Quantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes: implications for classification of enzyme function
| Autor: | John B. O. Mitchell, Daniel Almonacid, Patricia C. Babbitt, Emmanuel R. Yera |
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| Přispěvatelé: | Orengo, Christine A, University of St Andrews. School of Chemistry, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. EaSTCHEM |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Escherichia-coli
Mathematical Sciences Nh3-dependent nad(+) synthetase Sequence Analysis Protein Models QD Databases Protein lcsh:QH301-705.5 chemistry.chemical_classification 0303 health sciences Ecology Genetics and Genomics/Functional Genomics 030302 biochemistry & molecular biology Genome project Biological Sciences Computational Biology/Evolutionary Modeling Enzyme structure Enzymes Biochemistry/Molecular Evolution Genetics and Genomics/Gene Function Infectious Diseases Biochemistry/Bioinformatics Crystal-structure Computational Theory and Mathematics Biochemistry Biochemistry/Small Molecule Chemistry Modeling and Simulation Biotechnology/Bioengineering Sequence Analysis Research Article Protein Binding Bioinformatics Molecular Sequence Data Biochemistry/Biocatalysis Chemical Sequence alignment Pyruvate formate-lyase Computational biology Biology Catalysis Inverse sequence similarity Structure-Activity Relationship Databases 03 medical and health sciences Cellular and Molecular Neuroscience Enzyme activator Similarity (network science) Information and Computing Sciences Genetics UDP-N-acetylglucosamine Computer Simulation Biochemistry/Macromolecular Chemistry Amino Acid Sequence Binding site Molecular Biology Genome-scale classification Ecology Evolution Behavior and Systematics 030304 developmental biology Binding Sites Protein Biochemistry/Chemical Biology of the Cell Platelet-activating-factor QD Chemistry Enzyme Activation Enzyme Models Chemical chemistry lcsh:Biology (General) Biophysics/Protein Chemistry and Proteomics Protein-tyrosine-phosphatase Biophysics/Biomacromolecule-Ligand Interactions |
| Zdroj: | PLoS Computational Biology, Vol 6, Iss 3, p e1000700 (2010) PLoS computational biology, vol 6, iss 3 PLoS Computational Biology |
| ISSN: | 1553-7358 |
| Popis: | Functionally analogous enzymes are those that catalyze similar reactions on similar substrates but do not share common ancestry, providing a window on the different structural strategies nature has used to evolve required catalysts. Identification and use of this information to improve reaction classification and computational annotation of enzymes newly discovered in the genome projects would benefit from systematic determination of reaction similarities. Here, we quantified similarity in bond changes for overall reactions and catalytic mechanisms for 95 pairs of functionally analogous enzymes (non-homologous enzymes with identical first three numbers of their EC codes) from the MACiE database. Similarity of overall reactions was computed by comparing the sets of bond changes in the transformations from substrates to products. For similarity of mechanisms, sets of bond changes occurring in each mechanistic step were compared; these similarities were then used to guide global and local alignments of mechanistic steps. Using this metric, only 44% of pairs of functionally analogous enzymes in the dataset had significantly similar overall reactions. For these enzymes, convergence to the same mechanism occurred in 33% of cases, with most pairs having at least one identical mechanistic step. Using our metric, overall reaction similarity serves as an upper bound for mechanistic similarity in functional analogs. For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity. By contrast, the three carboxylic-ester hydrolases (EC 3.1.1) catalyze overall reactions with identical bond changes and have converged to almost identical mechanisms. The large proportion of enzyme pairs that do not show significant overall reaction similarity (56%) suggests that at least for the functionally analogous enzymes studied here, more stringent criteria could be used to refine definitions of EC sub-subclasses for improved discrimination in their classification of enzyme reactions. The results also indicate that mechanistic convergence of reaction steps is widespread, suggesting that quantitative measurement of mechanistic similarity can inform approaches for functional annotation. Author Summary When species evolve, their genes duplicate and diverge to allow for adaptation of their functional repertoires to the changing environment. In this scenario, unrelated genes can convergently evolve to produce proteins with the same molecular function, termed “functionally analogous.” A quantitative determination of the reaction similarities among functionally analogous enzymes could provide insight about the different structural solutions nature has used to evolve similar catalysts. Bond changes between substrates and products, and between successive reaction intermediates, were used to compare the reactions catalyzed and the mechanisms of catalysis for 95 pairs of functionally analogous enzymes. Less than half of the reactions catalyzed by unrelated enzymes, but defined as similar by the Enzyme Commission (EC) classification, are similar in terms of bond changes, suggesting that this classification often fails to capture quantitative differences between many enzyme reactions. Furthermore, we addressed for the first time whether the chemical mechanisms by which similar overall reactions are achieved in functional analogs are also similar. We conclude that convergence of reaction is often accompanied by convergence of chemical mechanism. These results will be useful for classifying enzymes, guiding functional annotation of newly determined enzyme sequences and structures and for informing the engineering of enzymes with new functions. |
| Databáze: | OpenAIRE |
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