Characterization of Lipid Binding Properties of Plasmodium falciparum Acyl-Coenzyme A Binding Proteins and Their Competitive Inhibition by Mefloquine

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Abstract

Malaria remains a worldwide concern in terms of morbidity and mortality. Limited understanding of the Plasmodium proteome makes it challenging to control malaria. Understanding of the expression and functions of different Plasmodium proteins will help in knowing this organism's virulence properties, besides facilitating the drug development process. In this study, we characterize the lipid binding and biophysical properties of the putative Plasmodium falciparum acyl-CoA binding proteins (PfACBPs), which may have intriguing functions in different stages of P. falciparum life cycle. While the PfACBPs can bind to long-chain fatty acyl-CoAs with high affinity, their affinity for short-chain fatty acyl-CoAs is weak. Base-stacking, electrostatic, and hydrophobic interactions between the aromatic rings, charged groups or residues, and hydrophobic chains or residues are responsible for acyl-CoA binding to PfACBPs. PfACBPs can also bind to phospholipids. PfACBPs cannot bind to the fatty acids and unphosphorylated fatty acid esters. PfACBPs are globular-helical proteins that contain a conserved acyl-CoA binding region. They exist in folded or unfolded conformations without attaining any intermediate state. In a systematic high-throughput in silico screening, mefloquine is identified as a potential ligand of PfACBPs. Binding affinities of mefloquine are much higher than those of fatty acyl-CoAs for all PfACBPs. Mefloquine binds to the acyl-CoA binding pocket of PfACBPs, thereby engaging many of the critical residues. Thus, mefloquine acts as a competitive inhibitor against fatty acyl-CoA binding to PfACBPs, leading to the prevention of P. falciparum growth and proliferation. Taken together, our study characterizes the functions of annotated PfACBPs and highlights the mechanistic details of their inactivation by mefloquine.

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