Food Lipids: Chemistry, Nutrition, and Biotechnology

Scheme 1 Synthesis of mevalonic acid from acetyl CoA.
degradation, which are in turn regulated by the amount of cholesterol in the cell.
Cholesterol content is influenced by the rate of biosynthesis, dietary uptake, and a
lipoprotein system that traffics in the intercellular movement of cholesterol. During
growth, cholesterol is mainly incorporated into the cell membrane. However, in homeostasis
cholesterol is mainly converted to bile acids and is transported to other
tissues via low density lipoprotein (LDL). High density lipoprotein (HDL) also serves
as a cholesterol carrier, which carries cholesterol from peripheral tissues to the liver.
The major metabolic route of cholesterol is its conversion to bile acids and neutral
sterols, which are excreted from the liver via the bile. Kandutsch and Chen and
others have shown that oxysterols regulate the biosynthesis of HMG-CoA reductase
as well as its digression, which controls cholesterol biosynthesis [37]; the regulation
of HMG-CoA reductase by oxysterols is discussed in more detail in a later section.
A number of substrate analogs have been tested for their inhibition of HMG-CoA
reductase. Some of them (e.g., compactin and melinolin) were found to be very
effective in treating hypocholesterol diseases [38,39].
The coupling of six molecules of mevalonic acid to produce squalene proceeds
through a series of phosphorylated compounds. Mevalonate is first phosphorylated
by mevalonic kinase to form a 5-phosphomevalonate, which serves as the substrate
for the second phosphorylation to form 5-pyrophosphomevalonate (Scheme 2). There
is then a concerted decarboxylation and loss of a tertiary hydroxy group from 5pyrophosphomevalonate
to form 3-isopentyl pyrophosphate, and in each step one
molecule of ATP must be consumed. 3-Isopentyl pyrophosphate is regarded as the
basic biological ‘‘isoprene unit’’ from which all isoprenoid compounds are elaborated.
Squalene is synthesized from isopentyl pyrophosphate by sequence coupling
reactions. This stage in the cholesterol biosynthesis starts with the isomerization of
isopentyl pyrophosphate to dimethylallyl pyrophosphate. The coupling reaction
shown in Scheme 2 is catalyzed by a soluble sulfydryl enzyme, isopentyl pyrophosphate–dimethylallyl
pyrophosphate isomerase. The coupling of these two isomeric
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