How Is Cholesterol Synthesized? - University of Rajshahi

Cholesterol Biosynthesis

Md. Abdur Rakib, PhD Associate Professor

Dept . of Biochemistry and Molecular Biology

University of Rajshahi

Cholesterol Biosynthesis Cholesterol Biosynthesis

Occurs primarily in the liver

Precursor of bile acids and steroid hormones, and vitamin D

The most prevalent steroid in animal cells is cholesterol

Cholesterol Biosynthesis Cholesterol Biosynthesis

Chemistry of Cholesterol

All steroids are made from cholesterol. The rings are called "hydrocarbon" rings because each corner of the ring is composed of a carbon atom, with two hydrogen atoms extending off the ring. The combination of the steroid ring structure and the hydroxyl (alcohol) group classifies cholesterol as a "sterol."

Cyclopentane perhydro phenanthrene

Vitamin D

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Steroid Hormones

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Synthesis takes place in four stages

1. Condensation of three acetate units to form a six-carbon intermediate, mevalonate;

2. Conversion of mevalonate to activated isoprene units;

3. Polymerization of six 5-carbon isoprene units to form the 30-carbon linear squalene; and 4. Cyclization of squalene to form the four rings of the steroid nucleus,

with a further series of changes (oxidations, removal or migration of methyl groups) to produce cholesterol.

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Formation of mevalonate from acetyl-CoA.

The origin of C-1 and C-2 of mevalonate from acetyl-CoA is shaded light red

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Conversion of mevalonate to activated isoprene units.

Six of these activated units combine to form squalene.

The leaving groups of 3-phospho-5-pyrophosphomevalonate are shaded light red. The bracketed intermediate is hypothetical.

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Formation of squalene.

This 30-carbon structure arises through successive condensations of activated isoprene (five-carbon) units.

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Cholesterol is synthesized from squalene via lanosterol.

The primary route from lanosterol involves 20 steps, the last of which converts 7-dehydrocholesterol to cholesterol.

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Summary of cholesterol biosynthesis

Summary of cholesterol biosynthesis

Most of the cholesterol synthesis in vertebrates takes

place in the liver. A small fraction of the cholesterol

made there is incorporated into the membranes of hepatocytes, but most of it is exported in one of three

forms: bile acids, biliary cholesterol, or cholesteryl Esters.

Fates of Cholesterol Fates of Cholesterol

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Fates of Cholesterol Fates of Cholesterol

Cholesterol Biosynthesis

Cholesterol Biosynthesis

Two natural products derived from fungi, lovastatin (also called mevinolin) and compactin are being widely used to lower the plasma cholesterol level.

Both are potent competitive inhibitors of HMG-CoA reductase, the key control point in the biosynthetic pathway.

Inhibition of Cholesterol Synthesis

Inhibition of Cholesterol Synthesis

Overproduction of cholesterol can lead to serious disease.

When the amount of cholesterol

synthesized and obtained in the diet exceeds the amount required for the synthesis of membranes, bile salts and steroids, the pathological accumulation of cholesterol in blood vessels

i.e., atherosclerotic plaques (Fig. 25-41) can develop into a heart disease in

humans called atherosclerosis,

characterized by the obstruction of blood vessels (Fig, 25–42). Heart failure from occluded coronary arteries is a major cause of death in industrialized societies.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis