Lanosterol, cholesterol from biosynthesis

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... 

S-H. Bae and Y-K. Paik Cholesterol biosynthesis from lanosterol Development of a novel assay method and characterization of rat liver microsomal lanosterol -reductase. Biochemical Journal 326,609 (1997). 

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). 

The first step in the biosynthesis of cholesterol (83) from lanosterol is the reduction of the A24,25-bond, and this involves addition of a 24-pro-S proton and overall ds-stereospecificity in the rat liver system in vitro. This result has been confirmed with rat liver in vivo139 and contrasts with the situation, previously reported and now fully described in detail,140 for the steroidal triterpenoid tigogenin biosynthesized by... 

An important intermediate in cholesterol biosynthesis is lanosterol, 4,4, 14a-trimethyl-Zl -cholestadien-3j8-ol (Clayton et al. 1956). The former is a major constituent of wool fat, but has also been isolated from liver. 

From lanosterol, the pathway for steroid biosynthesis continues on to yield cholesterol. Cholesterol then becomes a branch point, serving as the common precursor from which all other steroids are derived. 

The evidence is strong that the biosynthesis of lanosterol actually proceeds by a route of this type. With squalene made from either methyl- or carboxyl-labeled ethanoate, all the carbons of lanosterol and cholesterol are labeled just... 

From Lanosterol to Cholesterol Takes Approximately 20 Steps Summary of Cholesterol Biosynthesis Lipoprotein Metabolism... 

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. 

A number of cytochrome P450 enzymes are involved in the conversion of acetate to sterols and bile acids (Figure 9.6). The participation of P450 enzymes in pathways of cholesterol biosynthesis and elimination demonstrate their important role in cholesterol homeostasis. Lanosterol 14a-desmethylase, encoded by CYP51A1, is a pivotal P450 involved in cholesterol biosynthesis. The synthesis of bile acids from... 

Fig. 8 is a schematic diagram of a cell which shows the known sites in which sterol carrier proteins are involved in cholesterol biosynthesis, utilization and intracellular transfer. SCP, participates in the conversion of squalene to lanosterol and SCP2 participates in the conversion of lanosterol to cholesterol, the conversion of cholesterol to cholesterol ester by ACAT, and probably also in the conversion of cholesterol to 7a-hydroxycholesterol. SCPj transfers cholesterol from cytoplasmic lipid inclusion droplets to mitochondria in the adrenal and SCPj also translocates cholesterol from the outer to the inner mitochondrial membrane. 

In addition to cholesterol and 5a-cholest-7-en-3y8-ol, many C2g and C29 conventional sterols are present in Echinodermata. These sterols are probably derived from the diet. However, echinoderms are able to synthesize sterols. Thus, [ C]mevalonic acid was incorporated into squalene, lanosterol and desmosterol by the sea urchin. Echinus esculentus [87]. The ability of ophiurpids to synthesize sterol from [ C]acetate has also been demonstrated [88]. Sterol biosynthesis by a holothuroid was first investigated by Numura [89], and sterol biosynthesis from [ C]acetate in sea cucumbers has also been reported [90]. 

The compound exhibited moderate to significant cholesterol biosynthesis inhibitory activity with an IC50 value of 8 pg/mL when compared with that of mevastatin (8 pg/mL), a commercially available HMG-CoA reductase inhibitor. However, this compound showed an inhibitory profile different from that of mevastatin. Analysis of the extracts of cells treated with 62, revealed the presence of accumulated lanosterol in the sterol fractions as evidenced by TLC, whereas no labeled sterol intermediate was detected in case of mevastatin under the same condition. 

Trzaskos, J., S. Kawata, and J.L. Gaylor (1986). Microsomal enzymes of cholesterol biosynthesis. Purification of lanosterol 14a-methyl demethy-lase cytochrome P-450 from hepatic microsomes. J. Biol Chem. 261, 14651-14657. 

Cholesterol represents the next milestone in the biosynthesis of the sex steroids. En route from lanosterol to cholesterol, the methyl groups at C-4 and C-14 have to be removed, the double bond is to migrate from C-8 to C-5, and the Z -double bond must be reduced. 

We saw in Sections 27.5 and 27.7 that all steroids, including cholesterol, are biosynthesized from the triterpenoid lanosterol, which in turn comes from acetyl CoA through isopentenyl diphosphate. If you knew all the mechanisms for all the chemical steps in cholesterol biosynthesis, you might be able to devise a drug that would block one of those steps, thereby short-circuiting the biosynthetic process and controlling the amount of cholesterol produced. 

Cholesterol Mosynthesis.—Some work on cholesterol biosynthesis which appeared during the early part of 1972 was included in Volume 1 of this series in an attempt to present a more complete picture. The reader is also referred to this work for much background information regarding this section. In agreement with previous observations, it has been demonstrated that cholesterol (30) biosynthesis from [2- C]mevalonate, [ C]squalene, or [ C]lanosterol is inhibited by carbon monoxide. Since lanosterol (29) and... 

The most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

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