Plasmodium falciparum η-carbonic anhydrase

Abstract

Malaria parasites belonging to the genus Plasmodium encode for a carbonic anhydrase (CA, EC 4.2.1.1) originally considered to belong to the α-class, which has been investigated starting with 2004 as a potential antimalarial target, considering the observation that CA levels in red blood cells infected with these parasites are much higher compared to those of uninfected cells. In plasmodia, CA is involved in metabolic pathways leading to the biosynthesis of pyrimidines, which are scarcely present in the blood of infected hosts, making this enzyme crucial for the life cycle of the parasite in many intraerythrocytic stages of its development. It has been then shown in 2014 that P. falciparum CA (PfCA) belongs in fact to a new CA genetic class, the η-CA, characterized by a particular zinc ion coordination within the active site, with two histidine and a glutamine as protein ligands. A short, truncated and longer PfCA forms have been cloned and characterized in detail, being shown that they act as efficient catalysts for the hydration of CO₂ to bicarbonate and protons, but neither of them were crystallized for the moment, and their 3D structure is not known. PfCA inhibition with anions, sulfonamides, phenols and coumarins has been investigated too, with many low nanomolar in vitro inhibitors being detected. Only for acetazolamide and an ureido-substituted benzenesulfonamide it has been demonstrated a potent growth inhibition of the pathogen in P. falciparum infected red blood cells. Although these results are encouraging but rather preliminary, η-CAs from malaria-producing protozoans and presumably other organisms encoding them, may be considered as innovative drug targets for obtaining anti-infectives with new mechanisms of action but these enzymes should be investigated in more details in order to better understand their structure and physiological/pathological roles.

Keywords: Carbonic anhydrase; Drug targets; Plasmodium falciparum; Protozoa; Pyrimidines metabolism.