***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:  In human B cells infected with Epstein-Barr virus (EBV), latency-associated virus gene products inhibit expression of the pro-apoptotic Bcl-2-family member Bim and enhance cell survival. This involves the activities of the EBV nuclear proteins EBNA3A and EBNA3C and appears to be predominantly directed at regulating Bim mRNA synthesis, although post-transcriptional regulation of Bim has been reported. Here we show that protein and RNA stability make little or no contribution to the EBV-associated repression of Bim in latently infected B cells. However, treatment of cells with inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT) enzymes indicated that epigenetic mechanisms are involved in the down-regulation of Bim. This was initially confirmed by chromatin immunoprecipitation analysis of histone acetylation levels on the Bim promoter. Consistent with this, methylation-specific PCR (MSP) and bisulphite sequencing of regions within the large CpG island located at the 5′ end of Bim revealed significant methylation of CpG dinucleotides in all EBV-positive, but not EBV-negative B cells examined. Genomic DNA samples exhibiting methylation of the Bim promoter included extracts from a series of explanted EBV-positive Burkitt's lymphoma (BL) biopsies. Subsequent analyses of the histone modification H3K27-Me3 (trimethylation of histone H3 lysine 27) and CpG methylation at loci throughout the Bim promoter suggest that in EBV-positive B cells repression of Bim is initially associated with this repressive epigenetic histone mark gradually followed by DNA methylation at CpG dinucleotides. We conclude that latent EBV initiates a chain of events that leads to epigenetic repression of the tumour suppressor gene Bim in infected B cells and their progeny. This reprogramming of B cells could have important implications for our understanding of EBV persistence and the pathogenesis of EBV-associated disease, in particular BL.


Output:

Bim is a cellular inducer of programmed cell death (pcd), so the level of Bim is a critical regulator of lymphocyte survival and reduced expression enhances lymphomagenesis in mice and humans. Regulation of Bim is uniquely important in the pathogenesis of Burkitt's lymphoma (BL), since in this human childhood cancer the Myc gene is deregulated by chromosomal translocation and Myc can induce pcd via Bim. Latent EBV represses Bim expression, and here we have discovered that this involves mechanisms that reprogramme B cells and their progeny. EBV does not significantly alter Bim protein or RNA stability, but relief of EBV-mediated repression by specific inhibitors suggested it involves modifications to chromatin. Consistent with this, reduced histone acetylation and increased levels of DNA methylation on the Bim promoter were found after latent EBV infection. Further analysis suggested that the DNA methylation is preceded by repression mediated via a polycomb protein repressive complex targeting the Bim gene. By initiating the heritable suppression of Bim, EBV increases the likelihood of B lymphomagenesis in general and BL in particular. This reprogramming of B cells by EBV may also play a role in the development of other chronic disorders such as autoimmune disease and suggests a general mechanism that could contribute to the pathogenesis associated with other microorganisms.
