Biosynthesis of Cholesterol

Cholesterol is not required in the diet

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• Cholesterol is an essential molecule but is not required in the diet because all cells can synthesize it from simple precursors

Cholesterol is made from acetyl-CoA in four stages

• all of its carbon atoms are provided by a single precursor – acetate

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Stage 1

• Three acetate units condense to form a six carbon intermediate, mevalonate

• Two molecules of acetate-CoA condense forming acetoacetyl-CoA.

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• Acetoacetyl-CoA condenses with acetyl-CoA to yield β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)

• The final step the reduction of HMG-CoA to mevalonate, catalyzed by HMG-CoA reductase.

Stage 2

• Conversion of mevalonate into activated isoprene units

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• Isoprene containing molecules are important intermediates in cholesterol biosynthesis

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Mevalonate is phosphorylated by 2 sequential P_i transfers from ATP, yielding the pyrophosphate derivative.

ATP-dependent decarboxylation, with dehydration, yields isopentenyl pyrophosphate.

Isopentenyl Pyrophosphate Isomerase inter-converts isopentenyl pyrophosphate & dimethylallyl pyrophosphate.

Mechanism: protonation followed by deprotonation.

Stage 3

• Polymerization of six 5-carbon isoprene units to form the 30-carbon linear structure of squalene.

Each condensation involves a carbocation formed as PP_i is eliminated.

Squalene Synthase: Head-to-head condensation of 2 farnesyl pyrophosphate, with reduction by NADPH, yields squalene.

Stage 4

• Cyclization of squalene forms the four rings of the steroid nucleus. Subsequent modifications leads to the final product, cholesterol.

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Conversion of lanosterol to cholesterol involves 19 reactions, catalyzed by enzymes in ER membranes.

Additional modifications yield the various steroid hormones or vitamin D.

The regulation of cholesterol biosynthesis

• Cholesterol synthesis is a complex, energy-expensive process and is regulated at various levels

The activity of HMG-CoA reductase regulates cholesterol biosynthesis

• The rate limiting step in the pathway to cholesterol is catalyzed by HMG-CoA reductase
• Its activity is modulated over a 100-fold range

Most of the cholesterol made in the liver is exported

• Much of cholesterol synthesis takes place in the liver
• Most is exported

Cholesterol is exported in two forms

1. Bile salts – amphipathic cholesterol derivatives that aid lipid digestion

2. Cholesteryl esters – transported and secreted in

lipoprotein particles to other

tissues that use cholesterol

or are stored in the liver

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Cholesteryl ester formation

Formed in the liver

Converting cholesterol to a more hydrophobic form

Cholesterol transport: the problem

• Cholesterol and cholesteryl esters are essentially insoluble in water
• These molecules must be moved from the tissue of origin to the tissues in which they are stored or are consumed

Cholesterol transport: the solution

• Cholesterol and cholesteryl esters are carried in the blood plasma from one tissue to another as plasma lipoproteins

Degradation of cholesterol

• The ring structure of cholesterol cannot be metabolized to CO₂ and H₂0 in humans
• The intact sterol ring is eliminated from the body by:
• Conversion to bile acids, which are excreted in feces
• Secretion of cholesterol into the bile, which transports it to the intestine for elimination

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Steroid hormones are formed from cholesterol

• All steroid hormones are derived form cholesterol
• In the cortex of adrenal glands two classes of hormones are synthesized – mineralocorticoids and glucocorticoids
• In the male and female gonads – sex hormones are produced
• Sex hormones include – progesterone, androgens and estrogens

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