Survival strategies of the malarial parasite Plasmodium falciparum

Plasmodium falciparum, the protozoan parasite causing falciparum malaria, is undoubtedly highly versatile when it comes to survival and defence strategies. Strategies adopted by the asexual blood stages of Plasmodium range from unique pathways of nutrient uptake to immune evasion strategies and multiple drug resistance. Studying the survival strategies of Plasmodium could help us envisage strategies of tackling one of the worst scourges of mankind

Analysis of proteins with the 'hot dog' fold: Prediction of function and identification of catalytic residues of hypothetical proteins

<p>Abstract</p> <p>Background</p> <p>The hot dog fold has been found in more than sixty proteins since the first report of its existence about a decade ago. The fold appears to have a strong association with fatty acid biosynthesis, its regulation and metabolism, as the proteins with this fold are predominantly coenzyme A-binding enzymes with a variety of substrates located at their active sites.</p> <p>Results</p> <p>We have analyzed the structural features and sequences of proteins having the hot dog fold. This study reveals that though the basic architecture of the fold is well conserved in these proteins, significant differences exist in their sequence, nature of substrate and oligomerization. Segments with certain conserved sequence motifs seem to play crucial structural and functional roles in various classes of these proteins.</p> <p>Conclusion</p> <p>The analysis led to predictions regarding the functional classification and identification of possible catalytic residues of a number of hot dog fold-containing hypothetical proteins whose structures were determined in high throughput structural genomics projects.</p

Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum

The antimicrobial biocide triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol] potently inhibits the growth of Plasmodium falciparum in vitro and, in a mouse model, Plasmodium berghei in vivo. Inhibition of [14C]acetate and [14C]malonyl-CoA incorporation into fatty acids in vivo and in vitro, respectively, by triclosan implicate FabI as its target. Here we demonstrate that the enoyl-ACP reductase purified from P. falciparum is triclosan sensitive. Also, we present the evidence for the existence of FabI gene in P. falciparum. We establish the existence of the de novo fatty acid biosynthetic pathway in this parasite, and identify a key enzyme of this pathway for the development of new antimalarials

Receptor-mediated targeting of toxins to intraerythrocytic parasite Plasmodium falciparum

The increasing prevalence of drug-resistant Plasmodium falciparum malaria and the absence of effective vaccines or of vector control measures makes the development of new antimalarial drugs and other approaches for treating malaria, an urgent priority. The development of immunotoxins for targeted cytotoxic effects to kill the parasite is an attractive alternative therapeutic concept. The cytocidal effect of such hybrid molecules is highly specific and requires only minute doses. Cell surface receptor-directed targeting of toxins (hybrid toxins or immunotoxins) to human malaria parasite could eventually be developed as an effective therapy for malaria. Hybrid toxins may provide means of controlling this dreadful disease and counter morbidity as well as mortality. Our results suggests that hybrid toxins are potent and efficacious in killing the parasite and that these agents should be examined in an appropriate in vivo model of malaria

Catalysis and mechanism of malonyl transferase activity in type II fatty acid biosynthesis acyl carrier proteins

One of the unexplored, yet important aspects of the biology of acyl carrier proteins (ACPs) is the self-acylation and malonyl transferase activities dedicated to ACPs in polyketide synthesis. Our studies demonstrate the existence of malonyl transferase activity in ACPs involved in type II fatty acid biosynthesis from Plasmodium falciparum and Escherichia coli. We also show that the catalytic malonyl transferase activity is intrinsic to an individual ACP. Mutational analysis implicates an arginine/lysine in loop II and an arginine/glutamine in helix III as the catalytic residues for transferase function. The hydrogen bonding properties of these residues appears to be indispensable for the transferase reaction. Complementation of fabD(Ts) E. coli highlights the putative physiological role of this process. Our studies thus shed light on a key aspect of ACP biology and provide insights into the mechanism involved therein

15-Deoxyspergualin inhibits eukaryotic protein synthesis through eIF2αeIF2\alpha phosphorylation

DSG (15-deoxyspergualin), an immunosuppressant with tumoricidal properties, binds potently to the regulatory C-terminal ‘EEVD’ motif of Hsps (heat-shock proteins). In the present study we demonstrate that DSG inhibits eukaryotic protein synthesis by sequestering Hsp70 which is required for maintaining HRI (haemregulated inhibitor), a kinase of the $eIF2\alpha$ (eukaryotic initiation factor $2\alpha$), inactive. DSG stalled initiation of protein synthesis through phosphorylation of HRI and $eIF2\alpha$. Addition of a recombinant $eIF2\alpha$ (S51A) protein, which lacks the phosphorylation site, lowered the inhibitory potential of DSG in reticulocyte lysate. The inhibitory effect of DSG was also attenuated in HRI knockdown cells. Moreover, exogenous addition of Hsp70 or the peptide ‘EEVD’ reversed the inhibitory effect of DSG. Interestingly, the inhibitory effect of DSG in different mammalian cancer cells was found to negatively correlate with the amount of Hsp70 expressed in the cells, emphasizing the link with Hsp70 in DSG inhibition of eukaryotic translation

Is the fatty acid synthesis pathway a good target for anti-malarial therapy?

Proteins and nucleic acids may be the basic building blocks of organisms, but without fatty acids, the scafold of life would be incomplete. Fatty acids are the essential components of phospholipids and sphingolipids that make up cellular and intracellular membranes, and cofactors, pigments, signaling molecules, etc. Fatty acids are synthesized from simple precursors by all organisms, save for a few like the mycoplasmas, which acquire them from their host (1). So, on to center stage! The action is where the fatty acids are synthesized!!