Cholesterol Synthesis

What is the main organ of cholesterol synthesis?

liver

T/F: cholesterol is the precursor to many steroid hormones

true

How many C atoms are in cholesterol?

27

What are the components of the biosynthesis of cholesterol?

• acetyl CoA

• NADPH

• enzymes

What are the sources of Acetyl CoA?

• glucose → pyruvate → acetyl CoA (TCA cycle stage 1)

• beta oxidation of fatty acid

• AA breakdown

The enzymes involved in the biosynthesis of cholesterol are located in the:

cytosol and endoplasmic reticulum (ER)

What are the reasons for cholesterol synthesis?

• low levels of cholesterol in the cell

• regulatory pathways involved:

  • enzyme catalyzed rxns

• cholesterol is synthesized

  • synthesis switched off once desired cellular levels are reached

  • cholesterol exerts negative feedback on pathway enzymes

What is the rate limiting step in cholesterol synthesis?

HMG CoA reductase

• catalyzes formation of HMG CoA → mevalonic acid

What is the role of HMG CoA?

1. 2 acetyl CoA condense to form acetoacetyl CoA

   • enzyme: beta-ketothiolase

2. another acetyl CoA linked to acetoacetyl CoA → HMG CoA

   • enzyme: HMG CoA synthase

HMG CoA synthase catalyzes what reactions?

• ketone body synthesis

• cholesterol synthesis

Describe the synthesis of mevalonate

• REDUCTION of HMG CoA → mevalonate

  • rate limiting step

  • enzyme: HMG CoA reductase

• mevalonate exerts neg feedback

• further converts to form IPP

  • isoprene unit

Describe the synthesis of isoprene

1. melavonate → 5-pyrophosphomevalonate

2. 5-pyrophosphomevalonate decarboxylated to isopentyl pyrophosphate (IPP)

   • 5C isoprene unit is important in the synthesis of medicinal natural products

Describe the synthesis of isoprene to Lanosterol

1. IPP → squalene

2. squalene → lanosterol

Describe the synthesis of lanosterol to cholesterol and CE

1. lanosterol → cholesterol (final product)

2. cholesterol → cholesterol esters (CE)

   • enzyme: acyl-CoA cholesterol acyltransferase (ACAT)

How is cholesterol “protected” in the CE form?

• prevents oxidation of secondary alcohols

• CE is hydrolyzed to obtain cholesterol

What kind of reaction is the rate limiting step in the synthesis of cholesterol?

redox rxn

What is the role of statins?

• lowers cholesterol

• competitive inhibitors of HMG CoA reductase

  • suppresses synthesis of cholesterol

What enzyme catalyzes the reduction of dihydroxyacetone phosphate to G3P? Where does this reaction occur?

• G3P dehydrogenase

• liver and adipose tissue

The major carrier(s) of dietary fat from the intestine is/are:

chylomicrons

HMG CoA is synthesized from acetyl CoA and:

acetoacetyl CoA

Cholesterol is synthesized from:

acetyl-CoA

How does the number of carbon atoms change upon synthesis of cholesterol starting from mevalonate?

C₆ → C₅ → C₁₀ → C₁₅ → C₃₀ → C₂₇

The committed step in cholesterol formation is the synthesis of:

mevalonate

Which compound is NOT an intermediate in the synthesis of lanosterol from acetyl-CoA?

a. malonyl CoA

b. squalene

c. mevalonate

d. IPP

malonyl CoA

Which compound(s) is derived from a sterol?

bile salts

A 30-carbon precursor of the steroid nucleus is:

squalene or lanosterol

Feedback regulation of cholesterol synthesis is mainly controlled at the step catalyzed by the enzyme:

3-hydroxy-3-methylglutaryl (HMG) CoA reductase.

Which contains the highest percentage of cholesteryl esters?

LDL

List all the intermediates involved in the synthesis of cholesterol in order.

1. Acetyl CoA (C2)

2. acetoacetyl CoA (C4)

3. HMG CoA (C6)

4. Mevalonate (C6)

5. IPP (C5)

6. squalene (C30)

7. lanosterol (C30)

8. cholesterol (C27)