Cholesterol Is Derived About Equally From The Diet From Biosynthesis

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-CoA Is the Source of All Carbon Atoms in Cholesterol

The biosynthesis of cholesterol may be divided into five steps: (1) Synthesis of mevalonate occurs from acetyl-CoA (Figure 26-1). (2) Isoprenoid units are formed from mevalonate by loss of CO2 (Figure 26-2). (3) Six isoprenoid units condense to form squalene. (4) Squa-lene cyclizes to give rise to the parent steroid, lanos-terol. (5) Cholesterol is formed from lanosterol (Figure 26-3).

Step 1—Biosynthesis of Mevalonate: HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) is formed by the reactions used in mitochondria to synthesize ketone bodies (Figure 22-7). 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 26-1).

Step 2—Formation of Isoprenoid Units: Meval-onate is phosphorylated sequentially by ATP by three kinases, and after decarboxylation (Figure 26-2) the active isoprenoid unit, isopentenyl diph osphate, is formed.

Step 3—Six Isoprenoid Units Form Squalene:

Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl diph osphate, then condensed with another molecule of isopentenyl diphosphate to form the ten-carbon intermediate ger-anyl diphosphate (Figure 26-2). 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.

Step 4—Formation of Lanosterol: Squalene can fold into a structure that closely resembles the steroid nucleus (Figure 26-3). Before ring closure occurs, squalene is converted to squalene 2,3-epoxide by a mixed-

CH3 C S CoA 2 Acetyl-CoA

Acetoacetyl-CoA o

HMG-CoA SYNTHASE

HMG-CoA SYNTHASE

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA)

Bile acid, cholesterol ie

HMG-CoA REDUCTASE

Mevalonate

Bile acid, cholesterol ie

HMG-CoA REDUCTASE

Statins, eg, simvastatin

Statins, eg, simvastatin

O.J. o -OOC — CH2 — C — CH2 — CH2 — OH II

OH Mevalonate

Figure 26-1. Biosynthesis of mevalonate. HMG-CoA reductase is inhibited by atorvastatin, pravastatin, and simvastatin. The open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA.

function oxidase in the endoplasmic reticulum, squa-lene epoxidase. The methyl group on Cw is transferred to Cj3 and that on C8 to Cw as cyclization occurs, catalyzed by oxidosqua!ene: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 side chain (Figure 26-3). The methyl groups on Cw 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.

Farnesyl Diphosphate Gives Rise to Dolichol & Ubiquinone

The polyisoprenoids dolichol (Figure 14-20 and Chapter 47) and ubiquinone (Figure 12-5) are formed from farnesyl diphosphate by the further addition of up to 16 (dolichol) or 3-7 (ubiquinone) isopentenyl diphosphate residues, respectively. Some GTP-binding proteins in the cell membrane are prenylated with far-nesyl or geranylgeranyl (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.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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