Cholesterol reaction sequences

Ozonization of A -steroids usually gives complex mixtures (however, see ref. 48). Ozonolysis became a practical step in the general synthesis of B-norsteroids with the discovery that added methanol" (or formaldehyde ) improves yields significantly. Thus, Tanabe and Morisawa prepared 5/ -hydroxy-6/ -formyl-B-norsteroids (74) from cholesterol acetate, dehydroepiandrosterone acetate and pregnenolone acetate in overall yields of 64-74% by the reaction sequence represented below. 

The insertion of hydroxyl groups into the 23- or 24-position of 5P-cholestane-3a,7a,12a,25-tetrol was found to be stereospecific. Although all these compounds were potential precursors of bile acid, studies in vivo and in vitro experiments using [3P- H] and (24- C) 5P-cholestane-3a,7a,12a,25-tetrol (46) (Figs.6, 7), (24- C) 5p-cholestane-3a,7a,12a,24R,25-pentol and (24- C) 5P-cholestane-3a,7a,12a,24S,25-pentol demonstrated the existence of a new 25-hydroxylation pathway for the transformation of cholesterol to cholic acid in these patients (2,10). The reaction sequence involved the stereospecific formation of a 24S-hydroxy pentol, 5P-cholestane-3a,7a,12a,24S,25-pentol, 3a7a,12a,25-tetrahydroxy-5P-cholestan-24-one and did not involve SP-cholestanoic acids as intermediates (Fig. 8). The two bile pentols, SP-cholestane-3a,7a,12a,24R, 25-pentol and 5P-cholestane-3a,7a,12a,23R,25-... 

Norethindrone 31a, the gestagenic component in the combination pill, is smoothly accessible from estrone-methylether by partial synthesis [71]. The reaction sequence begins with a dearomatization (Birch reduction) and ends with an ethynylation (Scheme 1-10), necessary for the oral applicability. Technical production of estrone 24 (or estradiol) from inexpensive steroids such as diosgenin or cholesterol by partial synthesis is also feasible. Pyrolytic aromatization (Inhoffen at Schering AG) assists the transition from the steroid to the 19-nor-steroid class (such as from androsta-1,4-dien-l 7/i-ol-3-one 32 to estradiol 33 [72]). 

The non-enzymatic determination of cholesterol developed by Burchard [12] is based on its reaction with strong acids as described by Llebermann [11]. The method was formerly developed in its manual version by Huan et al. [13] and later automated by Levine et al. [14]. The reaction sequence taking place after the serum sample is mixed with sulphuric acid involves a colour change from red to violet (bis-cholestadienylmonosulphonic acid, BCDMSA) and then to green (bis-cholestadienyldisulphonic acid, BCDDSA), which is monitored at 630 nm ... 

The conversion of cholesterol into 7-dehydrocholesterol is a process of importance in the manufacture of vitamin D3. Suggest one reaction sequence for this conversion. 

Biosynthesis The primary B. are synthesized in the liver from cholesterol by a complicated, multi-step reaction sequence. The 7o-hydroxy group is introduced first while the 12-hydroxy group is added later to a further intermediate with subsequent formation of both chenodeoxycholic acid and cholic acid. Deoxycholic acid is not synthesized in the liver but rather in the intestines by 7a-dehydroxylation of cholic acid by intestinal bacteria. 

The reaction sequence in the conversion of cholesterol into 5/5-choles-tane-3a,7a,12a-triol and 5/5-cholestane-3a,7a-diol has been shown to be the same in human and rat liver homogenates (3). All of these reactions occur with the 20,000g supernatant fluid of homogenates of human liver. The 12a-hydroxylation of 7a-hydroxycholest-4-en-3-one proceeds efficiently in the presence of a microsomal fraction fortified with NADPH (3). 

E. Quantitative Studies on the Consecutive Reaction Sequences between Cholesterol and Pregnenolone 316... 

The most commonly postulated mechanism for the desmolase reaction has been the suggestion of the enzymatic consecutive reaction sequence cholesterol 20a-hydroxycholesterol — (22R)-20a,22-dihydroxycholesterol pregnenolone (Shimizu et al., 1961, 1962 Constantopoulos and Tchen, 1961). This hypothetical scheme was actually advanced on the basis of three suppositions (1) cholesterol is cleaved between C-20 and C-22, as was discussed in a previous section, (2) 20a-hydroxycholesterol was formed from cholesterol-4- C by a cow adrenocortical homogenate in the presence of 20a-hy-droxycholesterol as a trapping agent (Solomon et al., 1956), and (3) both 20a-hydroxycholesterol and (22R)-20a,22-dihydroxycholesterol are much more efficiently transformed to pregnenolone than is cho-... 

The mechanism and the reaction sequence of the formation of bile acids from cholesterol have been studied extensively and a number of steps involved have been characterized. Excellent review s in this field have been published (Bergstrom ei al., 1960 Danielsson, 1963 van Belle, 1965 Danielsson and Tchen, 1968). Only a few points will be discussed here. 

The conversion of lanosterol to cholesterol involves a 19-step reaction sequence catalysed by microsomal enzymes. The exact order of the reactions has not been delineated and, indeed, there may be more than one pathway. The main features of the transformation are the removal of three methyl groups, reduction of the 24(25)-double bond and isomerization of the 8(9)-double bond to position 5 in cholesterol. 

