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

The η-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 η- and the other CA families.

In this review, the authors underlined as the η-CAs, like α-, γ- and δ-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 α-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 η-CAs, which are conserved in all α-CAs.

Plasmodium falciparum η-CA showed a moderate but significant activity for the CO2 hydration reaction, with a kcat of 1.4 × 10(5)s(-1) and a kcat/Km of 5.4 × 10(6) M(-1) × s(-1). Several inhibition studies with anions and sulfonamides/sulfamates, allowed the identification of interesting lead compounds. The discovery of η-CA-specific inhibitors may lead to novel such agents with a new mechanism of action.