Steroid moiety acetylation

Figure 26-3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. Asterisks Refer to labeling of squalene in Figure 26-2.

Like in Chapt. 7, we begin the discussion with acetates, since acetic acid is the simplest nontoxic acyl group, formic acid being less innocuous. An informative study was carried out to compare the kinetics of hydrolysis of two types of corticosteroid esters, namely methyl steroid-21-oates (which are active per se) and acetyl steroid-21-ols (which are prodrugs), as exemplified by methyl prednisolonate (8.69) and prednisolone-21-acetate (8.70), respectively [89]. In the presence of rat liver microsomes, the rate of hydrolytic inactivation of methyl steroid-21-oates was much slower than the rate of hydrolytic activation of acetyl steroid-21-ols. Thus, while the Km values were ca. 0.1 -0.3 mM for all substrates, the acetic acid ester prodrugs and the methyl ester drugs had Vmax values of ca. 20 and 0.15 nmol min-1 mg-1, respectively. It can be postulated that the observed rates of hydrolysis were determined by the acyl moiety, in other words by the liberation of the carboxylic acid from the acyl-enzyme intermediate (see Chapt. 3). 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially Lire same biosynlheLic scheme (Fig. 3). The sell-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid (22). Phosphorylation of (22) followed by concomitant decarboxylation and dehydration processes... 

LDL takes place by way of specific ceE surface LDL receptors on the adrenal gland surface that internalize the cholesterol moiety, releasing it as substrate for steroidogenesis however, ail steroidogenic cells are capable of de novo synthesis from acetyl coenzyme A. To ensure a continuous supply of free cholesterol for steroid synthesis, lipoprotein cholesterol uptake is coordinated with intracellular cholesterol synthesis and with the mobilization of intracellular cholesteryl ester pools. When the rate of cholesterol uptake exceeds the rate of steroidogenesis, intracellular cholesterol synthesis is suppressed, and cholesterol in excess of cellular needs is esterified and stored for future use. 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). 

The structures of the hepta-O-acetylsucroses produced by deacetylation of octa-O-acetylsucrose on aluminium oxide impregnated with potassium carbonate have been determined. Four principal hepta-O-acetyl components were obtained in 34% total yield, all having a hydroxy group free in the fructose moiety (ratios of free hydroxy groups, 4 (43%) 1 (23%), 3 (19%) and 6 (15%)) Likewise two hexacetates (3 4 and 1, 3 -dihydroxy compounds) were isolated in 42% yield, others only being present in trace amounts. The tetra-acetyl disaccharide 2,3>4-tri-0-acetyl-ik-L-rhamnopyranosyl-(l-2)-4-0-acetyl- <-L-arabino-pyranose has been isolated as a steroidal glycoside from the plant Trillium 10 -----------------------------------------------------... 

Kicha et al. 644) reported the occurrence of a new substance, aste-rosaponin Pj (960), in the Pacific starfish Patiria pectinifera. This saponin belongs to the group of 24-0-glycosidal steroids, but differed from those encounted previously, because the sugar moiety bears a sulfate residue. The structure of 960 was elucidated by spectroscopic and chemical methods. These latter included solvolysis of 960 to 961 and subsequent conversion by acetylation or methylation to the penta-acetate 962 or hexa-O-methyl derivative 963. Oxidation with CrOa-C5H5N resulted in the triketone 964, oxidation with CrOa-CHaCOOH in the diketone 965. 

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