Synthesis of Cholesterol

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Chapter: Biochemistry : Cholesterol, Lipoprotein, and Steroid Metabolism

Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta, make the largest contributions to the body’s cholesterol pool.


Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta, make the largest contributions to the body’s cholesterol pool. As with fatty acids, all the carbon atoms in cholesterol are provided by acetyl coenzyme A (CoA), and nicotinamide adenine dinucleotide phosphate (NADPH) provides the reducing equivalents. The pathway is endergonic, being driven by hydrolysis of the high-energy thioester bond of acetyl CoA and the terminal phosphate bond of adenosine triphosphate (ATP). Synthesis requires enzymes in both the cytosol and the membrane of the smooth endoplasmic reticulum (ER). The pathway is responsive to changes in cholesterol concentration, and regulatory mechanisms exist to balance the rate of cholesterol synthesis within the body against the rate of cholesterol excretion. An imbalance in this regulation can lead to an elevation in circulating levels of plasma cholesterol, with the potential for vascular disease.


A. Synthesis of 3-hydroxy-3-methylglutaryl coenzyme A

The first two reactions in the cholesterol synthetic pathway are similar to those in the pathway that produces ketone bodies (see Figure 16.22). They result in the production of 3-hydroxy-3-methylglutaryl CoA ([HMG CoA] Figure 18.3). First, two acetyl CoA molecules condense to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added by HMG CoA synthase, producing HMG CoA, a six-carbon compound. [Note: Liver parenchymal cells contain two isoenzymes of the synthase. The cytosolic enzyme participates in cholesterol synthesis, whereas the mitochondrial enzyme functions in the pathway for ketone body synthesis.]

Figure 18.3 Synthesis of HMG CoA. CoA = coenzyme A.


B. Synthesis of mevalonate

The next step, the reduction of HMG CoA to mevalonate, is catalyzed by HMG CoA reductase and is the rate-limiting and key regulated step in cholesterol synthesis. It occurs in the cytosol, uses two molecules of NADPH as the reducing agent, and releases CoA, making the reaction irreversible (Figure 18.4). [Note: HMG CoA reductase is an integral membrane protein of the ER, with its catalytic domain projecting into the cytosol.] Regulation of reductase activity is discussed below.

Figure 18.4 Synthesis of mevalonate. HMG CoA = hydroxymethylglutaryl coenzyme A; NADP(H) = nicotinamide adenine dinucleotide phosphate.


C. Synthesis of cholesterol

The reactions and enzymes involved in the synthesis of cholesterol from mevalonate are illustrated in Figure 18.5. [Note: The numbers shown in brackets below correspond to numbered reactions shown in this figure.]

Figure 18.5 Synthesis of cholesterol from mevalonate. ADP = adenosine diphosphate; P =  phosphate; P~P = pyrophosphate; NADP(H) = nicotinamide adenine dinucleotide phosphate.

[1] Mevalonate is converted to 5-pyrophosphomevalonate in two steps, each of which transfers a phosphate group from ATP.

[2] A five-carbon isoprene unit, isopentenyl pyrophosphate (IPP), is formed by the decarboxylation of 5-pyrophosphomevalonate. The reaction requires ATP. [Note: IPP is the precursor of a family of molecules with diverse functions, the isoprenoids. Cholesterol is a sterol isoprenoid. Nonsterol isoprenoids include dolichol and ubiquinone, or coenzyme Q.]

[3] IPP is isomerized to 3,3-dimethylallyl pyrophosphate (DPP).

[4] IPP and DPP condense to form ten-carbon geranyl pyrophosphate (GPP).

[5] A second molecule of IPP then condenses with GPP to form 15-carbon farnesyl pyrophosphate (FPP). [Note: Covalent attachment of farnesyl to proteins, a process known as “prenylation,” is one mechanism for anchoring proteins (such as ras) to plasma membranes.]

[6] Two molecules of FPP combine, releasing pyrophosphate, and are reduced, forming the 30-carbon compound squalene. [Note: Squalene is formed from six isoprenoid units. Because three ATP are hydrolyzed per mevalonate residue converted to IPP, a total of 18 ATP are required to make the polyisoprenoid squalene.]

