20, 22-dihydroxycholesterol pregnenolone
FIGURE 3 Conversion of cholesterol to pregnenolone. Carbons 20 and 22 are sequentially oxidized (in either order) followed by oxidative cleavage of the bond between them. All three reactions are catalyzed by cytochrome P450scc.
facilitates discussion of the biosynthesis and metabolism of the steroid hormones. When drawing structures of steroid hormones, carbon atoms are indicated by junctions of lines that represent chemical bonds. The carbons are numbered and the rings lettered as shown in Fig. 3. Remember that steroid hormones have complex three-dimensional structures; they are not flat, two-dimensional molecules as we depict them for simplicity. Substituents on the steroid nucleus that project toward the reader are usually designated by the prefix p. Those that project away from the reader are designated by a and are shown diagrammatically with dashed lines. The fully saturated 21-carbon molecule is called pregnane. When a double bond is present in any of the rings, the -ane in the ending is changed to -ene, or to -diene when there are two double bonds, i.e., pregnene or pregnadiene. The location of the double bond is designated by the Greek letter A followed by one or more superscripts to indicate the location. The presence of a hydroxyl group (OH) is indicated by the ending -ol, and the presence of a keto group (O) by the ending -one. Thus the important intermediate in the biosynthetic pathway for steroid hormones shown in Fig. 3 has a double bond in the B ring, a keto group on carbon 20, and a hydroxyl group on carbon 3, and hence is called A5 pregnenolone.
The starting material for steroid hormone biosynthesis is cholesterol, most of which arrives at the adrenal cortex in the form of low-density lipoproteins (LDL), which are avidly taken up from blood by a process of receptor-mediated endocytosis. Adrenal cortical cells also synthesize cholesterol from carbohydrate or fatty acid precursors. Substantial amounts of cholesterol are stored in steroid hormone-producing cells in the form of fatty acid esters.
Key reactions in the biosynthesis of the adrenal hormones are catalyzed by a particular class of oxidizing enzymes, the cytochromes P450, that includes a large number of hepatic detoxifying enzymes called mixed function oxidases. They contain a heme group covalently linked through a sulfur-iron bond and absorb light in the visible range. The name P450 derives from the property of these Pigments to absorb light at 450 nm when reduced by carbon monoxide. The P450 enzymes utilize molecular oxygen and electrons donated from NADPH+ to oxidize their substrates. Although they have a single substrate-binding site, some of the P450 enzymes catalyze more than one oxidative step in steroid hormone synthesis.
The rate-limiting step in the biosynthesis of all of the steroid hormones is cleavage of the side chain to convert the 27-carbon cholesterol molecule to the 21-carbon pregnenolone molecule (Fig. 3). The enzyme that catalyzes this complex reaction, is called P450scc (for side-chain cleavage) and is located on the inner mito-chondrial membrane. P450scc catalyzes the oxidation of carbons 20 and 22 and then cleaves the bond between them to shorten the side chain. This initial step in hormone biosynthesis requires a complicated series of molecular events. Cholesterol must first be released from its esterified storage form by the action of an esterase. The free, but water-insoluble cholesterol must then be transferred to the mitochondria perhaps through the agency of a cholesterol binding protein and participation of cytoskeletal elements. Cholesterol must then enter the mitochondria to gain access to P450scc whose activity is limited primarily by availability of its substrate. The steroid acute regulatory (StAR) protein plays an indispensable role in presenting cholesterol to P450scc through mechanisms that are still incompletely understood. The StAR protein has a very short half-life, and stimulation of its synthesis appears to be the critical regulated step in steroid hormone biosynthesis. Unlike cholesterol, 21-carbon steroids apparently pass through the mitochondrial membrane rather freely.
Pregnenolone is the common precursor of all steroid hormones produced by the adrenals or the gonads. An early step in hormone biosynthesis is oxidation of the hydroxyl group at carbon 3 to a keto group. This reaction is catalyzed by the enzyme 3-p-hydroxysteroid dehydro-genase (3pHSD) and initiates a rearrangement that shifts the double bond from the B ring to the A ring. A ketone group at carbon 3 is found in all biologically important
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