Cholesterol

Cholesterol

A critical component of biological membranes and the body:

• It maintains proper fluidity of animal cell membranes

• It is the precursor of steroid hormones such as progesterone, testosterone, estradiol, and cortisol

Synthesized in the liver and, to a lesser extent, in other tissues:

• The rate of its synthesis is highly responsive to its cellular level

• All 27 carbon atoms of cholesterol are derived from acetyl CoA in a three-stage synthetic process

Stage 1 of Cholesterol Synthesis:

• takes place in the cytoplasm

• the formation of isopentenyl pyrophosphate from acetyl-CoA

• starts with the formation of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) from acetyl CoA and acetoacetyl CoA.

• HMG CoA is reduced to mevalonate for the synthesis of cholesterol.

• Mevalonate is converted into 3-isopentenyl pyrophosphate in three consecutive reactions requiring ATP

• ends with the production of isopentenyl pyrophosphate, an activated five-carbon isoprene unit

Committed and Rate Limiting Step in Cholesterol Synthesis

The synthesis of mevalonate by 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase)

HMG-CoA Reductase

• enzyme that reduces HMG CoA to mevalonate

• the key control site in cholesterol biosynthesis

• controlled in multiple ways

• Statins resemble mevalonate and therefore reduce cholesterol synthesis

The Synthesis of Mevalonate

Initiates the synthesis of cholesterol

The first stage in the synthesis of cholesterol:

the formation of mevalonate by HMG-CoA reductase, the committed step in cholesterol synthesis

Mevalonate

gets converted into isopentenyl pyrophosphate, an activated isoprene

What is the end result of Stage 1 in Cholesterol Synthesis

the production of isopentenyl pyrophosphate, an activated five-carbon isoprene unit

Stage 2 of Cholesterol Sythesis:

1. Isopentenyl pyrophosphate isomerizes to dimethylallyl pyrophosphate

2. The two isomer C5 units (one of each) condense to begin the formation of squalene (30 carbons)

Squalene

synthesized from isopentenyl pyrophosphate

Stage 3 of Cholesterol Synthesis:

1. Squalene is first activated by conversion into squalene epoxide in a reaction that uses O2 and NADPH.

2. Squalene epoxide is then cyclized to lanosterol.

3. Lanosterol (C30) is subsequently converted into cholesterol (C27) in a multistep process, during which three carbon units are removed.

Liver

the primary site of cholesterol synthesis, although most tissues synthesize some cholesterol

Acetyl CoA

The basic molecule for cholesterol synthesis

Cholesterol synthesis occurs in three stages:

1. Isopentenyl pyrophosphate is synthesized from mevalonate.

2. Six molecules of isopentyl pyrophosphate condense to form squalene.

3. Squalene cyclizes and is converted into cholesterol.

• Stage 1 occurs in the cytoplasm and stages 2 and 3 in the endoplasmic reticulum.

Fates of Cholesterol After Synthesis

In vertebrates, most cholesterol is synthesized in the liver, then exported:

• Exported as bile acids, biliary cholesterol, cholesteryl esters, or as lipoproteins.

Physical Properties of Cholesterol and Phospholipids

• They are amphipathic molecules

• Phospholipids are reasonably soluble in water

• A significant proportion of cholesterol
  structure prefer not to be associated with water

Physical Properties of Triglycerides

They are generally hydrophobic:

• They have essentially no solubility in water