Investigations of Enzyme-Catalyzed Reactions Based on Physicochemical Descriptors Applied to Hydrolases

Abstract

The EC number system for the classification of enzymes uses different criteria such as reaction pattern, the nature of the substrate, the type of transferred groups or the type of acceptor group. These criteria are used with different emphasis for the various enzyme classes and thus do not contribute much to an understanding of the mechanisms of enzyme catalyzed reactions. To explore the reasons for bonds being broken in enzyme catalyzed metabolic reactions, we calculated physicochemical effects for the bonds reacting in the substrate of these enzymatic reactions. These descriptors allow the definition of similarities within these reactions and thus can serve as a method for the classification of enzyme reactions. To foster an understanding of the investigations performed here, we compare the similarities found on the basis of the physicochemical effects with the EC number classification. To allow a reasonable comparison we selected enzymatic reactions where the EC number system is largely built on criteria based on the reaction mechanism. This is true for hydrolysis reactions, falling into the domain of the EC class 3 (EC 3.b.c.d). The comparison is made by a Kohonen neural network based on an unsupervised learning algorithm. For these hydrolysis reactions, the similarity analysis on physicochemical effects produces results that are, by and large, similar to the EC number. However, this similarity analysis reveals finer details of the enzymatic reactions and thus can provide a better basis for the mechanistic comparison of enzymes.

Similarity Perception of Reactions Catalyzed by Oxidoreductases and Hydrolases Using Different Classification Methods

“…In this work, three more subclasses (EC 3.3.c.d, EC 3.10.c.d, and EC 3.11.c.d) than in the previous publication 9 were investigated. There was only one reaction in subclass EC 3.10.c.d, and it was located in a neuron of its own; the two reactions of subclass EC 3.11.c.d were both projected into a single neuron, as shown in Figure 3.…”

“…9 have investigated the similarity of reactions catalyzed by hydrolases comprising 135 reactions. In the present work, the data set of hydrolases was expanded to 311 reactions containing three more subclasses of hydrolases than in the previous publication: 9 by an enzyme whose EC code was not fully assigned: EC 1.1.-.-. The reactions catalyzed by enzymes of these subsubclasses are shown in Figure 1.…”

“…15 This study builds on a publication by Sacher et al 9 The reactions studied here were represented by the same descriptors as those used in the previous work. 9 In the present work, a larger data set for hydrolases (EC 3.b.c.d) and a new data set of oxidoreductases (EC 1.b.c.d) were analyzed. In the previous work, 9 only the classification method of Kohonen's self-organizing neural network (KohNN) was used; in this work, two additional classification methods, support vector machine (SVM) and hierarchical clustering analysis (HCA), were also applied.…”

“…9 In the present work, a larger data set for hydrolases (EC 3.b.c.d) and a new data set of oxidoreductases (EC 1.b.c.d) were analyzed. In the previous work, 9 only the classification method of Kohonen's self-organizing neural network (KohNN) was used; in this work, two additional classification methods, support vector machine (SVM) and hierarchical clustering analysis (HCA), were also applied. The results obtained from the three different methods were then compared with the EC classification system.…”

Some solved and unsolved problems of chemoinformatics

“…However, what has been said about reaction databases in section 4.1 applies here also: the quality of databases on biochemical reactions has to be improved by storing more details on the individual reactions. We have shown in several publications with the BioPath.Database [21] how we can increase our knowledge on biochemical reactions [22][23][24][25]. Real progress in this field can best be made by collaborations between chemoinformatics and bioinformatics.…”