Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Lipid Biosynthesis
Cholesterol and other steroids are also synthesized from two-carbon precursors

Cholesterol is not only a vital component of certain Cell membranes (Section 12.10) and plasma Lipoproteins (Section 12.8), but also a precursor to numerous other biologically important Steroids, including Bile acids and various Steroid Hormones. Much like long-chain Fatty acids, cholesterol is synthesized from acetyl-CoA, although the acetyl groups are linked together in a different manner. This Conclusion was drawn from experiments in which animals were fed acetate labeled with radioactive carbon (¹⁴C) at either the methyl group or the carboxyl group. Labeled cholesterol was subsequently isolated from the Tissues of animals fed these Two Types of labeled molecules. Through sequential degradation using established Chemical Reactions, characteristic products were obtained. Determining the radioactivity of these products made it possible to pinpoint the positions within the cholesterol molecule occupied by carbon atoms originating from the methyl and carboxyl groups. The results of these pioneering experiments, conducted by Konrad Bloch, Robert Woodward, and other researchers, are illustrated in Fig. 21-23. This information provided the key to elucidating the multi-step sequence of enzymatic reactions involved in Cholesterol Biosynthesis (Fig. 21-24).

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Fig. 21-23. Origin of carbon atoms in the cholesterol molecule, as determined in experiments using acetate labeled with radioactive carbon at the methyl group (shaded gray) and the carboxyl group (shaded red).

In The First stage, mevalonic acid is formed through the three reactions outlined below (Fig. 21-25):

During the subsequent reactions constituting the Second Stage of cholesterol biosynthesis, three phosphate groups are attached to mevalonate, after which the phosphorylated mevalonate loses a carboxyl group and two hydrogen atoms to yield ∆³-isopentenyl pyrophosphate (Fig. 21-26)—the activated form of the isoprene unit (Section 10.13). Six isopentenyl groups then combine, shedding their pyrophosphate groups, to form the hydrocarbon squalene (Fig. 21-27), which consists of 30 carbon atoms, 24 of which are linked in a chain while the remaining 6 form methyl side groups. Squalene was first isolated from the livers of sharks (genus Squalus).

The Third Stage of cholesterol biosynthesis involves a series of complex enzymatic reactions that convert the linear squalene molecule into the cyclic compound lanosterol, which contains the four fused rings characteristic of steroids (Fig. 21-24). In the fourth and final series of reactions, lanosterol is converted into cholesterol. For deciphering this remarkable biosynthetic pathway—the most complex known—American Konrad Bloch, German Feodor Lynen, and Englishman John Cornforth were awarded the Nobel Prize in 1961.

The regulation of cholesterol biosynthesis is likewise a highly intricate process. The rate-limiting step occurs early in the pathway: The conversion of hydroxymethylglutaryl-CoA into mevalonate (Fig. 21-25). This reaction is catalyzed by a complex regulatory enzyme, hydroxymethylglutaryl-CoA reductase, whose activity can fluctuate by up to two orders of magnitude depending on cellular conditions. The enzyme is inhibited by the end product of this biosynthetic pathway, cholesterol, as well as by mevalonate. Hydroxymethylglutaryl-CoA reductase is localized in the Endoplasmic reticulum and can exist in either a phosphorylated (inactive) or dephosphorylated (active) state. Cholesterol biosynthesis is also regulated by the concentration of a specific sterol carrier protein; this protein binds Water-insoluble biosynthetic intermediates, thereby making them more accessible to subsequent enzymatic reactions. The rate of cholesterol biosynthesis depends not only on the levels of cholesterol and Other Steroids in tissues, but also changes during starvation, in response to dietary regimens, and in the presence of malignant tumors. Furthermore, cholesterol biosynthesis is inhibited by specific cholesterol-containing plasma lipoproteins when they bind to corresponding cell-surface receptors.

Fig. 21-24. Stages of cholesterol biosynthesis. Three condensing acetyl-CoA molecules yield mevalonate, the phosphorylation of which produces 3-phospho-5-pyrophosphomevalonate. The elimination of CO₂ and a phosphate group from this intermediate yields ∆³-isopentenyl pyrophosphate. Sequential Condensation of six molecules of ∆³-isopentenyl pyrophosphate forms the linear hydrocarbon squalene, which then undergoes cyclization to form lanosterol, which is subsequently converted into cholesterol.

Dysregulation of cholesterol biosynthesis is one of the factors contributing to the Pathogenesis of atherogenesis, a process in which plaques rich in cholesterol and other Lipids develop within the walls of Arteries and arterioles. The formation of such plaques can impair Blood supply to various Organs, with The Heart and Brain most frequently suffering from the resulting oxygen deprivation (Chap. 26).

Fig. 21-25. Formation of mevalonate from acetyl-CoA. Carbon atoms 1 and 2 of the mevalonate molecule derived from acetate are highlighted in red.

Fig. 21-26. Conversion of mevalonate into ∆³-isopentenyl pyrophosphate, the activated form of the isoprene unit. Six such units combine to form squalene.

Fig. 21-27. Squalene, a 30-carbon isoprenoid hydrocarbon and precursor to lanosterol and cholesterol. Isoprene units are separated by colored dashed lines.