Department of Chemistry, KU Leuven, 3001 Leuven, Belgium
Effective catalysts for the controlled transformation of large and complex biomolecules are rare and challenging to develop. In particular, selective hydrolysis of proteins by non-enzymatic catalysis is difficult to achieve, yet it is crucial for many modern applications in biotechnology and proteomics. In recent years we have discovered the conceptually new way selectively cleaving proteins by combining the enzyme-like molecular recognition ability of soluble metal-oxo clusters such as polyoxometalates (POM) with the hydrolytic activity of a strong Lewis acid metal cation imbedded into the POM structure.[1] A selective cleavage has been demonstrated in a range of different proteins differing in structure, size, and charge. More recently, we have shown that {Zr6O8} -based MOFs act as very effective heterogeneous catalysts for the hydrolysis of the peptide bond.[2,3] The catalytic activity of MOFs was shown to be excellent through a broad pH range, resulting in the rate constants which are more than 4 orders of magnitude faster compared to the uncatalyzed reaction. [2,3] The potential of metal-oxo clusters as nanozymes for protein hydrolysis has been further demonstrated on the example of discrete cluster which showed excellent selectivity in the hydrolysis of, cleaving the protein only at six solvent accessible Asp residues among 154 residues.[4]
Materials with enzyme-like characteristics (aka nanozymes) have gained increasing attention as potential enzyme mimics due to their stability and unique physicochemical properties which provide great opportunities for a rational design of catalysts. During the past decade, our group has intensively studied water soluble polyoxometalates (POMs) as artificial metallopeptidases. POMs are a large class of anionic metal oxo clusters typically formed by early transition metals in their highest oxidation state, and we have shown that they can be rendered reactive by imbedding Lewis acid metal ions such as Zr(IV) or Hf(IV) in their structures, resulting in efficient catalysts for the hydrolytic cleavage of peptide bonds in a range of proteins. More recently we discovered that Zr-based metal-organic frameworks (Zr-MOFs), also possess a remarkable peptidase activity, which by far surpassed the most active metal-POM catalysts. These MOFs were also able to selectively hydrolyze peptide bonds in more complex substrates such as proteins. In addition, UiO-66 Zr-MOF has been found to effectively catalyze intramolecular and intermolecular peptide bond formation without any signs of epimerization using ethanol as a solvent, a desired but uncommon green biomass-derived solvent. Ultimately, these findings indicate that materials based on Zr(IV)- and Hf(IV) -oxo clusters have a large potential to be developed as a novel class of nanozymes for peptide bond formation and hydrolysis.
References
[1] Ly, H.G.T. et.al. J. Am. Chem. Soc. 2018,140, 6325.
[2] Moons, J. et.al. Angew. Chem. Int. Ed. 2020, 59, 9094.
[4] de Azambuja, F.; et.al. ACS Catal. 2021, 11, 271.
[5] de Azambuja F., et.al. Acc. Chem. Res., 2021, 54, 1673.
[6] de Azambuja, F.; ACS Catal., 2021, 11, 7647.
[7] Wang, S. et.al. Nat. Commun. 2022, 13, 1284.
[8] S. A. M. Abdelhameed, et.al. Nat. Commun., 2023, 14, 486
