There through the reaction of isopentenyl pyrophosphate and dimethylallyl

There are many areas of Saudi Arabia like Al-Hassa, Hail and Madinah where the disease is common. There are three different forms of leishmaniasis, visceral, cutaneous and mucocutaneous. Current available drugs to cure leishmaniasis are far from satisfactory outcomes due to their serious side effects and rise in cases of drug resistance Reithinger et al., 2007; Mishra et al 1992). In view of this, it is pertinent to look into novel biochemical molecules as drug targets to control the detrimental effects of Leishmania. STEROL PATHWAY IN TRYPANOSOMATIDS: Sterol biosynthesis is an important metabolic pathway in eukaryotes. It consists of 20 necessary metabolic steps (Figure 1) under three  different  stages:  (i) the formation of isopentenyl  pyrophosphate  from acetyl CoA or another reserve of carbon like leucine which is reported in trypanosomatids (Urbina, 1997);  (ii)  formation of squalene the  through the reaction of  isopentenyl pyrophosphate and dimethylallyl pyrophosphate; and (iii) formation of lanosterol from squalene through ring formation reactions.

  The major sterols in these organisms consist of ?5, 7-compounds related to C28-ergostane or the C29-stigmastane family (Arish et al., 2015; Ishida 2009). Leishmania mainly have ergosta-5, 7, 24 (241)-trien-3 ?-ol (5-dehydroepisterol) sterol in both of its important stages (promastigotes and amastigotes) of life cycle. In addition, promastigotes  also  possess  stigmastane type of  sterols  comprising  the  5%  of  total  sterols  whereas amastigotes consist of same up to 20 %. Ergosterol in Leishmania species is necessary for its development and proliferation, but missing in its human counterparts (Mishra et al 1992). The mammals instead synthesize cholesterol which differs from ergosterol in having only one double bond and in saturation of side chain fatty acid  at C24.

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The cholesterol in the membrane of trypanosomatids is generally incorporated from growth-medium or through the infected person’s body (Urbina, 1997). Formation of ergosterol as well as cholesterol takes several steps in the respective organisms. One of the important step during ergosterol biosynthesis and invariably  different  from  cholesterol  synthesis  is  the  transfer  of  methyl  group  from  S-Adenosyl-L- methionine (SAM) to C-24 of ?24 sterols to produce ?24 (28)-sterols, which is regulated by a key enzyme sterol 24-c- methyltransferase (Figure 1).

 ERGOSTEROL PATHWAY AS DRUG TARGET:Ergosterol is a major sterol in Leishmania membrane, so the 24-c- methyltransferase (SMT) is a requisite enzyme during its synthesis. Mammals lack this enzyme and therefore, it may be a valuable target for drug development to cure the leishmaniasis. In addition, there are many other enzymes in the ergosterol biosynthetic pathway like C-8 sterol isomerase, delta7-sterol 5-desaturase, sterol 22-desaturase and delta 24(24(1))-sterol reductase which are different from the mammalian sterol biosynthetic pathway Magaraci et al., 2003; Figure 1. So far, azasterol and amphotericin B have been reported to exhibit the effective anti-leishmanicidal activity in vitro (Magaraci et al., 2003), which interferes with C-24 alkylation by SMT during the late stage of ergosterol synthesis.

However, in vivo significance of these drugs is often associated with unsatisfactory outcome. It is required that all the enzymes of ergosterol biosynthetic pathway to be expressed, purified and crystallized. Further structure based drug screening through bioinformatical tools and biochemical methods are required to develop effective cheap and new drugs against leishmaniasis.  CONCLUSION: The available chemotherapeutic drugs against leishmaniasis are costly, toxic and less effective. It is very important to search for new drugs which are cheap, effective and have least side effects. All the pathogens of trypanosomatid family have common ergosterol biosynthetic pathway that is why targeting the different enzymes of ergosterol biosynthetic pathway will have broader application in the development of new therapeutics against other infectious diseases also.