Sterol biosynthesis pathway inhibitors

Figure 2. Sterol biosynthesis pathway as it is understood in yeast biochemical products, enzymes, and inhibitors (double arrows represent mote than one step).

Many of the enzymes in the sterol biosynthesis pathway have selective-inhibitors (Fig. 3). These include some extremely important classes of drugs such as Statins , used to treat high cholesterol, bisphosphonates, used to treat osteoporosis, allylamines (e.g., terbinafine) and azoles used to treat fungal infections, and morpholines which are used as fungicidal agrochemicals. 

Some of imidazoles and triazoles are the potential inhibitors of 14-demethylase, a key enzyme in the sterol biosynthesis pathway, thus directly interfere with cell wall biosynthesis in Leishmania. Fluconazole, a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections, has been used for the treatment of L. major in Old World. Similarly, ketoconazole has been used in the New World against L. panamensis and L. mexicana. Itraconazole... 

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

Target site studies can identify new processes for inhibition, ideally unique to the pest, and sometimes give information about the molecular geometry of active sites. However, investigations of fundamentally new targets is still limited. The tendency is to re-fkie understanding of well known inhibitors, or to look at untapped enzymes in proven multi-step pathways such as amino acid or sterol biosynthesis. 

Bach, T.J., 1988. Current trends in the development of sterol biosynthesis inhibitors Early aspects of the pathway. J. Amer Oil Chem. Soc. 65,591-595 Burgstahler R.J., 1985. On the mode of action of sethoxydim (PoastT, a cyclohexane-1,3-dione derivative. Karlsruhe Contribution to Plant Physiology 13, 1-111.(ISSN 0173-3133). 

Consequences for the so-called segregation model ofisoprenoid biosynthesis The presence of such alternative pathways as outlined above could provide a further explanation for the observations obtained with the HMGR inhibitor mevinolin, viz. its great efficiency in blocking cytoplasmic sterol biosynthesis, but its low efficiency to affect ubiquinone biosynthesis, and its practically complete inefficiency to block the accumulation of isoprenoids and prenyl lipids of the chloroplast (summarized and discussed earlier 14, 17]. It could also explain the puzzling observation that, in contrast to phytosterols, prenyl-subsituted coumarins were not labeled from [2- ]acetate or [2- C]MVA in elicitor-treated cultures oiAmnd majus, suggesting that the DMAPP needed for the (plastid ) umbelliferone dimethylallyl transferases (EC 2.5.1.3) is formed from IPP synthesized de novo within the plastid, rather than from IPP imported into the plastid from the cytosol [86]. Elicitor-induced inhibition of phytosterol biosynthesis should occur by specific inhibition of one of the enz)ones on the c) osolic pathway from MVA to DMAPP. 

Oximes of certain sterols were examined as inhibitors of cholesterol biosynthesis, by suppressing two enzymes that are involved in the biochemical pathway of cholesterol biosynthesis. This dual activity indicates a promising series of biologically reactive oximes (and oxime ethers) capable of reducing cholesterol levels . 

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