2,3-Oxidosqualene: 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.

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. 

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... 

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... 

Brown and coworkers found use for the Meyer-Schuster rearrangement in their synthesis of quinuclidine inhibitors of 2,3-oxidosqualene cyclase/lanosterol synthase (OSC). The rearrangement was the last step in the synthesis of one such inhibitor, utilizing concentrated H2SO4 to carry out the transformation from 37. 

Class 11 terpene cyclases are known for the cycUzation of di-, sester-, and triterpenoids. Prominent examples of triterpene cyclases are the human lanosterol synthase (oxidosqualene cyclase, OSC) and the squalene/hopene cyclase (SHC) firom A. acidocaldarius [1]. Both enzymes have a py-domain architecture (Fig. 87.15a). The p-domain exhibits a highly regular Oe-Oe barrel structure with six inner and six outer helices surrounding a central cavity (Fig. 87.15b) [198,199, 208]. The y-domains may have originated from the p-domains by gene duplicatimi... 

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