Food Lipids: Chemistry, Nutrition, and Biotechnology

sterols is confined to the isolation, purification, and characterization of sterols from
various sources. Readers interested in the chemical reactions and total syntheses of
sterols may refer to the monographs in these areas [33–35].
B. Biosynthetic Origins of Sterols
1. Cholesterol Biosynthesis
Cholesterol is the principal mammalian sterol and the steroid that modulates the
fluidity of eukaryotic membranes. Cholesterol is also the precursor of steroid hormones
such as progesterone, testosterone, estradiol, cortisol, and vitamin D. The
elucidation of the cholesterol biosynthesis pathway has challenged the ingenuity of
chemists for many years. The early work of Konrad Bloch in the 1940s showed that
cholesterol is synthesized from acetyl coenzyme A (acetyl CoA) [36]. Acetate isotopically
labeled in its carbon atoms was prepared and fed to rats. The cholesterol
that was synthesized by these rats contained the isotopic label, which showed that
acetate is a precursor of cholesterol. In fact, all 27 carbon atoms of cholesterol are
derived from acetyl CoA. Since then, many chemists have put forward enormous
efforts to elucidate this biosynthetic pathway, and this work has yielded our present
detailed knowledge of sterol biosynthesis. This outstanding scientific endeavor was
recognized by the awarding of several Nobel prizes to investigators in research areas
related to sterol [1].
The cholesterol biosynthetic pathway can be generally divided into four stages:
(a) the formation of mevalonic acid from three molecules of acetyl CoA; (b) the
biosynthesis of squalene from six molecules and mevalonic acid through a series of
phosphorylated intermediates; (c) the biosynthesis of lanosterol from squalene via
cyclization of 2,3-epoxysqualene; and (d) the modification of lanosterol to produce
cholesterol.
The first stage in the synthesis of cholesterol is the formation of mevalonic
acid and isopentyl pyrophosphate from acetyl CoA. Three molecules of acetyl CoA
are combined to produce mevalonic acid as shown in Scheme 1. The first step of
this synthesis is catalyzed by a thiolase enzyme and results in the production of
acetoacetyl CoA, which is then combined with third molecule of acetyl CoA by the
action of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) is its cleavage to acetyl CoA
and acetoacetate. Acetoacetate is further reduced to D-3-hydroxybutyrate in the mitochondrial
matrix. Since it is a �-keto acid, acetoacetate also undergoes a slow,
spontaneous decarboxylation to acetone. Acetoacetate, D-3-hydroxybutyrate, and acetone,
sometime referred to as ketone bodies, occur in fasting or diabetic individuals.
Alternatively, HMG-CoA can be reduced to mevalonate and is present in both the
cytosol and the mitochondria of liver cells. The mitochondrial pool of this intermediate
is mainly a precursor of ketone bodies, whereas the cytoplasmic pool gives
rise to mevalonate for the biosynthesis of cholesterol.
The reduction of HMG-CoA to give the mevalonic acid is catalyzed by a
microsomal enzyme, HMG-CoA reductase, which is of prime importance in the control
of cholesterol biosynthesis. The biomedical reduction of HMG-CoA is an essential
step in cholesterol biosynthesis. The reduction of HMG-CoA is irreversible and
proceeds in two steps, each requiring NADPH as the reducing reagent. A hemithioacetal
derivative of mevalonic acid is considered to be an intermediate. The
concentration of HMG-CoA reductase is determined by rates of its synthesis and
Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.