***TASK***
the task is to simplify the input abstract of a biomedical literature

***INPUT***
the input is the abstract of a biomedical literature

***OUTPUT***
the output is the simplified abstract for the input abstract of a biomedical literature
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Input: 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.
Output:  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.

Input:  Evolutionary expansion of signaling pathway families often underlies the evolution of regulatory complexity. Expansion requires the acquisition of a novel homologous pathway and the diversification of pathway specificity. Acquisition can occur either vertically, by duplication, or through horizontal transfer, while divergence of specificity is thought to occur through a promiscuous protein intermediate. The way by which these mechanisms shape the evolution of rapidly diverging signaling families is unclear. Here, we examine this question using the highly diversified Rap-Phr cell–cell signaling system, which has undergone massive expansion in the genus Bacillus. To this end, genomic sequence analysis of >300 Bacilli genomes was combined with experimental analysis of the interaction of Rap receptors with Phr autoinducers and downstream targets. Rap-Phr expansion is shown to have occurred independently in multiple Bacillus lineages, with >80 different putative rap-phr alleles evolving in the Bacillius subtilis group alone. The specificity of many rap-phr alleles and the rapid gain and loss of Rap targets are experimentally demonstrated. Strikingly, both horizontal and vertical processes were shown to participate in this expansion, each with a distinct role. Horizontal gene transfer governs the acquisition of already diverged rap-phr alleles, while intralocus duplication and divergence of the phr gene create the promiscuous intermediate required for the divergence of Rap-Phr specificity. Our results suggest a novel role for transient gene duplication and divergence during evolutionary shifts in specificity.


Output:

Many molecular pathways are found multiple times in a given organism, where they are often reutilized for different functions. Such expansion of a family of pathways requires two main evolutionary processes—acquisition of additional copies of the pathway's genes and divergence of interaction specificity to prevent cross-talk between pathways while preserving interactions within each copy of the pathway. In bacteria, acquisition can occur horizontally, by transfer between different lineages, or vertically, by duplication within the lineage. Interaction specificity is thought to diverge through a promiscuous intermediate component that prevents loss of interaction during the process. In this work, we study the mechanisms underlying the extreme expansion of the Rap-Phr cell–cell signaling family in the Bacillus genus. Specificity of Rap-Phr interaction is critical for guiding preferential action towards kin. We find that horizontal transfer and not duplication guides the acquisition of an already divergent Rap-Phr variant. Surprisingly, duplication still has a key role during expansion, as duplication and subsequent divergence of the signaling molecule gene provide the promiscuous intermediate state needed for divergence of specificity. We therefore identify two complementary roles for horizontal and vertical processes in the evolution of social bacterial pathways.
