Structural Biochemistry/Lipids/Biosynthesis of Cholestrol

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Cholestrol is an important component of biological membranes. It is a steroid that regulates cell membrane fluidity. Its biosynthesis is a fundamental process in extending carbon skeletons beyond five units of carbon. Steroid hormones are derived from cholestrol.

The Biosynthesis of Cholestrol

All the carbons in cholestrol come from acetyl coenzyme A in the following synthesis, summarized in three steps:

1. Isopentenyl pyrophosphate is synthesized.
2. Six molecules of isopentenyl pyrophosphate are condensed into a squalene.
3. The squalene cyclizes and converts into cholestrol.

Complex Regulation of Cholestrol Biosynthesis

Cholestrol synthesis is through de novo reactions, or through uptake in the diet. Synthesis mainly occurs in the liver, and the rate of it is highly regulated by feedback of 3-hydroxy-3-methylglutaryl coenzyme A reductase. When there is too much cholestrol, it is expelled as a lipoprotein of very low density. The four mechanisms of regulation are summarized in the following list:

1. Sterol regulatory element binding protein (SREBP) controls the rate of syntehsis of reductase mRNA.
2. Nonsterol metabolites inhibit the rate of translation of reductase mRNA.
3. There is high control of reductase degradation. The membrane domain can alter its oligomerization state to increase proteolysis.
4. Reductase activity is decreased by phosphorylation. Synthesis of cholestrol will therefore stop when ATP is running low.

So What?

The biosynthesis and metabolism of cholestrol is important because cholestrol is a necessary component of blood. Diseases involving the regulation of cholestrol cause significant problems. Examples of these diseases include familial hypercholestrolemia, which results to high levels of cholestrol in the blood. This may result in the presence of cholestrol deposits in the blood, which in severe cases may cause childhood heart attacks.

Cholestrol is also a major component of of bile salts, which are needed to digest lipids. Many steroid hormons also come from cholestrol. The five main classes of these are androgens, glucocorticoids, mineralocorticoids, estrogens, and progestagens.

Source: Berg, Jeremy and Stryer, Lubert. Biochemistry: Fifth Edition. United States of America: W.H. Freeman and Company, 2002.