Lanosterol synthase

Fig. 5.1 Cyclization of 2,3-oxidosqualene to sterols and triterpenoids. The 2,3-oxidosqualene cyclase enzymes that catalyse the formation of the different products are indicated LS, lanosterol synthase CS, cycloartenol synthase LuS, lupeol synthase PAS, P-amyrin synthase aAS, a-amyrin synthase.

The deduced amino acid sequence of AsbASl contains the conserved DCTAE motif implicated in substrate binding in OSCs,37 and also four conserved QW motifs that are characteristic for the OSC superfamily.38 Remarkably, AsbASl is clearly distinct from the other cloned PAS enzymes that have been characterized to date from other plant species, and is more closely related to lanosterol synthases from animals and fungi than to triterpenoid synthases or cycloartenol synthases from plants (Fig. 5.3).35 There are substantial mechanistic differences in the processes of... 

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). 

Saccharomyces cerevisiae Lanosterol synthase ERG7 U04841 40... 

Candida albicans Lanosterol synthase ERG7 L04305 38... 

Rattus norvegicus Lanosterol synthase (LS). . ngvtfyaklBaedBhB.. reemvrylrsvBlpnBgB.. wiv,... 

Corey, E.J., Matsuda, S.P.T. and Bartel, B. (1993) Isolation oi an Arabidopsis thaliana gene encoding cycloartenol synthase by functional expression in a yeast mutant lacking lanosterol synthase by the use of a chromatographic screen. Proc. Natl. Acad. Sci. USA, 90,11628-32. 

Squalene synthase, 3 = Squalene monooxygenase, 4 = 2,3-Oxidosqualene lanosterol cyclase, 5 = Enzymes catalyzing 20 separate reactions. Note that squalene and lanosterol are acted upon by ER membrane enzymes while they are bound to carrier proteins in the cytoplasm. 

A group of fungicides that inhibit squalene epoxidation has been developed primarily for use against pathogenic fungi in medicine. Epoxidation of squalene is catalyzed by squalene epoxidase (a flavoprotein) that starts the complicated cyclization of squalene. The squalene-2,3-epoxide formed by this enzyme is further metabolized to a protosterol cation intermediate, which is transformed to either cycloartenol in plants (cycloartenol synthase) or lanosterol (lanosterol synthase). Cycloartenol is the precursor to plant sterols, whereas lanosterol is the precursor of cholesterol and the other sterols in animals, and to ergosterol in plants. 

The conversion of oxidosqualene 50 to lanosterol 52, the so-called squalene folding in the biosynthesis of steroids has initiated much research efforts (Scheme 10) [23]. This process is catalyzed by the enzyme lanosterol synthase, which controls precisely the formation of four rings and six new stereocenters. According to the pioneering work by Eschen-moser and Stork the cyclization proceeds in a concerted fashion due to favorable orbital overlap [24, 25]. In contrast Nishizawa et al. were able to trap several cationic intermediates 55-57 from a related model system 54... 

H.J. Harwood, Jr., W.W. Ku, M.R. Waterman, and D. Rozman (2000). Lanosterol 14a-demethylase (CYP51), NADPH-cytochrome P450 reductase and squalene synthase in spermatogenesis Late spermatids of the rat express proteins needed to synthesize follicular fluid meiosis activating sterol. J. Endocrinol. 166, 463-474. 

Trypanosome and animal lanosterol synthase use different catalytic motifs. Org. Lett. 3, 1957-1960. 

Squalene synthase Squaiene epoxidase Lanosterol synthase... 

Lanosterol synthase Erg 7 oxidosqualene cyclase Side tai et of some amines (G2)... 

LSSA t Lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase) Lipid metabolism/cholesterol biosynthesis... 

---