Cholesterol lanosterol converted

Cho SY, Kim JH, Paik YK (1998) Cholesterol biosynthesis from lanosterol differential inhibition of sterol delta 8-isomerase and other lanosterol-converting enzymes by tamoxifen. Mol Cells 8(2) 233-239... 

Further work in the phylum Echinodermata shows a variable ability to biosynthesize steroids. In the class Holothuroidea and Echinoidea, the representatives examined could synthesize squalene but not triterpenoids or sterols from acetate. However, several examples from the class Asteroidea were able to synthesize squalene, lanosterol, and other steroids. In the later stages of steroid metabolism it was shown that cholesterol was converted into cholest-7-enol via cholestanol. 

S. Y. Cho, J-H. Kim, and Y-K. Paik Cholesterol biosynthesis from lanosterol Differential inhibition of sterol A -isomerase and other lanosterol-converting enzymes by tamoxifen. Molecules and Cells 8,233 (1998). 

Lanosterol is converted into cholesterol, 16.19, in 19 ( ) steps catalyzed by enzymes in the endoplasmic reticulum. In the liver, cholesterol is converted into cholic acid, 16.20, and other bile acids. In various other tissues, it is converted via pregnenolone, 16.21, to all the steroid hormones. Formally, there are five classes of these ... 

Although lanosterol may appear similar to cholesterol in structure, another 20 steps are required to convert lanosterol to cholesterol (Figure 25.35). The enzymes responsible for this are all associated with the endoplasmic reticulum. The primary pathway involves 7-dehydroeholesterol as the penultimate intermediate. An alternative pathway, also composed of many steps, produces the intermediate desmosterol. Reduction of the double bond at C-24 yields cholesterol. Cholesterol esters—a principal form of circulating cholesterol—are synthesized by acyl-CoA cholesterol acyltransferases (ACAT) on the cytoplasmic face of the endoplasmic reticulum. 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

The compensatory effect of cholesterol observed in D407 cells have also been demonstrated in other cell lines (Cho et al. 1998 Holleran et al. 1998) and may well be a consequence of tamoxifen-induced severe inhibition of lanosterol (to cholesterol)-converting enzymes. In rat liver preparations and CHO cells, sterol A8-isomerase (IC50 0.21-0.15. iM) was the most sensitive... 

The route for the cyclization was easier to determine than the identification of the very reactive isoprene unit, and was understood in outline by 1960. Studies of labeled compounds detected within 10 min. of 14C-acetate addition to intestinal preparations showed label in squalene, lanosterol, and a further, unidentified ring compound, all with higher specific activities than cholesterol. By 75 min cholesterol was the main labeled compound. Clayton and Bloch then confirmed that lanosterol, previously known from sheep s wool, was converted to cholesterol with the extra three (methyl) carbon atoms being lost as carbon dioxide. 

By far the most impressive example of electrophilic addition in natural prodnct formation is in the biosynthesis of steroids. The snbstrate sqnalene oxide is cyclized to lanosterol in a process catalysed by a single enzyme. Lanosterol is then converted into the primary animal-steroid cholesterol. Sqnalene oxide comes from sqnalene, which is itself formed throngh a combination of two molecules of farnesyl diphosphate. 

The all-tra 5 -squalene (C30H50), discovered in shark liver oil in the 1920s, is a triterpene, but one in which the isoprene rule at violated in one point. Rather than a head-to-tail arrangement of six units of isoprene, there appear to be farnesyl units that have been connected tail to tail. Almost aU steroids are biosynthesized from cholesterol. Cholesterol is biosynthesized from squalene, which is first converted to lanosterol. The conversion of squalene to the steroid skeleton is an oxirane, squalene-2,3-oxide, which is transformed by enzymes into lanosterol, a steroid alcohol naturally found in wool fat. The whole process is highly stereoselective. 

Squalene is an important biological precursor of many triterpenoids, one of which is cholesterol. The first step in the conversion of squalene to lanosterol is epoxidation of the 2,3-douhle bond of squalene. Acid-catalysed ring opening of the epoxide initiates a series of cyclizations, resulting in the formation of protesterol cation. Elimination of a C-9 proton leads to the 1,2-hydride and 1,2-methyl shifts, resulting in the formation of lanosterol, which in turn converted to cholesterol by enzymes in a series of 19 steps. 

The synthesis of all isoprenoids starts with acetyl-CoA, which in a series of six different enzyme reactions is converted into isopentenyl-diphosphate (-PP), the basic C-5 isoprene unit that is used for the synthesis of all subsequent isoprenoids (Fig. 5.1.1). At the level of farnesyl-PP the pathway divides into several branches that are involved in the production of the various isoprenoid end products. One of the major branches involves the cholesterol biosynthetic part of the pathway, of which squalene is the first committed intermediate in the production of sterols. Following cycliza-tion of squalene, lanosterol is produced. To eventually produce cholesterol from la-... 

Isotopic labeling experiments show that cholesterol is derived from ethanoate by way of squalene and lanosterol. The evidence for this is that homogenized liver tissue is able to convert labeled squalene to labeled lanosterol and thence to labeled cholesterol. The conversion of squalene to lanosterol is particularly interesting because, although squalene is divisible into isoprene units, lanosterol is not—a methyl being required at C8 and not C13 ... 

