SUMMARY

• 29.1 Phosphatidate Is a Precursor of Storage Lipids and Many Membrane Lipids

  Phosphatidate is formed by successive acylations of glycerol 3-phosphate by acyl CoA. The hydrolysis of its phosphoryl group followed by acylation yields a triacylglycerol. CDP-diacylglycerol, the activated intermediate in the de novo synthesis of several phospholipids, is formed from phosphatidate and CTP. The activated phosphatidyl unit is then transferred to the hydroxyl group of a polar alcohol, such as inositol, to form a phospholipid such as phosphatidylinositol. In mammals, phosphatidylethanolamine is formed by CDP-ethanolamine and diacylglycerol. Phosphatidylethanolamine is methylated by S-adenosylmethionine to form phosphatidylcholine. In mammals, this phospholipid can also be synthesized by a pathway that utilizes dietary choline. CDP-choline is the activated intermediate in this route.

  Sphingolipids are synthesized from ceramide, which is formed by the acylation and reduction of dihydrosphingosine. Gangliosides are sphingolipids that contain an oligosaccharide unit having at least one residue of N-acetylneuraminate or a related sialic acid. They are synthesized by the step-by-step addition of activated sugars, such as UDP-glucose, to ceramide.

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• 29.2 Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages

  Cholesterol is a steroid component of animal membranes and a precursor of steroid hormones. The committed step in its synthesis is the formation of mevalonate from 3-hydroxy-3-methylglutaryl CoA (derived from acetyl CoA and acetoacetyl CoA). Mevalonate is converted into isopentenyl pyrophosphate (C₅), which condenses with its isomer, dimethylallyl pyrophosphate (C₅), to form geranyl pyrophosphate (C₁₀). The addition of a second molecule of isopentenyl pyrophosphate yields farnesyl pyrophosphate (C₁₅), which condenses with itself to form squalene (C₃₀). This intermediate cyclizes to lanosterol (C₃₀), which is modified to yield cholesterol (C₂₇).

• 29.3 The Regulation of Cholesterol Synthesis Takes Place at Several Levels

  In the liver, cholesterol synthesis is regulated by changes in the amount and activity of 3-hydroxy-3-methylglutaryl CoA reductase. Transcription of the gene, translation of the mRNA, and degradation of the enzyme are stringently controlled. In addition, the activity of the reductase is regulated by phosphorylation.

• 29.4 Lipoproteins Transport Cholesterol and Triacylglycerols Throughout the Organism

  Cholesterol and other lipids in excess of those needed by the liver are exported in the form of very low density lipoprotein. After delivering its content of triacylglycerols to adipose tissue and other peripheral tissue, VLDL is converted into intermediate-density lipoprotein and then into low-density lipoprotein, both of which carry cholesteryl esters. Liver and peripheral-tissue cells take up LDL by receptor-mediated endocytosis. The LDL receptor, a protein spanning the plasma membrane of the target cell, binds LDL and mediates its entry into the cell. Absence of the LDL receptor in the homozygous form of familial hypercholesterolemia leads to a markedly elevated plasma level of LDL cholesterol and the deposition of cholesterol on blood-vessel walls, which, in turn, may result in childhood heart attacks. High-density lipoproteins transport cholesterol from the peripheral tissues to the liver.

• 29.5 Cholesterol Is the Precursor of Steroid Hormones

  Five major classes of steroid hormones are derived from cholesterol: progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens. Hydroxylations by P450 monooxygenases that use NADPH and O₂ play an important role in the synthesis of steroid hormones and bile salts from cholesterol. Vitamin D, which is important in the control of calcium and phosphorus metabolism, is formed from a derivative of cholesterol by the action of light.