Exploring the chemistry and evolution of the isomerases

Abstract

Isomerization reactions are fundamental in biology, and isomers usually differ in their biological role and pharmacological effects. In this study, we have cataloged the isomerization reactions known to occur in biology using a combination of manual and computational approaches. This method provides a robust basis for comparison and clustering of the reactions into classes. Comparing our results with the Enzyme Commission (EC) classification, the standard approach to represent enzyme function on the basis of the overall chemistry of the catalyzed reaction, expands our understanding of the biochemistry of isomerization. The grouping of reactions involving stereoisomerism is straightforward with two distinct types (racemases/epimerases and cis-trans isomerases), but reactions entailing structural isomerism are diverse and challenging to classify using a hierarchical approach. This study provides an overview of which isomerases occur in nature, how we should describe and classify them, and their diversity.

Keywords: EC classification; EC-BLAST; enzyme reaction; isomerases; reaction similarity.

Fig. 1.

Analysis of the EC classification of isomerases. (A) Distribution of isomerases in six subclasses, with the type of isomerism highlighted. Different attributes of the reaction are used to divide subclasses into sub-subclasses. (B) Distribution of isomerase reactions by bond changes. The symbol “↔” indicates change of bond order.

Fig. 2.

Cluster analysis of isomerase reactions based on bond changes. (A) Bond change composition of three clusters (A, B, and F), which displays reactions as rows and bond changes as columns. The blue scale represents the number of bond changes in reactions. As shown to the left of the graphs, reactions are annotated in colors according to their EC subclass. Bond changes were ordered left to right by increasing number. Outliers are annotated with an arrow (SI Appendix, Table S2). (B) Bond change similarity matrix used to find the six chemically optimal clusters. The blue-to-red scale represents increasing bond change similarity, with identical reactions having similarity of 1 (red). More details of A and B are shown in SI Appendix, Fig. S2. (C) Comparative analysis of the reaction clustering by bond changes (Left) and clustering by substrates and products (Right) using tanglegrams (Materials and Methods and SI Appendix, Fig. S5).

Fig. 3.

Domain composition of isomerase 3D structures. (A) Distribution of isomerase domains aggregated by EC sub-subclass (rows) and second level of CATH (columns). A red square represents one or more domains involved in an EC number. More details are shown in SI Appendix, Fig. S8. (B) Distribution of CATH domains per isomerase EC number. (C) Distribution of isomerase EC numbers per CATH domain. The frequency axes represent the counts of isomerase EC numbers (B) and CATH domains (C).