Tetrahydroforms

Androsterone (28) 3-Epi-androsterone (29) Etiocholanolone (30) 3-Epi-etiocholanolone (31)

FIGURE 2-6 Structural isomers derived by reduction of the A4,5-double bond and the 3-oxo function of androst-4-ene-3,17-dione.

Androsterone (28) 3-Epi-androsterone (29) Etiocholanolone (30) 3-Epi-etiocholanolone (31)

FIGURE 2-6 Structural isomers derived by reduction of the A4,5-double bond and the 3-oxo function of androst-4-ene-3,17-dione.

and methyl carbons of the starting acetate are given in Figure 2-12.

The overall biosynthetic pathway of cholesterol can be subdivided into four steps: (1) the formation of mevalonic acid (six carbons) from three molecules of acetate; (2) the conversion of six molecules of mevalonic acid through a series of phosphorylated intermediates into the hydrocarbon squalene (30 carbons); (3) the oxidation and cyclization of squalene into lanos-terol, the first cyclic sterol precursor; and (4) the processing of lanosterol (to remove three methyl groups and rearrange double bonds) to yield cholesterol (27 carbons). These steps are outlined in the following sections.

1. Conversion of Acetate to Mevalonate

As summarized in Figure 2-13, mevalonic acid is derived by the condensation of three molecules of acetyl-CoA, which pass through the key intermediate 3-hydroxy-3 methylglutaryl-CoA (HMG-CoA). This latter compound is reduced by NADPH to yield mevalonic acid. As will be discussed later, the enzyme HMG-CoA reductase is an important control point in regulating the biosynthesis of cholesterol. Once the product, mevalonic acid, is produced, it is virtually irreversibly committed to conversion to cholesterol.

2. Conversion of Mevalonic Acid into Squalene

Figure 2-14 summarizes the series of eight enzymatic steps necessary to convert six molecules of mevalonic acid into the 30-carbon squalene plus six C02 molecules. Mevalonic acid is sequentially phosphorylated by 3 mol of ATP and then decarboxylated to yield the key isoprene building block, 3-isopentenyl pyrophosphate. The nucleophilic reagent, isopentenyl pyrophosphate, is then subjected to isomerization into the electrophilic (as a consequence of its double-bond position and its esterification with a strong acid) di-methylallyl pyrophosphate. These latter two 5-carbon units are then condensed by a "head-to-tail" mechanism, yielding the 10-carbon intermediate geranyl pyrophosphate. Geranyl pyrophosphate is then condensed in a second head-to-tail step with isopentenyl pyrophosphate, yielding the 15-carbon farnesyl pyrophosphate. Finally, two farnesyl pyrophosphate units are reductively condensed in a "nose-to-nose" mechanism to yield first presqualene pyrophosphate (which contains a cyclopropane ring) and then finally, after reduction by NADPH, the symmetric squalene (56).

3. Conversion of Squalene into Lanosterol

As summarized in Figure 2-15, the final steps of cholesterol biosynthesis involve the conversion of squalene into lanosterol. E. E. van Tamelen chemically

2. Steroid Hormones

CHS Asymmetrie I carbon 20 H-C-OH

R configuration (clockwise)

S configuration (counterclockwise)

FIGURE 2-7 Application of the sequence rules of Cahn to determine the R (rectus) and S (sinister) asymmetry for carbon-20 present in the two-carbon steroid side chain. The asymmetric carbon being evaluated is indicated by the arrow; St indicates the remainder of the steroid nucleus.

synthesized 2,3-oxidosqualene and studied its spontaneous (nonenzymatic) cyclization into lanosterol. The initial step starts with the reactive species squalene epoxide, where the double bond between carbon-6

FIGURE 2-8 Asymmetric carbons of cholesterol. The asymmetric carbons are indicated by •. There are 28 or 256 structural isomers of cholesterol.

Cholesterol (3)

FIGURE 2-8 Asymmetric carbons of cholesterol. The asymmetric carbons are indicated by •. There are 28 or 256 structural isomers of cholesterol.

Chair 32

Boat 33

FIGURE 2-9 Principal conformational representations of cyclo-hexane.

and -7 attacks the epoxide to form the first ring and generate a carbonium ion at carbon-6. This ion is attacked by the double bond between carbon-10 and -11 to form the second ring and generate a new carbonium ion at carbon-10. This sequence continues until all four rings are formed, followed by migration of the methyl carbons on carbon-13 and -14 to yield the first steroid product, lanosterol (59).

Cholestanol (34)

Cholestanol 5a- or A/B-trans alio ser-ies (stanols) (34)

Cholestanol (34)

Cholestanol 5a- or A/B-trans alio ser-ies (stanols) (34)

FIGURE 2-10 Structural representations of cholestanol: (A) typical two-dimensional structure; (B) planar conformational model; (C) a Dreiding model emphasizing bond angles and interatomic distances; (D) a Corey-Pauling space-filling model.

ch20h

Nonsteroid estrogenic compounds ch20h

Nonsteroid estrogenic compounds

Genistein (38)

Diethylstilbestrol (39)

RU-486 (Mifepristone) (41)

Genistein (38)

Diethylstilbestrol (39)

Orally active contraceptive steroids oh o

RU-486 (Mifepristone) (41)

h3co

Mestranol (45)

Norethindrone Norethynodrel (43) Medroxyprogesterone (norlutin) (42) acetate (44)

Mestranol (45)

Bile acids h0v c00h c00h cooh c00h c00h cooh

Lithocholic acid (46) Cholic acid (47)

Chenodeoxycholic acid (48)

Deoxycholic acid (49)

FIGURE 2-11 Structures of other biologically significant steroids. Top row: The insect hormone, ecdysone, and two synthetic glucocorticoids. Second row: Nonsteroid estrogenic compounds and the abortifacient RU-486. Third row: Orally active contraceptive steroids. Bottom row: Common bile acids.

cooh

Lithocholic acid (46) Cholic acid (47)

Chenodeoxycholic acid (48)

Deoxycholic acid (49)

FIGURE 2-11 Structures of other biologically significant steroids. Top row: The insect hormone, ecdysone, and two synthetic glucocorticoids. Second row: Nonsteroid estrogenic compounds and the abortifacient RU-486. Third row: Orally active contraceptive steroids. Bottom row: Common bile acids.

4. Metabolism of Lanosterol to Cholesterol

Three separate enzyme-catalyzed steps are required to convert lanosterol into cholesterol. These include (a) oxidative removal of the two methyl groups at car-bon-4 and the single methyl groups at carbon-14; (b) reduction of the side chain carbon-24 double bond; and (c) movement of the A8-double bond to the A4-position.

C. Role of Sterol Carrier Protein

The early precursors of sterol biosynthesis are all water soluble, but after the production of squalene the cholesterol precursors become markedly water insoluble. The activity of the microsomal enzymes between squalene and cholesterol has been found to be stimu lated by the addition of sterol carrier protein (SCP). SCPs are heat stable, with molecular weights around 16,000.

Three sterol carrier proteins have been isolated. SCPi enhances the conversion of squalene, but not cholesta-4,7-dien-3/3-ol (7-dehydrocholesterol), to cholesterol. SCP2 is active in the conversion of 7-dehydrocholesterol to cholesterol, but is inactive with squalene. SCP3 is required for the conversion of 4,4-dimethylcholest-8-3/6-ol to polar precursors of cholesterol.

D. Regulation of Cholesterol Biosynthesis

The level of total body cholesterol is determined by a complex interplay of dietarily available cholesterol, de novo synthesis of cholesterol, and excretion of choles-

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