In nature, the biologically active form of acetic acid is acetyl-coenzyme A (acetyl-CoA) (see Box 7.18). Two molecules of acetyl-CoA may combine in a Claisen-type reaction to produce acetoacetyl-CoA, the biochemical equivalent of ethyl acetoacetate. This reaction features as the start of the sequence to mevalonic acid (MVA), the precursor in animals of the sterol cholesterol. Later, we shall see another variant of this reaction that employs malonyl-CoA as the nucleophile (see Box 10.17). 

A metabolite, molecular entity, or some other event/ process that precedes another component in a longer sequence of events or conversions. For example, the isoprenoid metabolite squalene is a precursor of cholesterol and glucose 6-phosphate is a precursor of glycogen, ribose, and pyruvate. See Series First Order Reaction Pulse-Chase Experiments... 

Chloroxytrifluoromethane, 26 137-139 reactions, 26 140-143 addition to alkenes, 26 145-146 oxidative addition, 26 141-145 vibrational spectra, 26 139 Chloryl cation, 18 356-359 internal force constants of, 18 359 molecular structure of, 18 358, 359 properties of, 18 357, 358 synthesis of, 18 357, 358 vibrational spectra of, 18 358, 359 Chloryl compounds, reactions of, 5 61 Chloryl fluoride, 18 347-356 chemical properties of, 18 353-356 fluoride complexes of, 5 59 molecular structure of, 18 349-352 physical properties of, 18 352, 353 preparation, 5 55-57 and reactions, 27 176 properties of, 5 48 reactions, 5 58-61, 18 356 synthesis of, 18 347-349 thermal decomposition of, 18 354, 355 vapor pressures, 5 57, 18 353 vibrational spectra of, 18 349-352 Chloryl ion, 9 277 Cholegobin, 46 529 Cholesterol, astatination, 31 7 Cholorofluorphosphine, 13 378-380 h CHjPRj complexes, osmium, 37 274 Chromatium, HiPIP sequence, 38 249 Chromatium vinosum HiPIP, 38 108, 133 Fe4S4 + core, 33 60 Chromato complexes, osmium, 37 287... 

FIGURE 21-37 Ring closure converts linear squalene to the condensed steroid nucleus. The first step in this sequence is catalyzed by a mixed-function oxidase (a monooxygenase), for which the cosubstrate is NADPH. The product is an epoxide, which in the next step is cyclized to the steroid nucleus. The final product of these reactions in animal cells is cholesterol in other organisms, slightly different sterols are produced, as shown. 

The sequence of cholesterol biosynthesis begins with a condensation in the cytosol of two molecules of acetyl-CoA in a reaction catalyzed by thiolase (fig. 20.3). The next step requires the enzyme /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) synthase. This enzyme catalyzes the condensation of a third acetyl-CoA with /3-ketobutyryl-CoA to yield HMG-CoA. HMG-CoA is then reduced to mevalonate by HMG-CoA reductase. The activity of this reductase is primarily responsible for control of the rate of cholesterol biosynthesis. 

The thiolase and HMG-CoA synthase exhibit some regulatory properties in rat liver (cholesterol feeding causes a decrease in these enzyme activities in the cytosol but not in the mitochondria). However, the primary regulation of cholesterol biosynthesis appears to be centered on the HMG-CoA reductase reaction. HMG-CoA reductase is found on the endoplasmic reticulum, has a molecular weight of 97,092, and consists of 887 amino acids in a single polypeptide chain. The sequence of the enzyme was deduced by Michael Brown and Joseph Goldstein from the sequence of a piece of complimentary DNA (cDNA) derived from mRNA that codes for the reductase. The enzyme... 

The last sequence of reactions in the biosynthesis of choles-terol involves approximately 20 enzymatic steps, starting with lanosterol. In mammals the major route involves a series of double-bond reductions and demethylations (fig. 20.10). The sequence of reactions involves reduction of the A24 double bond, the oxidation and removal of the 14a methyl group followed by the oxidation and removal of the two methyl groups at position 4 in the sterol. The final reaction is a reduction of the A7 double bond in 7-dehydro-cholesterol. An alternative pathway from lanosterol to cholesterol also exists. The enzymes involved in the transformation of lanosterol to cholesterol are all located on the endoplasmic reticulum. 

This sequence of reactions is incompletely understood but involves numerous oxidations of carbon groups, for example, the conversion of methyl groups to carboxylic acids, followed by decarboxylation. The end product, cholesterol, is the precursor to cholesterol esters in the liver and is transported to the peripheral tissues where it is a precursor to membranes (all cells), bile salts (liver), steroid hormones (adrenals and reproductive tissues), and vitamin D (skin, then liver, and finally kidney). 

Our study on the distribution of electron transferring proteins in animal sources is still in progress. From present knowledge, adrenodoxin can be found in adrenal cortexes from pig, beef, and rat. Further, a similar protein was isolated from pig testis (see II-A-2), and it was also found in the ovary. However, brain, heart, liver, kidney, and pancreas appear to lack adrenodoxin-like protein. If this is correct, the proteins of the ferredoxin family are located solely in the glands which directly act in the biosynthesis of steroid hormones. It is of interest that adrenodoxin-like protein does not participate in the steroid hydroxylation involved in cholesterol and cholic acid biosyntheses. All of these reactions without the participation of adrenodoxin are similar to enzymes responsible for microsomal non-specific hydroxylation, which consist of the following sequence of electron transfer ... 

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