Lipid Synthesis - General

Question 1

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

Answer 1

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.

Question 2

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

Answer 2

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).

Question 3

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

Answer 3

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

Question 4

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

Answer 4

Phosphatidate.

Question 5

How is phosphatidate synthesized?

Answer 5

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

Question 6

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?

Answer 6

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.

Question 7

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?

Answer 7

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

Question 8

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

Answer 8

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

Question 9

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

Answer 9

Amphiphilic

Question 10

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

Answer 10

Endoplasmic reticulum, phosphatidate.

Question 11

During lipid synthesis, one of the components is _____.

Answer 11

Activated

Question 12

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

Answer 12

Cytidine diphosphate (CDP).

Question 13

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

Answer 13

Diacylglycerol or the alcohol group.

Question 14

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

Answer 14

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

Question 15

In what organisms does synthesis using an activated diacylglycerol occur?

Answer 15

Primarily in yeast and bacteria.

Question 16

In what organisms does synthesis from an activated alcohol occur?

Answer 16

Mammals.

Question 17

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

Answer 17

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

Question 18

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

Answer 18

Ethanolamine, CDP-ethanolamine.

Question 19

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

Answer 19

Phosphatidylcholine, 50% of membrane mass.

Question 20

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?

Answer 20

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.

Question 21

Why is cholesterol an important molecule? (2)

Answer 21

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

Question 22

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

Answer 22

Acetyl CoA. All 27.

Question 23

Where does the synthesis of cholesterol occur?

Answer 23

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

Question 24

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

Answer 24

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.

Question 25

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

Answer 25

The intracellular concentration of cholesterol.

Question 26

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

Answer 26

HMG-CoA reductase

Question 27

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

Answer 27

1. **C****holesterol**in the cell regulates the**transcription 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.

Question 28

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

Answer 28

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**.

Question 29

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

Answer 29

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.

Question 30

What is the general structure of a lipoprotein particle?

Answer 30

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.

Question 31

How are lipoproteins classified? What are the 4 classes?

Answer 31

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). ​

Question 32

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

Answer 32

Chylomicrons

Question 33

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

Answer 33

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.

Question 34

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

Answer 34

Low density lipoproteins

Question 35

How is cholesterol packaged in LDLs?

Answer 35

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.

Question 36

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?

Answer 36

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

Question 37

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.

Answer 37

High density lipoprotein

Question 38

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

Answer 38

1. Steroid hormones 2. Bile acids 3. Vitamin D

Question 39

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

Answer 39

1. Estradiol 2. Progesterone 3. Testosterone 4. Mineralocorticoids 5. Glucocorticoids

Question 40

What is the main role of mineralocorticoids vs glucocorticoids?

Answer 40

**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.

Question 41

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

Answer 41

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.

Question 42

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

Answer 42

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