Lanosterol structure

Figure 3/ for example/ places the lanosterol so as the 3f hydroxyl polar group lies over the propionate side chains. To reduce the complexity of this picture one can now replace the lanosterol structure by a surface canopy to represent the extent of the hydrophobic substrate binding site. There is also the facility to code this surface to signify the electronic properties of the substrates such as their electron density/ electrostatic potential/ or HOMO/LUMO values. Theoretical work of this type is currently suggesting quite remarkable complementarity of electron properties between bound substrates and protein binding sites. (10). 

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. 

Problem 27.10 Compare the structures of lanosterol and cholesterol, and catalog the changes needed for the transformation. 

Step 4—Formation of Lanosterol Squalene can fold into a structure that closely resembles the steroid nucleus (Figure 26-3). Before ring closure occurs, squalene is converted to squalene 2,3-epoxide by a mixed-... 

The application of this procedure to the fused polycyclic compound E, which already has a linear dual and only the last two steps (iii-iv) apply to it, leads to a linear acyclic structure F which may be traced back to the biogenetic cyclisation of squalene to lanosterol via cationic intermediates, as well as to the stereospecific cationic cyclisation of polyolefins studied by Johnson [18]. 

Rozman D, Stromstedt M, Waterman MR. 1996. The three human cytochrome P450 lanosterol 14 alpha-demethylase (CYP51) genes reside on chromosomes 3, 7, and 13 structure of the two retrotransposed pseudogenes, association with a line-1 element, and evolution of the human CYP51 family. Arch Biochem Biophys 333 466-474. 

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

A general type of chemical reaction between two compounds, A and B, such that there is a net reduction in bond multiplicity (e.g., addition of a compound across a carbon-carbon double bond such that the product has lost this 77-bond). An example is the hydration of a double bond, such as that observed in the conversion of fumarate to malate by fumarase. Addition reactions can also occur with strained ring structures that, in some respects, resemble double bonds (e.g., cyclopropyl derivatives or certain epoxides). A special case of a hydro-alkenyl addition is the conversion of 2,3-oxidosqualene to dammara-dienol or in the conversion of squalene to lanosterol. Reactions in which new moieties are linked to adjacent atoms (as is the case in the hydration of fumarate) are often referred to as 1,2-addition reactions. If the atoms that contain newly linked moieties are not adjacent (as is often the case with conjugated reactants), then the reaction is often referred to as a l,n-addition reaction in which n is the numbered atom distant from 1 (e.g., 1,4-addition reaction). In general, addition reactions can take place via electrophilic addition, nucleophilic addition, free-radical addition, or via simultaneous or pericycUc addition. 

Lewis, D. F. V., Wiseman, A., and Tarbit, M. H. (1999) Molecular modeling of lanosterol 14-alpha-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives../. Enz. Inhib. 14, 175-192. 

Squalene is converted to the sterol lanosterol by a sequence of reactions that use molecular oxygen and NADPH. The hydroxy-lation of squalene triggers the cyclization of the structure to lanosterol. 

Cholesterol is the most common steroid of mammalian membranes. It is formed biologically from lanosterol, as shown. Ergosterol is the most common steroid of fungal membranes. It differs from cholesterol by the presence of two additional double bonds that affect its three dimensional structure. Also shown are three so-called steroid hormones, andros-terone, estradiol, and testosterone. Note the presence of an aromatic A-ring in estradiol. 

Fig. 34. 3. Structures of selected sterols. Sources animal - lanosterol, cholesterol and ergosterol (also microbial) plant - all others. (From Warner, K., Su, C, and White, P.J. "Role of Antioxidants and Polymerization Inhibitors in Protecting Frying Oils" in Frying Technology and Practices, M.K. Gupta, K. Warner, and P.J. White (Eds.), pp. 37-49, AOCS Press, Champaign, IL 2004. With permission.)...

If as above we simply represent alicyclic rings sharing two Gs by a vertical line, then we can represent the basic tetracyclic structure of lanosterol as G61G61 G6 C5 (noting that there are two double bonds and various alkyl substituents and also a 3-hydroxyl on the first of the alicyclic rings). Many subsequent reactions yield cholesterol, a major triterpene membrane component that modifies the fluidity of animal cell membranes and is a precursor for synthesis of animal bile acids (fat solubilizing amphipathic detergents) plant triterpenes and steroid hormones such as the corticosteroids cortisol and cortisone, the mineralocorticoid aldosterone and the sex hormones testosterone and 17-(3-oestradiol. The structure and bioactivity of the plant terpenes is sketched below. 

Phytosterols are structurally very similar to cholesterol and the major phytosterols (campesterol, sitosterol and stigmasterol) have the same kind of membrane viscosity modulating function in plants that cholesterol (C27 3-OH-C6 C6 G61 C5—C8) has in animals. Campesterol (24-methylcholesterol), sitosterol (24-ethylcholesterol) and stigmasterol (A22, 24-ethylcholesterol) are widespread phytosterols. The animal sterols lanosterol and cholesterol are present in particular plants. Phytosterol esters reduce cholesterol absorption and lower LDL-cholesterol. 

Figure 26.11. Squalene Cyclization. The formation of the steroid nucleus from squalene begins with the formation of squalene epoxide. This intermediate is protonated to form a carbocation that cyclizes to form a tetracyclic structure, which rearranges to form lanosterol.

In related work, a series of important studies have been devoted to enzymatic cyclization of unnatural lanosterol precursors. Thus both epoxides (23) and (29), despite being notably different in structure from squalene oxide (32), were transformed enzymatically into the pentanorlanosterol (33a) and dihydrolano-sterol (33b), respectively. These results lend support to the suggestion that the methyl-hydrogen migration sequence rests solidly on physico-chemical... 

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