Besides its cytosolic localization, it is also present in the parasite membrane fraction.In vitrostudies using HeLa cell microsomal membranes showed that PfGAPDH was recruited to the membrane, which was dependent AM 103 on the mammalian GTPase Rab2, indicating a probable role of PfGAPDH in vesicular transport and apical organelle biogenesis [66]. The crystal structure of PfGAPDH was decided based on rabbit GAPDH. for novel therapeutic targets and drugs against the disease [2]. Parasite-specific processes such as hemoglobin degradation, parasite egress from the host cell, and host cell invasion by the parasite have been the focus of drug discovery efforts against malaria [3]. In addition to these pathways, one attractive pathway for drug development is usually parasite’s energy producing machinery. A compound targeting parasite’s ATP-generating machinery could be a potential antimalarial. == 2. Review == == 2.1.P. falciparumGlycolysis == Glycolysis is an ancient conserved metabolic energy producing machinery, which converts glucose to pyruvate and lactate under aerobic and anaerobic conditions, respectively. It has been an established fact thatP. falciparumsolely depends on glycolysis for energy generation and fulfills its energy needs by anaerobic metabolism of glucose to lactate as the parasite and the red blood cells (RBCs) both are devoid of functional Kreb’s cycle [4]. The rate of glycolysis inP. falciparum-infected erythrocytes is usually 20100 times higher than uninfected erythrocytes [5,6]. A study by Roth Jr. et al. (1988) exhibited that nearly all the glycolytic enzymes were upregulated inP. falciparum-infected RBCs, which was proportional to the parasitemia level. The enzymes particularly upregulated were hexokinase, aldolase, enolase, pyruvate kinase, and adenosine deaminase [7]. SeveralP. falciparumglycolytic enzymes, although being homologous to their human counterparts, possess distinct structural and biochemical features [814]. To selectively target parasite glycolytic enzymes, these differences between the host and parasite enzymes could be exploited. This review Nr2f1 focuses on the potential of AM 103 unique structural and functional properties of malarial glycolytic enzymes as targets of antimalarial drug discovery. == 2.2. Moonlighting Functions of Glycolytic Enzymes and Unique Structural and Functional Properties of Malarial Glycolytic Enzymes == In prior years, it was believed that a single gene encodes a single polypeptide and was generally expected to carry out a single function [15,16] but later it was found that a single protein could carry out multiple functions. This phenomenon was termed as moonlighting by Jeffery and referred to unrelated functions of glycolytic enzymes and many other metabolic enzymes exhibit within or outside the cell [17]. Moonlighting functions in proteins may arise due to structural changes occurring in the proteins due AM 103 to differential binding partners AM 103 and/or posttranslational modifications (PTMs). This phenomenon is usually involved in pathologies related to many cellular and infectious diseases; hence an improved understanding of moonlighting proteins will provide opportunity to selectively target these functions [18]. The first example of moonlighting proteins was cytokine neuroleukin, secreted by lectin-stimulated T cells that induce immunoglobulin secretion by cultured human peripheral blood mononuclear cells. This cytokine was also found to have phosphoglucose isomerase activity, which converts glucose 6-phosphate to fructose 6-phosphate during glycolysis [1921]. In the metabolic map of glycolysis, 7 of the 10 glycolytic enzymes exhibit moonlighting activities. In addition, other metabolic enzymes closely linked to glycolysis (e.g., glycerol kinase and fructose-1,6-bisphosphatase) also possess moonlighting functions. Seven of the eight enzymes of tricarboxylic acid cycle have also been supposed to possess moonlighting functions [22]. Some of the major moonlighting functions of glycolytic enzymes are transcriptional regulation (hexokinase-2, lactate dehydrogenase-A, and enolase 1), apoptosis (hexokinase and glyceraldehyde 3-phosphate dehydrogenase), and cell motility (glucose 6-phosphate isomerase) (reviewed by Kim and Dang 2005) [23]. Examples of moonlighting functions of glycolytic enzymes in various organisms are listed inTable 1. == Table 1. == Examples of nonglycolytic functions of glycolytic enzymes in various organisms. P. falciparumglycolytic enzymes are significantly divergent from their human homologs (Table 2) and several of these enzymes possess unique structural and functional.
