Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Section III. METABOLISM OF MAJOR CLASSES OF BIOMOLECULES

CHAPTER 16. LIPID METABOLISM. III. CHOLESTEROL METABOLISM. LIPID TRANSPORT

An important role in human physiology and pathology is played by the METABOLISM of steroid Lipids. Cholesterol is the principal animal sterol whose transport and biotransformation are closely linked to the metabolism of Other Steroids. It is an essential compound for normal Cell function, the maintenance of biomembrane physical state, and the synthesis of hormone-active substances. Impairments in cholesterol and triacylglycerol transport are underlying factors in The Development of many severe human diseases.

16.1. CHOLESTEROL BIOSYNTHESIS

Cholesterol is a steroid that performs vital structural and regulatory Functions, being a component of Biomembranes and serving as a precursor in the synthesis of various classes of physiologically active compounds. The Human Body obtains cholesterol through endogenous Biosynthesis and dietary intake from animal products.

On average, an adult human synthesizes from 0.5 to 1.0 g of cholesterol per day, while dietary intake contributes 0.3-0.5 g (up to 1.0-1.2 g in some cases). The capacity for cholesterol synthesis is possessed by all animal Cells, with the exception of mature erythrocytes. However, the largest amount of endogenous cholesterol (50 to 80%) is synthesized in the Liver, with the remainder formed in the intestines (10-15%) and Skin (about 5%). It is specifically in the cells of The Liver and intestinal mucosa that the sterol is synthesized not only for their own needs but also for "export".

The precursor in Cholesterol Biosynthesis is acetyl-CoA, which is formed during glucose oxidation via Oxidative Decarboxylation of Pyruvate or through the β-Oxidation of Fatty acids.

Class="center">ENZYMATIC REACTIONS OF cholesterol synthesis

Cholesterol biosynthesis occurs in The Cell Cytosol, and its initial stages involve The formation of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) from acetyl-CoA via mechanisms discussed in Chapter 14:

When the process is directed toward The biosynthesis of Ketone Bodies, HMG-CoA is cleaved by mitochondrial lyase to yield acetoacetate. When HMG-CoA enters the metabolic pathway of cholesterol biosynthesis, the following biochemical reactions take place:

1. Reduction of HMG-CoA to form mevalonic acid. The reaction is catalyzed by NADPH-dependent HMG-CoA reductase:

HMG-CoA reductase is a regulatory enzyme whose activity is inhibited by the end product of this biosynthetic pathway—cholesterol (of either endogenous or exogenous, dietary origin).

2. Formation of isoprenoid units from mevalonic acid.

The process takes place in several stages and includes:

2.1. Activation of mevalonate involving ATP to form pyrophosphomevalonic acid:

2.2. Decarboxylation of pyrophosphomevalonate to yield isopentenyl pyrophosphate ("active isoprene") and its isomer, 3,3-dimethylallyl pyrophosphate:

3. Condensation of five-carbon (5 C) phosphorylated isoprenes to form a thirty-carbon (30 C) terpene hydrocarbon—squalene (С₃₀Н₅₀).

This multistep process involves the formation of polyisoprenoid intermediates and proceeds According to the following scheme:

4. Cyclization of the linear isoprenoid hydrocarbon squalene to form steroid molecules (cyclopentanoperhydrophenanthrene derivatives). The immediate precursor of cholesterol is the cyclic hydrocarbon lanosterol:

These reactions involve epoxidation, oxidative hydroxylation, and demethylation processes, and are catalyzed by Enzymes belonging to the monooxygenase class (microsomal mixed-function oxidases) that incorporate cytochrome P-450 and require NADPH and oxygen.

The overall equation for the Biosynthesis of Cholesterol (C₂₇H₄₆O) from acetyl-CoA can be represented as follows:

The General scheme of cholesterol synthesis is shown in Fig. 16.1.

Fig. 16.1. Metabolic pathway map of cholesterol biosynthesis.

Regulation of Cholesterol Biosynthesis

The rate-limiting step in cholesterol biosynthesis is the formation of mevalonate from β-HMG-CoA, catalyzed by β-HMG-CoA reductase. The process is regulated via negative feedback inhibition, whereby the accumulation of the anabolic pathway's end product—cholesterol—decreases The rate of its synthesis.

The enzyme is inhibited by cholesterol or cholesterol-containing LDL Lipoproteins (see below). Consistent with these mechanisms, dietary cholesterol intake suppresses its hepatic synthesis, whereas a cholesterol-free diet, conversely, activates endogenous Cholesterol synthesis in hepatocytes.

The molecular mechanisms regulating the β-HMG-CoA reductase reaction involve both Covalent Modification of the enzyme (the phosphorylated form is inactive, whereas the dephosphorylated form is active) and The Influence of biochemical modulators on the rate of enzyme synthesis (enzyme induction) or degradation.

Insulin and THYROID Hormones increase The activity of β-HMG-CoA reductase, whereas Glucagon and glucocorticoids decrease it.