Food Lipids: Chemistry, Nutrition, and Biotechnology

Scheme 2 Synthesis of isopentenyl pyrophosphate, the biological ‘‘isoprene unit,’’ and
dimethylallyl pyrophosphate.
C5 units yields geranyl pyrophosphate, which is catalyzed by geranyl pyrophosphate
synthetase (Scheme 3). This reaction proceeds by the head-to-tail joining of isopentyl
pyrophosphate to dimethylallyl pyrophosphate. A new carbon–carbon bond is formed
between the C-1 of dimethylallyl pyrophosphate and C-4 of isopentyl pyrophosphate.
Consequently, geranyl pyrophosphate can couple in a similar manner with a second
molecule of isopentyl pyrophosphate to produce farnesyl pyrosphate (C15 structure).
The last step in the synthesis of squalene is a reductive condensation of two molecules
of farnesyl pyrophosphate (Scheme 4). This step is actually a two-step sequence,
catalyzed by squalene synthetase. In the first reaction, presqualene pyrophosphate
is produced by a tail-to-tail coupling of two farnesyl pyrophosphate
molecules. In the following conversion of presqualene pyrophosphate to squalene,
the cyclopropane ring of presqualene pyrophosphate is opened with a loss of the
pyrophosphate moiety. A molecule of NADPH is required in the second conversion.
The third stage of cholesterol biosynthesis is the cyclization of squalene to
lanosterol (Scheme 5). Squalene cyclization proceeds in two steps requiring, molecular
oxygen, NADPH, squalene epoxidase, and 2,3-oxidosqualene–sterol cyclase.
The first step is the epoxidation of squalene to form 2,3-oxidosqualene–sterol cyclase.
The 2,3-oxidosqualene is oriented as a chair–boat–chair–boat conformation
in the enzyme active center. The acid-catalyzed epoxide ring opening initiates the
cyclization to produce a tetracyclic protosterol cation. This is followed by a series
of concerted 1,2-trans migrations of hydrogen and methyl groups to produce
lanosterol.
The last stage of cholesterol biosynthesis is the metabolism of lanosterol to
cholesterol. Scheme 6 gives the general biosynthetic pathway from lanosterol to
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