26.1 Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and Triacylglycerols

Phosphatidate is formed by successive acylations of glycerol 3-phosphate by acyl CoA. 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 phosphoglyceride can also be synthesized by a pathway that utilizes dietary choline. CDP-choline is the activated intermediate in this route.

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Sphingolipids are synthesized from ceramide, which is formed by the acylation of sphingosine. 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.

26.2 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).

26.3 The Complex Regulation of Cholesterol Biosynthesis 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.

Triacylglycerols exported by the intestine are carried by chylomicrons and then hydrolyzed by lipases lining the capillaries of target tissues. 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. IDL and LDL carry cholesteryl esters, primarily cholesteryl linoleate. 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.

26.4 Important Derivatives of Cholesterol Include Bile Salts and Steroid Hormones

In addition to bile salts, which facilitate the digestion of lipids, five major classes of steroid hormones are derived from cholesterol: progestogens, 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. P450 enzymes, a large superfamily, also participate in the detoxification of drugs and other foreign substances.

Pregnenolone (C₂₁) is an essential intermediate in the synthesis of steroids. This steroid is formed by scission of the side chain of cholesterol. Progesterone (C₂₁), synthesized from pregnenolone, is the precursor of cortisol and aldosterone. Hydroxylation of progesterone and cleavage of its side chain yields androstenedione, an androgen (C₁₉). Estrogens (C₁₈) are synthesized from androgens by the loss of an angular methyl group and the formation of an aromatic A ring. 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.

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