Dinuclear Zn^II and mixed Cu^II–Zn^II complexes of artificial patellamides as phosphatase models

Abstract

The patellamides (cyclic pseudo-octapeptides) are produced by Prochloron, a symbiont of the ascidians, marine invertebrate filter feeders. These pseudo-octapeptides are present in the cytoplasm and a possible natural function of putative metal complexes of these compounds is hydrolase activity, however the true biological role is still unknown. The dinuclear Cu complexes of synthetic patellamide derivatives have been shown in in vitro experiments to be efficient hydrolase model catalysts. Many hydrolase enzymes, specifically phosphatases and carboanhydrases, are Zn-based enzymes and therefore, we have studied the Zn and mixed Zn/Cu solution chemistry of a series of synthetic patellamide derivatives, including solution structural and computational work, with the special focus on model phosphatase chemistry with bis-(2,4-dinitrophenyl)phosphate (BDNPP) as the substrate. The Zn complexes of a series of ligands are shown to form complexes of similar structure and stability compared to the well-studied Cu analogues and the phosphatase reactivities are also similar. Since the complex stabilities and phosphatase activities are generally a little lower compared to those of Cu and since the concentration of Zn in Prochloron cells is slightly smaller, we conclude that the Cu complexes of the patellamides are more likely to be of biological importance.

Is CuII Coordinated to Patellamides inside Prochloron Cells?

“…The formation of Cu II complexes inside Prochloron cells indicates that the catalysis of various hydrolysis reactions observed in vitro, such as those of carbonic anhydrase, phosphatase, lactamase, and glycosidase, and possibly others not yet explored, might be the metabolic purpose of patellamides. The corresponding Zn II complexes, which have also been shown to form and to be catalytically active, are less likely to be of biological relevance, and the Cu II complexes might therefore be a rare case of Cu II hydrolase enzymes. As yet, it is unclear as to whether mono‐ or dinuclear complexes are formed in vivo, and their structures are unknown.…”

“…Small cyclic octapeptides extracted from the blue‐green algae Prochloron have been the subject of extensive investigations regarding their putative biological role . They are commonly referred to as “patellamides”, as they were initially isolated from the sea squirt Lissoclinum patella , the host of Prochloron .…”

Metal‐coordinated Hydroxide as a Nucleophile: a Brief History

“…Indeed they do. In an extensive series of papers Comba and his group have studied the Cu II and Zn II complexes of analogues of the patellamides . What is most significant in the sense of this present article is that the Cu II and Zn II complexes of these patellamide analogues exhibit hydrolytic activity towards a number of substrates through a nucleophilic M –OH moiety (Scheme ).…”

“…We end by highlighting some work involving metal‐coordinated hydroxide carried out by the dedicatee of this review, Professor Peter Comba. Comba and his associates have studied the chemistry of cyclic octapeptides, synthetic analogues of marine metabolites found in ascidians of the Pacific and Indian Oceans and originally isolated from genus Lissoclinum bistratum and Lissoclinum patella , . The ascidians (or tunicates) are filter‐feeding animals, found as individuals or in colonies on the ocean floor and importantly metabolites isolated from these animals exhibit antiviral, antitumor and cytotoxic properties.…”

“…Additionally, the β‐lactamase and α‐ and β‐glycosidase activities were reported as k cat = 11.34 ± 0.91 × 10 –4 s –1 (β‐lactamase), k cat = 1.55 ± 0.13 × 10 –4 s –1 (α‐glycosidase) and k cat = 1.22 ± 0.09 × 10 –4 s –1 (β‐glycosidase). [301] And finally, the Zn II and mixed Zn II /Cu II solution chemistry of a series of synthetic patellamide derivatives has been investigated with the focus on model phosphatase chemistry using bis(2,4‐dinitrophenyl)phosphate (BDNPP) as the substrate , . Typical BDNPP hydrolysis data for the complex [Cu 2 (H 2 pat1)(OH)] 2+ were k cat = 4.0 ± 0.1 × 10 –3 s –1 , with K m = 26.4 ± 2.2 mM , …”