BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART III. BIOSYNTHESIS OF MACROMOLECULE PRECURSORS

CHAPTER 20. BIOSYNTHESIS OF MEMBRANE LIPIDS AND STEROID HORMONES

Summary

Phosphatidate, an intermediate in the synthesis of phosphoacylglycerols (phosphoglycerides) and triacylglycerols (triglycerides), is formed by the acylation of glycerol 3-phosphate using acyl-CoA. Hydrolysis of its phosphoryl group followed by subsequent acylation yields triacylglycerol. CDP-acylglycerol, an activated intermediate in the de novo synthesis of phosphoacylglycerols, is formed from phosphatidic acid and CTP. The activated phosphatidyl moiety is then transferred to the hydroxyl group of a polar alcohol, such as Serine, resulting in The formation of phosphatidylserine. Decarboxylation of this phosphoacylglycerol yields phosphatidylethanolamine, which is methylated by S-adenosylmethionine to give phosphatidylcholine. This phosphoacylglycerol can also be synthesized from preformed residues utilizing existing Choline. The activated intermediate of this pathway is CDP-choline. Sphingolipids are synthesized from ceramide, which is formed by the acylation of sphingosine. Gangliosides are sphingolipids containing an oligosaccharide moiety. This oligosaccharide contains at least one residue of N-acetylneuraminate or another similar sialic acid. Gangliosides are synthesized through the stepwise addition of activated sugars, such as UDP-glucose, to ceramide.

Cholesterol is a steroidal component of Introduction/5.html">Eukaryotic Cell membranes and a precursor to Steroid Hormones. It is synthesized from acetyl-CoA. The rate-limiting step in cholesterol formation is the synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (formed from acetyl-CoA and acetoacetyl-CoA). Mevalonate is converted into isopentenyl pyrophosphate (C₅), which condenses with its isomer dimethylallyl pyrophosphate (C₅) to yield geranyl pyrophosphate (C₁₀). Addition of a second molecule of isopentenyl pyrophosphate gives farnesyl pyrophosphate (C₁₅). Two molecules of farnesyl pyrophosphate condense to form squalene (C₃₀). This intermediate cyclizes into lanosterol (C₃₀), which undergoes modification to be converted into cholesterol (C₂₇). Cholesterol synthesis in the Liver is regulated by Changes in the amount and activity of 3-hydroxy-3-methylglutaryl-CoA reductase, The enzyme catalyzing the rate-limiting step of its Biosynthesis. The low-density lipoprotein receptor plays a major role in regulating the cellular uptake of cholesterol in most extrahepatic and extraintestinal Tissues.

Five Major Classes of steroid hormones are derived from cholesterol: progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens. Hydroxylation reactions, catalyzed by mixed-function oxygenases requiring NADPH and O₂, play a crucial role in the synthesis of steroid hormones and Bile acids from cholesterol. Pregnenolone (C₂₁), the key intermediate in steroid hormone synthesis, is formed by the Cleavage of the cholesterol side chain. Progesterone (C₂₁), synthesized from pregnenolone, serves as a precursor to cortisol and aldosterone. Cleavage of the progesterone side chain yields androstenedione (C₁₉), an androgen. Estrogens (C₁₈) are synthesized from androgens by the removal of a methyl group and the aromatization of ring A.

Vitamin D, which plays a vital role in regulating Calcium and phosphorus METABOLISM, is photochemically produced from a cholesterol derivative. In addition to cholesterol and its derivatives, a staggering variety of other molecules are synthesized from the fundamental five-carbon building block, isopentenyl pyrophosphate. Examples of extended chains assembled from this activated five-carbon unit include the hydrocarbon side chains of vitamin K₂, coenzyme Q₁₀, and chlorophyll.