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Classification of chemical reactions: Potential, possibilities, and continuing relevance

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Abstract

An overview is given of the nature of, and methods for, classification of chemical reactions. Particular emphasis is placed on classifications based on formal structural change and on reaction mechanism, and on the role of classifications within computerized reaction retrieval systems. It is argued that classification is of great and continuing value in information retrieval, information discovery, and education.

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... Methods to measure similarity between biochemical reactions first relied on the structure of the EC classification system (Tohsato et al., 2000), however current approaches were extended to include chemical attributes (Bawden, 1991;Latino & Aires-de Sousa, 2011;Rose & Gasteiger, 1994). First, some strategies depend solely on the structure of the reactants and involve changes in the overall reaction, for instance bond changes and reaction centres. ...
Thesis
The study of the evolution of proteins has been traditionally undertaken from a sequence and structural point of view. However any attempt to understand how protein function changes during evolution benefits from consistent definitions of function and robust approaches to quantitatively compare them. The function of enzymes is described as their ability to catalyse biochemical reactions according to the Enzyme Commission (EC). This dissertation explores aspects of the chemistry and evolution of a small class of enzymes catalysing geometrical and structural rearrangements between isomers, the isomerases (EC 5). A comprehensive analysis of the overall chemistry of isomerase reactions based on bond changes, reaction centres and substrates and products revealed that isomerase reactions are chemically diverse and difficult to classify using a hierarchical system. Although racemases and epimerases (EC 5.1) and cis-trans isomerases (EC 5.2) are sensibly grouped according to changes of stereochemistry, the overall chemistry of intramolecular oxidoreductases (EC 5.3), intramolecular transferases (EC 5.4) and intramolecular lyases (EC 5.5) is challenging. The subclass \other isomerases" (EC 5.99) sits apart from other subclasses and exhibits great diversity. The current classification of isomerases in six subclasses reduces to two subclasses if the type of isomerism is considered. In addition, the separation of groups of isomerases sharing similar chemistry such as oxidosqualene cyclases and pseudouridine synthases from chemically complex sub-subclasses like intramolecular transferases acting on \other groups" (EC 5.4.99) might also improve the classification. An overview of the evolution of isomerase function in superfamilies revealed three main findings. First, isomerases are more likely to evolve new functions in different EC primary classes, especially lyases (EC 4), rather than evolve to perform different isomerase reactions. Second, isomerases change their overall chemistry and conserve the structure of their substrates and products more often than conserving the chemistry and changing substrates and products. Last, the relationship between sequence and functional similarity suggests that correlations should be investigated on the basis of closely related enzymes. Although previous research assumes a one-to-one relationship between EC number and biochemical reaction, almost one-third of all known EC numbers are linked to more than one biochemical reaction. This complexity was characterised for isomerase reactions and used to develop an approach to automatically explore it across the entire EC classification. Remarkably, about 30% of the EC numbers bearing more than one reaction are linked to different types of reactions, bearing key differences in catalysed bond changes. Several recommendations to improve the description of complex biochemical reaction data in the EC classification were proposed. This dissertation explores enzymes from a functional perspective as an alternative to classical studies based on homology. This standpoint might prove useful to help to search for sequence candidates for orphan enzymes and in the design of enzymes with novel activities.
... The problem of classification of chemical reactions is considered a complex one (Bawden, 1991). The complexity arises from interrelations between reactions, which we shall see is the essence of any reaction classification. ...
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