To what extent do structural changes in catalytic metal sites affect enzyme function?
Open accessAbstract
About half of known enzymatic reactions involve metals. Enzymes belonging to the same superfamily often evolve to catalyze different reactions on the same structural scaffold. The work presented here investigates how functional differentiation, within superfamilies that contain metalloenzymes, relates to structural changes at the catalytic metal site. In general, when the catalytic metal site is unchanged across the enzymes of a superfamily, the functional differentiation within the superfamily tends to be low and the mechanism conserved. Conversely, all types of structural changes in the metal binding site are observed for superfamilies with high functional differentiation. Overall, the catalytic role of the metal ions appears to be one of the most conserved features of the enzyme mechanism within metalloenzyme superfamilies. In particular, when the catalytic role of the metal ion does not involve a redox reaction (i.e. there is no exchange of electrons with the substrate), this role is almost always maintained even when the site undergoes significant structural changes. In these enzymes, functional diversification is most often associated with modifications in the surrounding protein matrix, which has changed so much that the enzyme chemistry is significantly altered. On the other hand, in more than 50% of the examples where the metal has a redox role in catalysis, changes at the metal site modify its catalytic role. Further, we find that there are no examples in our dataset where metal sites with a redox role are lost during evolution. SYNOPSIS: In this paper we investigate how functional diversity within superfamilies of metalloenzymes relates to structural changes at the catalytic metal site. Evolution tends to strictly conserve the metal site. When changes occur, they do not modify the catalytic role of non-redox metals whereas they affect the role of redox-active metals.
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Metal ions, particularly iron, play a critical role in the activity of many enzymes involved in the detoxification of reactive oxygen species.
“One striking example is the critical role of metal ions, particularly iron, in the activity of many enzymes involved in the detoxification of reactive oxygen species (ROS) [54–56].”
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- Authors
- Valasatava, Y., Rosato, A., Furnham, N., Thornton, J. M., & Andreini, C.
- Affiliations
- University of Florence (IT)
- London School of Hygiene & Tropical Medicine (GB)
- European Bioinformatics Institute (GB)
- Corresponding author
- Andreini, Claudia
- Venue
- Journal of Inorganic Biochemistry
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 179
- Pages
- 40-53
- ISSN
- 0162-0134 (ISSN-L)
- PMC
- PMC5760197
- OpenAlex
- W2767581071
- Cited by
- 77
- References
- 69
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 6 · 2023: 4 · 2022: 12 · 2021: 16 · 2020: 16 · 2019: 4 · 2018: 3
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Inorganic Biochemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Florence Research (University of Florence) (submittedVersion, other-oa)
- Funders
- European Commission (284209, MR/K020420/1)
- Medical Research Council (284209, MR/K020420/1)
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- metalloenzymes, enzyme superfamilies, functional diversification, structural evolution, redox-active metal ions, metal binding sites
- MeSH terms
- Enzymes, Metals, Alkaline Earth, Oxidation-Reduction, Metals, Heavy, Evolution, Chemical, Catalytic Domain
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