10
Q

Phospholipid synthesis takes place in the _____ and uses _____ as a precursor to which an alcohol is linked (ethanolamine, choline, or serine).

A

Endoplasmic reticulum, phosphatidate.

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11
Q

During lipid synthesis, one of the components is _____.

A

Activated

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12
Q

In the case of lipid synthesis, the activated precursor is a derivative of what?

A

Cytidine diphosphate (CDP).

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13
Q

In the case of lipid synthesis, either the _____ or the _____ may be linked to CDP to activate it, depending on the reactant.

A

Diacylglycerol or the alcohol group.

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14
Q

Phospholipid synthesis from an activated diacylglycerol is accomplished by linking what two things? Describe this reaction (3 steps).

A

A cytidine diphosphate (CDP) molecule to a phosphatidate, forming CDP-phosphatidate

Reaction:

  1. Phosphatidate reacts with CTP to form CDP-diacylglycerol.
  2. The pyrophosphate (PPi) released is quickly hydrolyzed in the cell to two Pi; the energy released from this hydrolysis drives this reaction strongly forward.
  3. CDP-diacylglycerol then reacts with an alcohol such as choline to form the phospholipid with the release of CMP
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15
Q

In what organisms does synthesis using an activated diacylglycerol occur?

A

Primarily in yeast and bacteria.

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16
Q

In what organisms does synthesis from an activated alcohol occur?

A

Mammals.

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17
Q

How an activated alcohol formed? The synthesis of what lipid is done by this pathway?

A

The alcohol is activated by linking it to CDP. The synthesis of phosphatidylethanolamine is done by this pathway.

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18
Q

Note that during lipid synthesis from an activated alcohol, _____ rather than diacylglycerol is linked to CDP, and that diacylglycerol reacts with _____.

A

Ethanolamine, CDP-ethanolamine.

19
Q

_____ is the most abundant phospholipid in animals. How much of the membrane mass is it?

A

Phosphatidylcholine, 50% of membrane mass.

20
Q

Both synthesis from an activated diacylglycerol and activated alcohol rely on sufficient dietary _____ being available. Describe the reactions that happen if it isn’t to form phosphatidylcholine. What enzyme is used?

A

Choline. The liver possesses an alternative route for the synthesis of phosphatidylcholine.

Phosphatidylcholine is synthesized from phosphatidylethanolamine by the enzyme phosphatidylethanolamine methyltransferase.

The amino group of ethanolamine is methylated three times using S-adenosylmethionine (SAM) as the methyl donor. This alternative pathway ensures that phosphatidylcholine needs will be met even if choline itself is in limited supply.

21
Q

Why is cholesterol an important molecule? (2)

A
  1. It is a critical component of cell membranes that ensures it has proper fluidity.
  2. It is the precursor for:
    1. Steroid hormones such as estrogen, progesterone, testosterone, and cortisol
    2. Bile salts, which aid in digestion
    3. Vitamin D
22
Q

What is the precursor for cholesterol synthesis? Of the 27 carbons in cholesterol, how many are from this precursor?

A

Acetyl CoA. All 27.

23
Q

Where does the synthesis of cholesterol occur?

A

The synthesis of cholesterol occurs partly in the cytosol and partly in the ER.

24
Q

What are the 4 stages of cholesterol synthesis? Where do the first two occur in the cell? Where do the last two occur?

A
  1. Regulated step, which is the synthesis of mevalonate from three acetyl CoA molecules.
    • Two molecules of acetyl CoA condense to form acetoacetyl CoA in the first step, and then a third acetyl CoA is condensed to form hydroxymethylglutaryl-CoA (HMG-CoA).
    • This molecule is then reduced, using NADPH, to mevalonate by the enzyme HMG-CoA reductase.
  2. Multi-step conversion of mevalonate to an activated isoprene molecule.
  3. Synthesis of squalene from six isoprene units.
  4. Completed synthesis of cholesterol from squalene that includes several cyclization steps to form the rings.
25
Q

What is the primary factor that regulates the synthesis of cholesterol?

A

The intracellular concentration of cholesterol.

26
Q

The regulation of the rate of cholesterol synthesis occurs primarily through _____ which catalyzes the committed step in cholesterol synthesis

A

HMG-CoA reductase

27
Q

What 4 ways is the amount of HMG-CoA reductase and its activity regulated?

A
  1. Cholesterolin the cell regulates thetranscription rate of the gene coding for HMG-CoA reductase.
    • High → transcription rate is slowed.
    • Low → transcription rate of the gene is increased in order to make more mRNA which is translated into HMG-CoA enzyme
  2. The rate of translation of HMG-CoA reductase mRNA is inhibited by high levels of cholesterol.
  3. Cholesterol levels control the degradation rate of the HMG-CoA reductase enzyme. High cholesterol concentrations speed up the degradation rate.
  4. AMPK which inhibits its activity by phosphorylation. This means that cholesterol synthesis is slowed when the energy state of the cell is low.
28
Q

What are statins and how are they used clinically? How does this mechanism work?