[7] Squalene is converted to the sterol lanosterol by a sequence of reactions catalyzed by ER-associated enzymes that use molecular oxygen and NADPH. The hydroxylation of linear squalene triggers the cyclization of the structure to lanosterol.

[8] The conversion of lanosterol to cholesterol is a multistep, ER-associated process involving shortening of the side-chain, oxidative removal of methyl groups, reduction of double bonds, and migration of a double bond. Smith-Lemli-Opitz syndrome (SLOS), an autosomal-recessive disorder of cholesterol biosynthesis, is caused by a partial deficiency in 7-dehydrocholesterol-7-reductase, the enzyme that reduces the double bond in 7-dehydrocholesterol (7-DHC), thereby converting it to cholesterol. SLOS is one of several multisystem, embryonic malformation syndromes associated with impaired cholesterol synthesis. [Note: 7-DHC is converted to vitamin D3 in the skin.]


D. Regulation of cholesterol synthesis

HMG CoA reductase is the major control point for cholesterol biosynthesis and is subject to different kinds of metabolic control.


1. Sterol-dependent regulation of gene expression: Expression of the gene for HMG CoA reductase is controlled by the transcription factor, SREBP-2 (sterol regulatory element–binding protein-2) that binds DNA at the cis-acting sterol regulatory element (SRE) upstream of the reductase gene. SREBP-2 is an integral protein of the ER membrane, and associates with a second ER membrane protein, SCAP (SREBP cleavage–activating protein). When sterol levels in the cell are low, the SREBP–SCAP complex moves from the ER to the Golgi. In the Golgi membrane, SREBP-2 is sequentially acted upon by two proteases, which generate a soluble fragment that enters the nucleus, binds the SRE, and functions as a transcription factor. This results in increased synthesis of HMG CoA reductase and, therefore, increased cholesterol synthesis (Figure 18.6). If sterols are abundant, however, they bind SCAP at its sterol-sensing domain and induce the binding of SCAP to yet other ER membrane proteins, the insigs (insulin-induced gene [products]). This results in the retention of the SCAP–SREBP complex in the ER, thereby preventing the activation of SREBP-2, and leading to downregulation of cholesterol synthesis. [Note: SREBP-1 upregulates expression of enzymes involved in fatty acid synthesis in response to insulin.]

Figure 18.6 Regulation of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase. SRE = sterol regulatory element; SREBP = sterol regulatory element-binding protein; SCAP = SREBP cleavage-activating protein; AMPK = adenosine monophosphate-activated protein kinase; ADP = adenosine diphosphate; P = phosphate; mRNA = messenger RNA.


2. Sterol-accelerated enzyme degradation: The reductase itself is a sterol-sensing integral protein of the ER membrane. When sterol levels in the cell are high, the enzyme binds to insig proteins. Binding leads to ubiquitination and proteasomal degradation of the reductase.


3. Sterol-independent phosphorylation/dephosphorylation: HMG CoA reductase activity is controlled covalently through the actions of adenosine monophosphate (AMP)-activated protein kinase ([AMPK]) and a phosphoprotein phosphatase (see Figure 18.6). The phosphorylated form of the enzyme is inactive, whereas the dephosphorylated form is active. [Note: Because AMPK is activated by AMP, cholesterol synthesis, like fatty acid synthesis, is decreased when ATP availability is decreased.]


4. Hormonal regulation: The amount of HMG CoA reductase is controlled hormonally. An increase in insulin and thyroxine favors upregulation of the expression of the gene for the reductase. Glucagon and the glucocorticoids have the opposite effect.


5. Inhibition by drugs: The statin drugs (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin) are structural analogs of HMG CoA, and are (or are metabolized to) reversible, competitive inhibitors of HMG CoA reductase (Figure 18.7). They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.

Figure 18.7 Structural similarity of hydroxymethylglutaric acid (HMG) and pravastatin, a clinically useful cholesterol-lowering drug of the “statin” family. CoA = coenzyme A.

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