The η-class carbonic anhydrases as drug targets for antimalarial agents. (April 2015)

• Record Type: Journal Article
• Authors: Supuran, Claudiu T; Capasso, Clemente
• Is Part Of: Expert opinion on therapeutic targets. Volume 19:Number 4(2015:Apr.)
• Page Start: 551
• Page End: 563
• Publication Date: 2015-04
• Subjects: Drugs -- Research -- Periodicals; 615.072
• DOI: 10.1517/14728222.2014.991312
• Languages: English
• ISSNs: 1744-7631

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold> <italic>Introduction:</italic> </bold> 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 <italic>Plasmodium</italic> 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.</p> <p> <bold> <italic>Areas covered:</italic> </bold> 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.</p> <p> <bold> <italic>Expert opinion:</italic> </bold> <italic>Plasmodium falciparum</italic> η-CA showed a moderate but significant activity for the CO<sub>2</sub> hydration reaction, with a <italic>k</italic><sub>cat</sub> of 1.4 × 10<sup>5</sup>s<sup>-1</sup> and a <italic>k</italic><sub>cat</sub>/<italic>K</italic><sub>m</sub> of 5.4 × 10<sup>6</sup> M<sup>-1</sup> × s<sup>-1</sup>. 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.</p> </abstract>