***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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Output:

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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:  For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects—all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09×10−3 and 4.37×10−3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10−5 and 1.02×10−4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.


Output:

Menarche is a physical milestone in a woman's life. Age at menarche (AAM) is related to many common female health problems. AAM is mainly determined by genetic factors. However, the specific genes and the associated mechanisms underlying AAM are largely unknown. Here, taking advantage of the most recent technological advances in the field of human genetics, we identified multiple genetic variants in a gene, SPOCK, which are associated with AAM variation in a group of Caucasian women. This association was subsequently confirmed not only in two independent groups of Caucasian women but also across ethnic boundaries in one group of Chinese women. In addition, SPOCK has a function in regulating a key factor involved in menstrual cycles, MMP-2, which provides further support to our findings. Our study provides a solid basis for further investigation of the gene, which may help to reveal the underlying mechanisms for the timing of menarche and for AAM's relationship with women's health in general.
