Carbonic anhydrase activity of dinuclear CuII complexes with patellamide model ligands

Abstract

The dicopper(II) complexes of six pseudo-octapeptides, synthetic analogues of ascidiacyclamide and the patellamides, found in ascidians of the Pacific and Indian Oceans, are shown to be efficient carbonic anhydrase model complexes with k_cat up to 7.3 × 10³ s⁻¹ (uncatalyzed: 3.7 × 10⁻² s⁻¹; enzyme-catalyzed: 2 × 10⁵–1.4 × 10⁶ s⁻¹) and a turnover number (TON) of at least 1700, limited only by the experimental conditions used. So far, no copper-based natural carbonic anhydrases are known, no faster model systems have been described and the biological role of the patellamide macrocycles is so far unknown. The observed CO₂ hydration rates depend on the configuration of the isopropyl side chains of the pseudo-octapeptide scaffold, and the naturally observed R*,S*,R*,S* geometry is shown to lead to more efficient catalysts than the S*,S*,S*,S* isomers. The catalytic efficiency also depends on the heterocyclic donor groups of the pseudo-octapeptides. Interestingly, the dicopper(II) complex of the ligand with four imidazole groups is a more efficient catalyst than that of the close analogue of ascidiacyclamide with two thiazole and two oxazoline rings. The experimental observations indicate that the nucleophilic attack of a Cu^II-coordinated hydroxide at the CO₂ carbon center is rate determining, i.e. formation of the catalyst-CO₂ adduct and release of carbonate/bicarbonate are relatively fast processes.