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Q – Discuss the structure and functions of cholesterol.

Answer- Cholesterol is the major sterol in the animal tissues.The structure of cholesterol consists of four fused rings (The rings in steroids are denoted by the letters A, B, C, and D.), with the carbons numbered in the sequence, and an eight numbered, and branched hydrocarbon chain attached to the D ring. Cholesterol contains two angular methyl groups: the C-19 methyl group is attached to C-10, and the C-18 methyl group is attached to C-13. The C-18 and C-19 methyl groups of cholesterol lie above the plane containing the four rings. A double is there between C5 and C6 (Figure-1-a and b)



















Figure-1-a) showing the structure of cholesterol, b)- Showing the numbering in the 4 fused rings.

Much of the plasma cholesterol is in the esterified form (with a fatty acid attached at carbon 3), which makes the structure even more hydrophobic and because of its hydrophobicity, cholesterol must be transported either in association with protein as a component of lipoprotein particle or solubilized by phospholipids and bile salts in the bile.)

Functions of cholesterol- Cholesterol is the most abundant sterol in humans and performs a number of essential functions in the body. For example-

1) It is a major constituent of the plasma membrane and of plasma lipoproteins.

2) It is a precursor of bile salts,

3)  It is a precursor of steroid hormones that include adrenocortical hormones, sex hormones, placental hormones etc

4) Also a precursor of vitamin D, cardiac glycosides, Sitosterol of the plant kingdom, and some alkaloids.

3) It is required for the nerve transmission. Cholesterol is widely distributed in all cells of the body but particularly abundant in nervous tissue.

As a typical product of animal metabolism, cholesterol occurs in foods of animal origin such as egg yolk, meat, liver, and brain. Plasma low-density lipoprotein (LDL) is the vehicle of uptake of cholesterol and cholesteryl ester into many tissues. Free cholesterol is removed from tissues by plasma high-density lipoprotein (HDL) and transported to the liver, where it is eliminated from the body either unchanged or after conversion to bile acids in the process known as reverse cholesterol transport .Cholesterol is a major constituent of gallstones. However, its chief role in pathologic processes is as a factor in the genesis of atherosclerosis of vital arteries, causing cerebrovascular, coronary, and peripheral vascular disease.

Q.-Discuss the steps of de novo synthesis of cholesterol

Answer- Cholesterol is derived from diet, de novo synthesis and from the hydrolysis of cholesteryl esters. A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the remainder is provided by the average diet. The liver and intestine account for approximately 10% each of total synthesis in humans. Virtually all tissues containing nucleated cells are capable of cholesterol synthesis, which occurs in the endoplasmic reticulum and the cytosol.

Acetyl co A acts as a precursor of cholesterol. All the 27 carbon atoms of cholesterol are derived from Acetyl co A.

Steps of synthesis of cholesterol

The biosynthesis of cholesterol may be divided into five steps:

(1) Synthesis of mevalonate from acetyl-CoA

(2) Formation of isoprenoid units from mevalonate by loss of CO2

(3) Condensation of six isoprenoid units to form squalene.

(4) Cyclization of squalene to give rise to the parent steroid, lanosterol.

(5) Formation of cholesterol from lanosterol

Details of reactions

(1) Synthesis of mevalonate from acetyl-CoA – HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) is formed by the reactions used in mitochondria to synthesize ketone bodies (Figure-2). However, since cholesterol synthesis is extramitochondrial, the two pathways are distinct. Initially, two molecules of acetyl-CoA condense to form acetoacetyl-CoA catalyzed by cytosolic thiolase. Acetoacetyl-CoA condenses with a further molecule of acetyl-CoA catalyzed by HMG-CoA synthase to form HMG-CoA, which is reduced to mevalonate by NADPH catalyzed by HMG-CoA reductase.This is the principal regulatory step in the pathway of cholesterol synthesis and is the site of action of the most effective class of cholesterol-lowering drugs, the HMG-CoA reductase inhibitors (statins).

























Figure-2- showing the formation of Mevalonate (Stage-1 of cholesterol biosynthesis) .The synthesis of mevalonate is the committed step in cholesterol formation. The enzyme catalyzing this irreversible step,3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is an important control site in cholesterol biosynthesis.

Step 2—Formation of Isoprenoid Units: Mevalonate is phosphorylated sequentially by ATP by three kinases, and after decarboxylation (Figure-3) the active isoprenoid unit, isopentenyl diphosphate, is formed.





































Figure-3- Showing the Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives.  A farnesyl residue is present in heme a of cytochrome oxidase. 

Step 3—Six Isoprenoid Units Form Squalene:

Squalene is synthesized from isopentenyl pyrophosphate by the reaction sequence-




Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl diphosphate, then condensed with another molecule of isopentenyl diphosphate to form the ten-carbon intermediate geranyl diphosphate (Figure-3 and 4).







Figure-4- Showing the conversion of IPP to Dimethyl Allyl prophosphate


A further condensation with isopentenyl diphosphate forms farnesyl diphosphate. Two molecules of farnesyl diphosphate condense at the diphosphate end to form squalene. Initially, inorganic pyrophosphate is eliminated, forming presqualene diphosphate, which is then reduced by NADPH with elimination of a further inorganic pyrophosphate molecule.

Step 4—Formation of Lanosterol: Squalene can fold into a structure that closely resembles the steroid nucleus (Figure-5). Before ring closure occurs, squalene is converted to squalene 2,3-epoxide by a mixed-function oxidase in the endoplasmic reticulum, squalene epoxidase. The methyl group on C14 is transferred to C13 and that on C8 to C14 as cyclization occurs, catalyzed by oxidosqualene:lanosterol cyclase.



















Figure-5- Showing the formation of Lanosterol from Squalene.

Step 5—Formation of Cholesterol: The formation of cholesterol from lanosterol takes place in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus and side chain (Figure-6). The methyl groups on C14 and C4 are removed to form 14-desmethyl lanosterol and then zymosterol. The double bond at C8–C9 is subsequently moved to C5–C6 in two steps, forming desmosterol. Finally, the double bond of the side chain is reduced, producing cholesterol. The exact order in which the steps described actually take place is not known with certainty.

Significance of Farnesyl pyrophosphate-

1) The polyisoprenoids  dolichol is formed from farnesyl diphosphate by the further addition of up to 16 isopentenyl diphosphate residues

2) Ubiquinone is formed from farnesyl diphosphate by the addition of or 3–7 isopentenyl diphosphate residues, respectively.

2) Some GTP-binding proteins in the cell membrane are prenylated with farnesyl or geranyl  geranyl (20 carbon) residues. Protein prenylation is believed to facilitate the anchoring of proteins into lipoid membranes and may also be involved in protein-protein interactions .



















Figure-6- Showing the formation of cholesterol from Lanosterol

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