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 cytosolic compartments.

Acetyl-CoA Is the Source of All Carbon Atoms in Cholesterol

Cholesterol is a 27-carbon compound consisting of four rings and a side chain . It is synthesized from acetyl CoA by a lengthy pathway that may be divided into five steps: (1) synthesis of mevalonate from acetyl-CoA (Figure1); (2) formation of isoprenoid units from mevalonate by loss of CO2 (Figure 2); (3) condensation of six isoprenoid units formsqualene(see Figure 2); (4) cyclization of squalene gives rise to the parent steroid,lanosterol (Figure 3); (5) formation of cholesterol from lanosterol (see Figure 3).

Fig1. Biosynthesis of mevalonate.HMG-CoA reductase is inhibited by statins. The open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA.

Fig2. Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives.(HMG, 3-hydroxy-3-methylglutaryl.) A farnesyl residue is present in heme of a cytochrome oxidase. The carbon marked with an asterisk becomes C₁₁ or C₁₂ in squalene. The open circles indicate the origin of the PPi eliminated in the formation of geranyl diphosphate. Squalene synthetase is a microsomal enzyme; all other enzymes indicated are soluble cytosolic proteins, and some are found in peroxisomes.

Fig3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. (*Refer to labeling of squalene in Figure 2.)

Step 1—Biosynthesis of Mevalonate: HMG-CoA (3-hydroxy 3-methylglutaryl-CoA) is formed by the reactions used in mitochondria to synthesize ketone bodies. 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 in a reaction catalyzed by HMG-CoA reductase. This last step 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 statins, which are HMG-CoA reductase inhibitors (see Figure 1).

Step 2—Formation of Isoprenoid Units: Mevalonate is phosphorylated sequentially using ATP by three kinases, and after decarboxylation (see Figure2) of the active isoprenoid unit, isopentenyl diphosphate, is formed.

Step 3—Six Isoprenoid Units Form Squalene: Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl diphosphate, and then condensed with another molecule of isopentenyl diphosphate to form the 10-carbon intermediate geranyl diphosphate (see Figure 2). 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. Farnesyl diphosphate is also an intermediate in the formation of other important com pounds which contain isoprenoid units such as dolichol and ubiquinone (see following discussion and Figure 2).

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

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 the side chain (see Figure 3). 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 (24-dehydrocholesterol). Finally, the double bond of the side chain is reduced, producing cholesterol.

Farnesyl Diphosphate Gives Rise to Dolichol & Ubiquinone

 The polyisoprenoids, dolichol and ubiquinone are formed from farnesyl diphosphate by the further addition of up to 16 (dolichol) or 3 to 7 (ubiquinone) isopentenyl diphosphate residues (see Figure 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 and membrane-associated protein trafficking.

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مواضيع ذات صلة

The Cholesterol Balance in Tissues is Tightly Regulated

Cholesterol Synthesis is Controlled by Regulation of HMG-CoA Reductase

Brown Adipose Tissue Promotes Thermogenesis

Hormones Regulate Fat Mobilization

Adipose Tissue is The Main Store of Triacylglycerol in The Body

Classification of Proteins

Precipitation Reactions of Proteins

Study of Protein Structure

Imbalance in the Rate of Triacylglycerol Formation & Export Causes Fatty Liver

The Liver Plays A Central Role in Lipid Transport & Metabolism

HDL Takes Part in Both Lipoprotein Triacylglycerol & Cholesterol Metabolism

Tertiary Structure of Proteins