The η-class carbonic anhydrases as drug targets for antimalarial agents

Introduction: The eta-class of carbonic anhydrases (CAs, EC 4.2.1.1) was recently discovered as the sixth genetic family of this metalloenzyme superfamily, and seems to be present only in various Plasmodium species, the malaria-provoking pathogens. The present review through detailed biochemical, kinetic and phylogenetic studies afford a clear view regarding the differences between eta-and the other CA families. Areas covered: In this review, the authors underlined as the eta-CAs, like alpha-, gamma- and delta-class enzymes, have the Zn(II) ion coordinated by three histidine residues and a water molecule. They seem to be more closely related to the alpha-CAs, but there are notable differences between them, such as the lack of the proton shuttle residue (His64) and gatekeeper residues, Glu106 and Thr199 in the eta-CAs, which are conserved in all alpha-CAs. Expert opinion: Plasmodium falciparum eta-CA showed a moderate but significant activity for the CO2 hydration reaction, with a k(cat) of 1.4 x 10(5)s(-1) and a k(cat)/K-m of 5.4 x 10 6 M-1 x s(-1). Several inhibition studies with anions and sulfonamides/sulfamates, allowed the identification of interesting lead compounds. The discovery of eta-CA-specific inhibitors may lead to novel such agents with a new mechanism of action.