A

HMG-CoA reductase inhibitors used to lower plasma cholesterol levels. Statins act as competitive inhibitors of HMG-CoA reductase, meaning that they compete directly with HMG-CoA for binding to the enzyme. Competitive inhibitors almost always share structural similarities with the normal substrate or product for the enzyme target.

29
Q

How does the body transport cholesterol and triacylglycerol throughout the body? Why can’t they just be secreted into the blood?

A

They are packaged into lipoprotein particles which carry these lipids throughout the cell. Since they are both very non-polar molecules, they can’t simply be secreted into the blood in free form.

30
Q

What is the general structure of a lipoprotein particle?

A

The hydrophobic lipids form the core of the particles, while more polar lipids and some proteins, which are more hydrophilic, form the shell, which is in contact with water in the blood.

31
Q

How are lipoproteins classified? What are the 4 classes?

A

Lipoproteins are classified in terms of their density

  1. Very low-density lipoproteins (VLDLs)
  2. Low density lipoproteins (LDLs)
  3. Intermediate density lipoproteins (IDLs)
  4. High-density lipoproteins (HDLs). ​
32
Q

_____ are formed in the small intestine and carry dietary fat (primarily TAG) to adipose and a small amount to the liver.

A

Chylomicrons

33
Q

Starting from the synthesis of triacylglycerol in the liver, give the 5 steps of its transport to other tissues.

A
  1. TAG and cholesterol synthesized in the liver is packaged up initially into VLDL particles.
  2. As the VLDLs circulate in the blood, enzymes in capillaries hydrolyze the TAGs.
    • This releases free fatty acids which are taken up by the cells in the vicinity.
  3. As this proceeds the TAG content decreases in the VLDLs; eventually these particles become IDLs (intermediate density lipoproteins) which can either be processed in the liver to LDLs or directly become LDLs by more TAG being hydrolyzed.
  4. LDLs deliver cholesterol to peripheral cells by binding to a receptor on the surface of cells, termed the LDL receptor.
  5. After binding, the entire LDL particle is endocytosed into the cell, where the cholesteryl esters are cleaved to release free cholesterol.
34
Q

Which type of lipoproteins are the main transport vehicle for cholesterol?

A

Low density lipoproteins

35
Q

How is cholesterol packaged in LDLs?

A

It is in the form of cholesterol ester which has a fatty acid linked to it which can be removed later to produce free cholesterol, there is very little free cholesterol in LDLs.

36
Q

There is a genetic disease called _____, that results from defects in the LDL receptor. What is the result of this disease and what can it cause?

A

Familial hypercholesterolemia. LDL levels (and as a result cholesterol) increase dramatically in the blood, significantly elevating risk of coronary heart disease.

37
Q

A different lipoprotein, termed _____, serves an opposite role for cholesterol transport. It picks up excess cholesterol dumped into the blood (e.g., from cells that have died) and brings them back to the liver.

A

High density lipoprotein

38
Q

What 3 things did we mention cholesterol serving as a precursor for?

A
  1. Steroid hormones
  2. Bile acids
  3. Vitamin D
39
Q

Name the 5 sex-hormones and corticoids produced by cholesterol.

A
  1. Estradiol
  2. Progesterone
  3. Testosterone
  4. Mineralocorticoids
  5. Glucocorticoids
40
Q

What is the main role of mineralocorticoids vs glucocorticoids?

A

Mineralocorticoids are steroids that act on the kidney to regulate blood pressure and salt balance (e.g., aldosterone).

Glucocorticoids (e.g., cortisol) regulate certain metabolic pathways as well as inhibit inflammation.

41
Q

What 2 things happen during the synthesis of steroid hormones from cholesterol? What do both of these modifications serve to do?

A

The cholesterol is cleaved at of some or all of the sidechain carbons linked to carbon 17 on the D-ring, as well as oxidation. This oxidation takes the form of additional hydroxyl or keto groups being added.

Both of these modifications serve to increase the hydrophilic nature of the molecules, which aids in their ability to be transported via the blood.

42
Q

Anabolic hormones are all based on the structure of _____. What 2 activities does this hormone have?

A

Testosterone.

  1. An anabolic activity which is responsible for the growth of lean muscle mass
  2. And an androgenic activity, which is responsible for the development of male characteristics such as male-pattern balding, growth of facial and chest hair, deepening of voice, etc
43
Q
A