Vitamin B6-Dependent Enzymes in the Human Malaria ParasitePlasmodium falciparum: A Druggable Target?

Thales Kronenberger,Flávia M Zimbres,Frank M Sauer,Monika A Coronado,Jasmin Lindner,Kamila A Meissner,Isolmar Schettert,Carsten Wrenger

doi:10.1155/2014/108516

Abstract

Malaria is a deadly infectious disease which affects millions of people each year in tropical regions. There is no effective vaccine available and the treatment is based on drugs which are currently facing an emergence of drug resistance and in this sense the search for new drug targets is indispensable. It is well established that vitamin biosynthetic pathways, such as the vitamin B6 de novo synthesis present in Plasmodium, are excellent drug targets. The active form of vitamin B6, pyridoxal 5-phosphate, is, besides its antioxidative properties, a cofactor for a variety of essential enzymes present in the malaria parasite which includes the ornithine decarboxylase (ODC, synthesis of polyamines), the aspartate aminotransferase (AspAT, involved in the protein biosynthesis), and the serine hydroxymethyltransferase (SHMT, a key enzyme within the folate metabolism).

Highlights

Malaria is a devastating infectious disease, which causes serious problems in tropical and subtropical areas
The causative agent of malaria is belonging to the genus Plasmodium, which can affect almost all vertebrates; only five species have been reported to be infective for humans, P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi [2]
Besides the well-established function of vitamin B6 in acting as a cofactor, the molecule is involved in the combat against reactive oxygen species (ROS), in particular against singlet oxygen [22, 28]. This additional mode of action is especially of relevance for the intraerythrocytic stage of the human malaria parasite, because Plasmodium is permanently exposed to ROS during proliferation within the erythrocytes due to the oxidative environment of its host cell which is accompanied by the parasite-driven haemoglobin degradation [29, 30]

Summary

Introduction

Malaria is a devastating infectious disease, which causes serious problems in tropical and subtropical areas. In the search for novel antimalarials, attention has been drawn on selective interference with the parasite’s metabolism without harming the human host [13] In this sense promising drug targets are vitamin biosynthetic pathways. Besides the well-established function of vitamin B6 in acting as a cofactor, the molecule is involved in the combat against reactive oxygen species (ROS), in particular against singlet oxygen [22, 28] This additional mode of action is especially of relevance for the intraerythrocytic stage of the human malaria parasite, because Plasmodium is permanently exposed to ROS during proliferation within the erythrocytes due to the oxidative environment of its host cell which is accompanied by the parasite-driven haemoglobin degradation [29, 30]. These molecules were shown to interfere with PLP-dependent enzymes by inhibiting their catalyses and the growth of the parasite [32]

PLP-Dependent Enzymes

Druggable PLP-Dependent Enzymes in the Malaria Vector

Conclusion