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

Abstract

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.

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

“…Interestingly, γ-CAs use only CO 2 as substrate, while β-CAs can hydrolyze CO 2, H 2 S and COS [18]. Furthermore, α-CAs not only hydrate CO 2 , CS 2 but also possess esterase activity, with a range of esters of carboxylic, sulfonic or phosphate acids [6,9,11,17,19,20]. Generally, bacterial genome encodes for three CA classes that in agreement with the CA family nomenclature are designed as α, β and γ [17].…”

“…The CA classification uses Greek letters for the designation of the seven CA families known to date, i.e., the α, β, γ, δ, ζ η and θ-CAs [5][6][7][8][9][10]. Detailed biochemical, kinetic, phylogenetic and structural studies afforded a clear view regarding the differences between CA families.…”

“…The *Address correspondence to these authors at the Istituto di Bioscienze e Biorisorse, CNR, via Pietro Castellino 111-80131 Napoli, Italy; Tel:/Fax: +39-081-6132559/+39-081-6132558; E-mail: clemente.capasso@ibbr.cnr.it; Laboratorio di Chimica Bioinorganica, and Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Universita` degli Studi di Firenze, via della Lastruccia 3 -50019, Sesto Fiorentino, Firenze, Italy; Tel:/Fax: +39-055-4573729/+39-055-4573005; E-mail:claudiu.supuran@unifi.it catalytic function of CO 2 hydration is maintained for all CA classes, despite the diverse spatial reorganization of the active sites [5,[11][12][13][14][15][16]. In general the catalytic efficiency of the γ-, δ-and ζ-CAs is low compared to the β-and η-CAs, which in turn are less efficient catalysts compared to many bacterial α-CAs [6,9,11,17]. Interestingly, γ-CAs use only CO 2 as substrate, while β-CAs can hydrolyze CO 2, H 2 S and COS [18].…”

“…The metal ion from the enzyme active site is coordinated by three His residues in the α-, γ-,δ-and θ-classes, by one His, and two Cys residues in β-and ζ-CAs or by two His and one Gln residues in η-class with the fourth ligand being a water molecule/hydroxide ion acting as nucleophile in the catalytic cycle of the enzyme [9,12,17,25]. The α-, β-, δ-and, probably η-and θ-CAs use Zn(II) ions at the active site, γ-CAs are Fe(II) enzymes but they are active also with bound Zn(II) or Co(II) ions, whereas ζ-class uses Cd(II) or Zn(II) to perform the physiologic reaction catalysis [6,9,12,17,26,27]. The α-, β-, γ-and ζ-CAs have been crystallized, but not δ-, η-and θ-CAs.…”

“…For example, α-CAs are normally monomers and rarely dimmers; β-CAs are dimers, tetramers or octamers; γ-CAs are trimers; the only ζ-CA crystallized so far has three slightly different active sites on the same polypeptide chain [8,28]. Phylogenetic analysis has shown that the most recent form is the α-CA class, whereas the γ-class is the most ancient CA class, catalyzing only CO 2 hydration with a rather weak catalytic efficiency and is the only CA class mainly identified in Archaea, the most ancient microorganisms that exist on earth [6,12,17,29].…”