All enzymes of the postsqualene or committed sterol pathway are conserved between mammals and fungal organisms until after the formation of zymosterol (Figs 2 and 3). After the formation of lanosterol, the ergosterol pathway proceeds in a linear fashion toward the production of ergosterol (Fig. 2), but the cholesterol pathway proceeds to AZD5363 cholesterol through either one of two routes: (1) through zymosterol or (2) through lathosterol (Fig. 3). These divergent routes to sterol production result in sterols that are uniquely suited for mammalian and fungal cells. In mammalian cell membranes, cholesterol is arranged in a bilayer conformation, allowing external forces to be distributed more
efficiently (Hildenbrand & Bayerl, 2005), while in fungal cell membranes, ergosterol is arranged in a monolayer conformation, causing the membrane to be more rigid and less flexible than mammalian cell membranes (Hildenbrand & Bayerl, 2005). These differences may be attributed to the lack of a cell wall in mammalian cells and the presence of one in fungal cells. The cell wall is located outside the cell membrane and provides structural integrity and protection from external forces. Mammalian cells lack a cell wall; therefore, the cell membrane establishes structural integrity and protection from
external forces. Consequently, mammalian cell membranes are more flexible than fungal cell membranes, and the divergence of the sterol pathways contributes to the nature of these two membranes. In ergosterol, two additional double bonds formed by the actions of the C-5 desaturase and C-22 desaturase enzymes (Arthington et al., 1991; Skaggs et C59 wnt price al., 1996) contribute to the rigidity of fungal cell membranes, whereas the cholesterol molecule lacks these additional modifications, allowing the mammalian
cell membrane more flexibility to protect it from outside forces (Hildenbrand & Bayerl, 2005). Data from several studies point toward the existence of a de novo sterol pathway in P. carinii (Florin-Christensen et al., 1994; Kaneshiro et al., 1994b; Giner et al., 2001, 2002). Incubation Sitaxentan of P. carinii with radiolabeled sterol precursors such as acetate, mevalonate, squalene, HMG-CoA and isopentenyl diphosphate resulted in the synthesis of radiolabeled sterols in P. carinii, and suggested that sterol synthesis occurs through the acetate–mevalonate pathway (Florin-Christensen et al., 1994; Kaneshiro et al., 1994b; Ellis et al., 1996; Sul & Kaneshiro, 2001). It is thought that this pathway leads to the formation of rarely detected C28 and C29Δ7 sterols such as fungisterol and stigmast-7-en-3β-ol (Florin-Christensen et al., 1994), which have only been found in Trypanosoma cruzi (Liendo et al., 1999) and plant pathogenic rust fungi of the class Uredinales (Weete, 1989). In addition to these rare sterols, the organism appears to synthesize its own unique sterols, including [(24Z)-ethylidenelanost-8-en-3β-ol] (pneumocysterol) (Florin-Christensen et al., 1994; Kaneshiro et al.