The biosynthesis of steroids begins with the conversion of three molecules of acetyl-CoA into mevalon-ate, the decarboxylation of mevalonate, and its conversion to isopentenyl pyrophosphate. Six molecules of isopentenyl pyrophosphate are polymerized into squalene, which is cyclized to yield lanosterol. Lanos-terol is converted to cholesterol, which is the precursor of bile acids and steroid hormones. 

In the biogenesis of steroids, the enzyme-catalyzed polycyclization of squalene (225) produces the tetracyclic substance lanosterol (225) which is eventually converted into cholesterol (227) Eschenmoser, Stork, and their co-workers (80-82) have proposed that the squalene-1anosterol conversion can be rationalized on the basis of stereoelectronic effects. The stereochemical course of this biological cyclization (83, 84) can be illustrated by considering the transformation of squalene oxide (228) (an intermediate in the biosynthesis of cholesterol (83, 84)) into dammaradienol 229. This transfor-... 

In animals, the triterpenoid alcohol lanosterol (Figure 5.55) is converted into cholesterol (Figure 5.76), a process requiring, as well as the loss of three methyl groups, reduction of the side-chain double bond, and generation of a A5,6... 

All 27 carbon atoms of cholesterol are derived from acetyl Co A. First acetyl CoA and acetoacetyl CoA combine to form HMG CoA which, in turn, is reduced to mevalonate by HMG CoA reductase. Mevalonate is converted into the five-carbon isoprene compounds 3-isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate. These two compounds condense to form the CIO geranyl pyrophosphate, which is elongated to the C15 farnesyl pyrophosphate by the addition of another molecule of isopentenyl pyrophosphate. Two molecules of farnesyl pyrophosphate condense to form the C30 squalene, which is then converted via squalene epoxide and lanosterol to cholesterol. 

Squalene is then converted into squalene epoxide in a reaction that uses 02 and NADPH (Fig. 2b). The squalene epoxide cyclizes to form lanosterol, and finally cholesterol is formed from lanosterol by the removal of three methyl groups, the reduction of one double bond by NADPH, and the migration of the other double bond (Fig. 2b). 

Glucose is oxidized in the pentose phosphate pathway (Chap. 11), to produce NADPH that can enter cholesterol synthesis. One molecule of glucose is required per molecule of lanosterol synthesized. (The reactions that convert lanosterol to cholesterol are outside the scope of Chap. 13.)... 

Stereospecific 2,3-epoxidation of squalene, followed by a nonconcerted carbocationic cyclization and a series of carbocationic rearrangements, forms lanosterol [79-65-0] (77) in the first steps dedicated solely toward steroid synthesis (109,110). Several biomimetic, cationic cydizations to form steroids or steroidlike nuclei have been observed in the laboratory (111), and the total synthesis of lanosterol has been accomplished by a carbocation—olefin cydization route (112). Through a complex series of enzyme-catalyzed reactions, lanosterol is converted to cholesterol (2). Cholesterol is the principal starting material for steroid hormone biosynthesis in animals. The cholesterol biosynthetic pathway is composed of at least 30 enzymatic reactions. Lanosterol and squalene appear to be normal constituents, in trace amounts, in tissues that are actively synthesizing cholesterol. 

Lanosterol is then converted to cholesterol by a multistep process that results in removal of three methyl groups. 

Figure 26.13. Cholesterol Formation. Lanosterol is converted into cholesterol in a complex process.

As expected, lanosterol (70) but not cycloartenol (72) was converted in rats into cholesterol on the other hand both triterpenoids are utilized by Zea mays in the formation of C-24-alkylated sterols. Sterol formation has been demonstrated in the fern Polypodium vulgare, tobacco, and Calendula... 

C,2iS- H,3R]mevalonate, Bloxham and Akhtar showed that a tritium atom was lost whereas when [3a- H,26,27- C2]lanosterol was used the tritium was retained. The latter result was also observed by Hornby and Boyd. Presumably NAD is necessary for the oxidation at C-3 to a ketone prior to decarboxylation. Similarly, Miller and Gaylor showed that 4a-methyl-5a-cholest-7-en-3) -ol was oxidized only as far as the 4a-carboxylic acid, with retention of tritium at C-3 but loss from a 4a-C H3 group. In the latter case, the recovered 4a-methyl sterol showed no sign of tritium enrichment due to isotope effects. In banana, alkylation at C-24 seems to precede loss of the 4a-methyl groups. When the rat liver system was inhibited by cholestane-3, 5a,6 -triol, sterols accumulated which retained a methyl group at C-4. Both 4,4-dimethyl- and 4 -methyl-cholest-8-en-3/I-ol Uere isolated, and were shown to be converted into cholesterol under normal conditions. 

As shown in Figure 6.13, squalene is converted in two steps to lanosteroL Conversion of lanosteiol to cholesterol involves 19 steps that are not shown. (Although cholesterol contains se cral rings, it is rot an aromatic compound because its rings do not resonate.)... 

The final stage of cholesterol biosynthesis starts with the cyclization of squalene (Figure 26.11). Squalene is first activated by conversion into squalene epoxide (2,3-oxi-dosqualene) in a reaction that uses O2 and NADPH. Squalene epoxide is then cyclized to lanosterol by oxi-dosqualene cyclase. This remarkable transformation proceeds in a concerted fashion. The enzyme holds squalene epoxide in an appropriate conformation and initiates the reaction by protonating the epoxide oxygen. The carbocation formed spontaneously rearranges to produce lanosterol. Lanosterol is converted into cholesterol in a... 

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