Sometimes, enzymes require more than one metal ion for its activity. In rare occasions, they require two different metal ions as well. The most common metals that involve in this are Fe, Zn, Cu, and Mn.
The metalloenzymes containing metal centers other than iron non-heme centers are wide spread in nature. Metal activated enzymes are enzymes that have an increased activity due to the presence of metal ions. Most of the times, these metal ions are either monovalent or divalent.
However, these ions are not tightly bound with the enzyme as in metalloenzymes. The metal can activate the substrate, thus engage directly with the activity of the enzyme. These enzymes require metal ions in excess. Ex: around times higher than the concentration of the enzyme. It is because they cannot bond with the metal ion permanently. However, these enzymes lose their activity during its purification.
The metalloenzymes are enzymes which contain a tightly bound metal ion. Finkelstein, J. Nature , Download citation.
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Rights and permissions Reprints and Permissions. About this article Cite this article Finkelstein, J. Copy to clipboard. Stachura , R. It was revealed that the axial Met ligand and the surrounding amino acids influence the reduction potential of Cu A via coordination, H-bond, and hydrophobic interactions [ , , ], and in the active site of the Cu B center, a novel Tyr—His cross-link was found to fine-tune the protein reactivity [ , ].
It is full of challenges to design an artificial enzyme with a Cuz center, and no report is availablein the literature yet. Meanwhile, some progresses have been made in the design of synthetic model complexes mimicking the structure and function of the Cuz cluster in native N 2 OR [ , ].
For example, Cramer et al. This simple dicopper complex was shown to be a functional model of the Cuz cluster, by the reduction of N 2 O to N 2 at room temperature. Recently, Mankad et al. Therefore, although these model complexes work in organic solvents such as CH 2 Cl 2 and acetone, they are very useful for gaining the structure and function relationship of native N 2 OR.
Moreover, the incorporation of these model complexes in suitable protein scaffolds might be able to produce artificial metalloenzymes working in physiological conditions. Many effects have been directed to synthetic mimics of the OEC. For example, Agapie et al. Zhang et al.
Moreover, the artificial Mn 4 CaO 4 cluster underwent four redox transitions similar to that of native OEC, which thus provides an ideal model for studying the structure and function relationship of native OEC, as well as an artificial enzyme model for applications in water oxidation. Copyright American Chemical Society. Since the above-synthesized cluster was not incorporated into a protein scaffold, the secondary coordination sphere interactions could hardly be fine-tuned. It is challengeable to design an artificial metalloenzyme with tunable PCET properties.
Recently, Tilley et al. By introduction of a proximal Tyr SY mutation , the X-ray crystal structure revealed that Tyr forms an H-bond interaction with the water molecule that acts as an axial ligand of the Co ion Figure 9 d. Note that the introduction ofa redox active residue such as Tyr and Trp in the heme distal pocketor on the protein surface was also shown to fine-tune the reactivity of artificial peroxidases designed in the protein scaffold of myoglobin [ 46 , , ].
In summary, artificial metalloproteins and metalloenzymes with diverse metalclusters have been rationally designed in recent years, in which the clustersare formed either in the protein pocket, between the interface of protein dimers, trimers, and oligomers, or within the scaffold of de novo designed proteins.
As shown in Figure 1 , the metal ions used for the design of metalclusters are not only those in natural biological systems, such as the first-row transition metals Mn, Co, Fe, Cu, and Zn, Figure 2 and Figure 6 , Figure 7 , Figure 8 and Figure 9 , but also non-native metal ions, such as those of the second-row transition metals Zr, Mo, Pd, Ag, and Cd, Figure 3 , Figure 4 a and Figure 5 a,c and the third-row transition metals Hf, W, and Au, Figure 4 b and Figure 5 b.
In most cases, these metal clusters were found to play a structural role, which stabilize the protein 3D structures, dimers, trimers, or oligomers. Moreover, the metal clusters, especially iron—sulfur clusters, have been successfully designed to play roles of both electron-transfer and catalysis Figure 6 and Figure 7.
Within this progress, some functional model complexes have been rationally designed and synthesized, which closely mimic the active metal clusters in more complex native metalloenzymes, such as the Cuz center in N 2 OR Figure 8 b—e and Mn 4 CaO 5 cluster in photosystem II Figure 9 a,b , respectively.
Currently, the design of artificial metalloproteins and metalloenzymes with metal clusters is still at the stage of providing insights into the structure and functional relationship for native metalloenzymes, and some synthetic models are still waiting for incorporation into suitable protein scaffolds to work in physiological conditions.
Comparatively, artificial metalloenzymes with a single active site have been designed to exhibit catalytic parameters similar to those of native enzymes [ 50 , 98 , , ], or even with a much higher catalytic efficiency [ ], which have potential applications in the future.
Moreover, some artificial metalloenzymes may catalyze reactions beyond the functionalities of natural enzymes, such as the catalytic formation of a C—Si bond by an engineered Cyt c [ ]. As suggested by Martinez et al. We are confident that in the near future, more advanced artificial metalloenzymes with metal clusters will be rationally designed andexplored for practical applications in different fields, such as in biological medicine, biofuel generation, and environmental protection.
The work on the heme protein design from my group was supported by the National Natural Science Foundation of China , and the double first-class construct program of the University of South China. National Center for Biotechnology Information , U. Journal List Molecules v.
Published online Jul Ying-Wu Lin 1, 2, 3. Author information Article notes Copyright and License information Disclaimer. Received Jun 21; Accepted Jul This article has been cited by other articles in PMC. Abstract Metalloproteins and metalloenzymes play important roles in biological systems by using the limited metal ions, complexes, and clusters that are associated with the protein matrix.
Keywords: metalloproteins, metalloenzymes, protein design, metalclusters, synthetic models. Introduction Metalloproteins and metalloenzymes play important roles in biological systems, including electron transfer, O 2 binding and delivery, and catalysis, etc.
Open in a separate window. Figure 1. Zinc Clusters Zinc ions play crucial roles in both protein scaffolds and protein—protein interfaces, acting as catalytic sites or supporting quaternary protein structures [ 56 ].
Figure 2. Cadmium Clusters Similar to a tetranuclear copper cluster Cu 4 S 4 that can be designed within a four-helical bundle [ 65 , 66 ], a tetranuclear cadmium cluster can also be designed, such as in the interior of a three-helical bundle, by using a metal-binding motif of CXXCE [ 67 ]. Figure 3. Figure 4. Other Metal Clusters In addition to those metal clusters mentioned in previous sections, other non-nativemetal clusters can also be formed in the protein scaffolds with a structural role, which were either rationally designed or found in experiments.
Figure 5. Figure 6. Artificial Metalloenzymes with Metal Clusters for Catalysis 4. Iron—Sulfur Clusters As mentioned in the previous section, iron—sulfur clusters play rolesof both electron transfer and catalysis in biology. Figure 7. Copper—Sulfur Clusters Copper is an essential element in biological systems. Figure 8. Figure 9. Conclusions and Perspectives In summary, artificial metalloproteins and metalloenzymes with diverse metalclusters have been rationally designed in recent years, in which the clustersare formed either in the protein pocket, between the interface of protein dimers, trimers, and oligomers, or within the scaffold of de novo designed proteins.
Acknowledgments I thank all the co-workers for their studies described in this review. Funding The work on the heme protein design from my group was supported by the National Natural Science Foundation of China , and the double first-class construct program of the University of South China. Conflicts of Interest The authors declare no conflict of interest.
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