The reduction of HMG CoA to mevalonate is carried out by HMG CoA reductase, which is the key regulated step and rate-limiting in cholesterol synthesis. This reaction occurs in the cytosol and utilizes two molecules of NADPH as the reducing agent, resulting in the release of CoA and making the reaction irreversible. HMG CoA reductase is an integral membrane protein of the SER, with its catalytic domain projecting into the cytosol. The regulation of reductase activity is discussed further below.

Cholesterol synthesis from mevalonate involves several reactions and enzymes, as illustrated in Figure 18.5. Mevalonate is first converted to 5-pyrophosphomevalonate in two steps, both of which involve the transfer of a phosphate group from ATP.

The decarboxylation of 5-pyrophosphomevalonate leads to the formation of a five-carbon isoprene unit called isopentenyl pyrophosphate (IPP), with ATP being required for this reaction. It's important to note that IPP serves as the precursor for a diverse family of molecules known as isoprenoids. Cholesterol, being a sterol isoprenoid, is one example of these molecules. Other nonsterol isoprenoids include dolichol and ubiquinone (coenzyme Q).

IPP is then isomerized to 3,3-dimethylallyl pyrophosphate (DPP). The condensation of IPP and DPP forms a 10-carbon geranyl pyrophosphate (GPP). Subsequently, a second molecule of IPP combines with GPP to produce a 15-carbon farnesyl pyrophosphate (FPP). This covalently attaches to proteins through prenylation, serving as a mechanism to anchor them to the inner face of plasma membranes. Two molecules of FPP combine and undergo reduction to form a 30-carbon compound known as squalene. Squalene, composed of six isoprenoid units, requires the hydrolysis of 3 ATP per mevalonate residue converted to IPP, resulting in a total of 18 ATP being required for the synthesis of the polyisoprenoid squalene.

The conversion of squalene to the sterol lanosterol involves a series of reactions catalyzed by SER-associated enzymes that utilize molecular oxygen (O2) and NADPH. The hydroxylation of linear squalene triggers the cyclization of its structure, leading to the formation of lanosterol.

The conversion of lanosterol to cholesterol is a complex process involving the 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) is a genetic disorder resulting from a partial deficiency in 7-dehydrocholesterol-7-reductase, an enzyme responsible for reducing the double bond in 7-dehydrocholesterol (7-DHC) and converting it into cholesterol. SLOS is categorized among various multisystem embryonic malformation syndromes associated with impaired cholesterol synthesis. Notably, 7-DHC is converted to vitamin D3 in the skin. 

HMG CoA reductase acts as a major control point in cholesterol biosynthesis and is subject to different forms of metabolic control.
HMG CoA is reduced to mevalonate by HMG CoA reductase. This 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 (Fig. 18.4). [Note: HMG CoA reductase is an integral membrane protein of the SER, with its catalytic domain projecting into the cytosol. Regulation of reductase activity is discussed in D. below.]
C. Cholesterol synthesis from mevalonate
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.] [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 (see p. 167) and ubiquinone (or, coenzyme Q; see p. 75).] [3] IPP is isomerized to 3,3-dimethylallyl pyrophosphate (DPP).
[4] IPP and DPP condense to form 10-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 (for example, ras) to the inner face of 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 3 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 two reactions catalyzed by SER-associated enzymes that use molecular oxygen (O2) and NADPH. The hydroxylation of linear squalene triggers the cyclization of the structure to lanosterol.
The conversion of lanosterol to cholesterol is a multistep 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-7reductase, the enzyme that reduces the double bond in 7dehydrocholesterol (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 (see p. 390).]
D.
HMG CoA reductase is the major control point for cholesterol biosynthesis and is subject to different kinds of metabolic control.
1.