Exploiting Unique Structural and Functional Properties of Malarial Glycolytic Enzymes for Antimalarial Drug Development

Abstract

Metabolic enzymes have been known to carry out a variety of functions besides their normal housekeeping roles known as “moonlighting functions.” These functionalities arise from structural changes induced by posttranslational modifications and/or binding of interacting proteins. Glycolysis is the sole source of energy generation for malaria parasite Plasmodium falciparum, hence a potential pathway for therapeutic intervention. Crystal structures of several P. falciparum glycolytic enzymes have been solved, revealing that they exhibit unique structural differences from the respective host enzymes, which could be exploited for their selective targeting. In addition, these enzymes carry out many parasite-specific functions, which could be of potential interest to control parasite development and transmission. This review focuses on the moonlighting functions of P. falciparum glycolytic enzymes and unique structural differences and functional features of the parasite enzymes, which could be exploited for therapeutic and transmission blocking interventions against malaria.

Plasmodium vivaxand human hexokinases share similar active sites but display distinct quaternary architectures

“…In addition, glycolysis inhibitors deplete parasite ATP (van Schalkwyk et al, 2008). Taken together, these results strongly indicate that glycolysis is vital for parasite growth and thus components of the glycolytic pathway should be considered as promising targets for novel therapeutics (Alam et al, 2014;Preuss et al, 2012). Consistent with this hypothesis, many glucose analogs have been shown to have antiparasitic activity (Santos de Macedo et al, 2001;Udeinya & Van Dyke, 1981;van Schalkwyk et al, 2008).…”

“…Only a single class of drug (8-aminoquinolines), the mode of action of which is not well understood, is active against hypnozoites, and its use is complicated and potentially lethal to the patient (Wells et al, 2010). During the intra-erythrocytic stage of the parasite, which causes pathogenesis in humans, glucose metabolism via glycolysis plays a critical metabolic role for the parasite (Alam et al, 2014;Preuss et al, 2012;Vaidya & Mather, 2009). Glucose consumption is up to 100-fold higher in erythrocytes infected with parasites (Roth et al, 1982) and knockout of the parasite glucose transporter appears to be lethal (Slavic et al, 2010).…”

Genetic engineering of Theileria parva lactate dehydrogenase gene: a new anti-theilerial target

“…Moreover, the substrate specificity loop (residues 97-112) has a penta peptide insertion (Bzik et al 1993) that forms a separate cavity in the surface adjacent to the catalytic region which is absent in mammalian LDHs (Dunn et al 1996). These structural differences could be exploited for selective targeting of the parasite enzyme (Alam et al 2014). Based on the previous investigations of Plasmodium species (Cameron et al 2004, Dunn et al 1996, we aimed to inquire the possibility of designing new anti-theilerial drugs from the data on TpLDH in this study.…”

Proteomic analysis of microparticles isolated from malaria positive blood samples

“…Enolase was found in MPs of 38 of the samples. It is known to play a crucial role in the parasite invasion of the midgut of the mosquito [38]. A study has shown that its levels are elevated in infected red blood cells compared to uninfected cells.…”