Ergosterol, biosynthetic pathway

D. Sanglard, E Ischer, T. Parkinson, D. Ealconer, J. Bille, Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents, Antimicrob. Agents Chemother. 47 2404-2412, 2003. 

A common feature of all products from the azole class is that their fungicidal activity is due to interference with the biosynthesis of fungal steroids, which are essential for cell wall construction in many of these organisms. The interference in ergosterol biosynthesis can occur at one or more points in the biosynthetic pathway depending on the nature of the azole. 

Figure 10. Biosynthetic pathway of ergosterol in Pyricularia oryzae indicating the site of inhibition by azoles and pyrimidines.

The biosynthetic pathway of ergosterol is shown in Figure 15 to explain the steps of inhibition by morpholines the accumulating sterols are framed. Inhibition of the A -reduction by fenpropimorph should lead to an accumulation of 4,4-dimethyl- A8, -ergo-statriene-ol. However, C -demethylation and side chain hydrogenation are obviously able to occur with the accumulating sterol as substrate... 

Since ergosterol is used in the formation of the leishmanial cell membrane, inhibition of ergosterol biosynthesis has been considered as a useful target for chemotherapeutic attack. Allylamines (eg. terbinafine) and imidazole antifungals (eg. ketoconazole) have been found to interfere with different steps in the biosynthetic pathway of C28 sterols in leishmania and fungi. Allylamines inhibit the microsomal squalene 2,3-epoxidase and, therefore, inhibit the synthesis of squalene epoxide, the precursor of lanosterol. Imidazoles, on other hand, inhibit cytochrome P-450 dependent C-14 demethylation of lanosterol leading to decreased or no synthesis of ergosterol [30]. 

A schematic of fungal ergosterol biosynthesis starting from squalene is shown in Figure 40.1. The biosynthetic pathway has been simplified to emphasize steps important to the action of currently employed antifungal drugs. The last nonsteroidal precursor to both ergosterol and cholesterol is the hydrocarbon squalene. Squalene is converted to squalene epoxide by the enzyme squalene epoxidase. Squalene epoxide is then cyclized to lanosterol, the first steroid in the biosynthetic pathway. The... 

In D. tertiolecta, we were able to idenhfy the majority of enzymes responsible for the biosynthesis of stigmasterol and p-sitosterol. We have also identified the enzymes synthesizing episterol, a precursor of campesterol, which is an important phytosterol known to have potential antiosteoarthritic properties (Gabay et al., 2010). Episterol is also a precursor for ergosterol however, the biosynthetic pathway branches after (S)-squalene-2,3-epoxide formation and follows a different route. Due to the fact that we did not identify most of the... 

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