Computational And Biochemical Studies On The Enzymes Of Type II Fatty Acid Biosynthesis Pathway : Towards Antimalarial And Antibacterial Drug Discovery
Gyanendra Kumar · 2007
Malaria, caused by the parasite Plasmodium, continues to exact high global morbidity and mortality rate next only to tuberculosis. It causes 300-500 million clinical infections out of which more than a million people succumb to death annually. Worst affected are the children below 5 years of age in sub-Saharan Africa. Plasmodium is a protozoan parasite classified under the phylum Apicomplexa that also includes parasites such as Toxoplasma, Lankestrella, Eimeria and Cryptosporidium. Of the four species of Plasmodium affecting man viz., P. falciparum, P. vivax, P. ovale and P. malariae, Plasmodium falciparum is the deadliest as it causes cerebral malaria. The situation has worsened recently with the emergence of drug resistance in the parasite. Therefore, deciphering new pathways in the parasite for developing lead antimalarial compounds is the need of the hour. The discovery of the type II fatty acid biosynthesis pathway in Plasmodium falciparum has opened up new avenues for the design of new antimalarials as this pathway is different from the one in human hosts. Although many biochemical pathways such as the purine, pyrimidine and carbohydrate metabolic pathways, and the phospholipid, folate and heme biosynthetic pathways operate in the malaria parasite and are being investigated for their amenability as antimalarial therapeutic targets, no antimalarial of commercial use based on the direct intervention of these biochemical pathways has emerged so far. This is due to the fact that the structure and function of the targets of these drugs overlaps with that of the human host. A description of the parasite, its metabolic pathways, efforts to use these pathways for antimalarial drug discovery, inhibitors targeting these pathways, introduction to fatty acid biosynthesis pathway, discovery of type II fatty acid biosynthesis pathway in Plasmodium falciparum and prospects of developing lead compounds towards antimalarial drug discovery is given in Chapter 1 of the thesis. In the exploration of newly discovered type II fatty acid biosynthesis pathway of P. falciparum as a drug target for antimalarial drug discovery, one of the enzymes; β-hydroxyacyl- acyl carrier protein dehydratase (PfFabZ) was cloned and being characterized in the lab. The atomic structure of PfFabZ was not known till that point of time. Chapter 2 describes the homology modeled structure of PfFabZ and docking of the discovered inhibitors with this structure to provide a rationale for their inhibitory activity. Despite low sequence identity of ~ 21% with the closest available atomic structure then, E. coli FabA, a good model of PfFabZ could be built. A comparison of the modeled structure with recently determined crystal structure of PfFabZ is provided and design of new potential inhibitors is described. This study provides insights to further improve the inhibition of this enzyme. Enoyl acyl carrier protein reductase (ENR) is the most important enzyme in the type II fatty acid biosynthesis pathway. It has been proved as an important target for…