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Quantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes: implications for classification of enzyme function.

Almonacid DE, Yera ER, Mitchell JB, Babbitt PC - PLoS Comput. Biol. (2010)

Bottom Line: For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
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.

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Related in: MedlinePlus

Venn diagram showing combinations of similarity of overall reaction and mechanism, and identical mechanistic steps for pairs of enzymes in the dataset.Sizes of shapes are not proportional to the number of pairs they contain.
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pcbi-1000700-g005: Venn diagram showing combinations of similarity of overall reaction and mechanism, and identical mechanistic steps for pairs of enzymes in the dataset.Sizes of shapes are not proportional to the number of pairs they contain.

Mentions: Identical mechanistic steps were more likely to occur in pairs of enzymes from EC sub-subclasses containing similar overall reactions (Table S4). Because there is a direct correlation between overall reaction and mechanistic similarity, it is unsurprising that identical mechanistic steps were also more likely to occur in pairs of enzymes from EC sub-subclasses containing similar mechanisms (Table S5). Figure 5 shows a Venn diagram summarizing all possible combinations of overall reaction similarity, mechanistic similarity and identical catalytic steps for the pairs of enzymes in the dataset of functional analogs. Twelve of the 21 identical steps were found in pairs with similar overall reactions, and of those, most (10 of 12 identical steps) were also included in pairs of enzymes with significantly similar mechanisms. An example of convergence to the same overall reaction (Figure S2), together with convergence of mechanisms and identical mechanistic steps (Figure S4) is offered by the carboxylic-ester hydrolases (EC 3.1.1), represented in the dataset by phospholipase A2 (MACiE M0083, EC 3.1.1.4, PDB 1l8s) [60],[61], 1-alkyl-2-acetylglycerophosphocholine esterase (MACiE M0094, EC 3.1.1.47, PDB 1bwp) [62],[63], and triacylglycerol lipase (MACiE M0218, EC 3.1.1.3, PDB 1hpl) [64]–[67].


Quantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes: implications for classification of enzyme function.

Almonacid DE, Yera ER, Mitchell JB, Babbitt PC - PLoS Comput. Biol. (2010)

Venn diagram showing combinations of similarity of overall reaction and mechanism, and identical mechanistic steps for pairs of enzymes in the dataset.Sizes of shapes are not proportional to the number of pairs they contain.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837397&req=5

pcbi-1000700-g005: Venn diagram showing combinations of similarity of overall reaction and mechanism, and identical mechanistic steps for pairs of enzymes in the dataset.Sizes of shapes are not proportional to the number of pairs they contain.
Mentions: Identical mechanistic steps were more likely to occur in pairs of enzymes from EC sub-subclasses containing similar overall reactions (Table S4). Because there is a direct correlation between overall reaction and mechanistic similarity, it is unsurprising that identical mechanistic steps were also more likely to occur in pairs of enzymes from EC sub-subclasses containing similar mechanisms (Table S5). Figure 5 shows a Venn diagram summarizing all possible combinations of overall reaction similarity, mechanistic similarity and identical catalytic steps for the pairs of enzymes in the dataset of functional analogs. Twelve of the 21 identical steps were found in pairs with similar overall reactions, and of those, most (10 of 12 identical steps) were also included in pairs of enzymes with significantly similar mechanisms. An example of convergence to the same overall reaction (Figure S2), together with convergence of mechanisms and identical mechanistic steps (Figure S4) is offered by the carboxylic-ester hydrolases (EC 3.1.1), represented in the dataset by phospholipase A2 (MACiE M0083, EC 3.1.1.4, PDB 1l8s) [60],[61], 1-alkyl-2-acetylglycerophosphocholine esterase (MACiE M0094, EC 3.1.1.47, PDB 1bwp) [62],[63], and triacylglycerol lipase (MACiE M0218, EC 3.1.1.3, PDB 1hpl) [64]–[67].

Bottom Line: For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus