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

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: Plasmodium falciparum η-CA showed a moderate but significant activity for the CO₂ hydration reaction, with a k_cat of 1.4 × 10⁵s^-1 and a k_cat/K_m of 5.4 × 10⁶ 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.

Keywords:

• η-class enzyme
• anion inhibitor
• antimalarials
• carbonic anhydrase
• drug target
• sulfonamide

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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