Exploring the Evolution of Novel Enzyme Functions within Structurally Defined Protein Superfamilies

Abstract

In order to understand the evolution of enzyme reactions and to gain an overview of biological catalysis we have combined sequence and structural data to generate phylogenetic trees in an analysis of 276 structurally defined enzyme superfamilies, and used these to study how enzyme functions have evolved. We describe in detail the analysis of two superfamilies to illustrate different paradigms of enzyme evolution. Gathering together data from all the superfamilies supports and develops the observation that they have all evolved to act on a diverse set of substrates, whilst the evolution of new chemistry is much less common. Despite that, by bringing together so much data, we can provide a comprehensive overview of the most common and rare types of changes in function. Our analysis demonstrates on a larger scale than previously studied, that modifications in overall chemistry still occur, with all possible changes at the primary level of the Enzyme Commission (E.C.) classification observed to a greater or lesser extent. The phylogenetic trees map out the evolutionary route taken within a superfamily, as well as all the possible changes within a superfamily. This has been used to generate a matrix of observed exchanges from one enzyme function to another, revealing the scale and nature of enzyme evolution and that some types of exchanges between and within E.C. classes are more prevalent than others. Surprisingly a large proportion (71%) of all known enzyme functions are performed by this relatively small set of 276 superfamilies. This reinforces the hypothesis that relatively few ancient enzymatic domain superfamilies were progenitors for most of the chemistry required for life.

Use of Structural Phylogenetic Networks for Classification of the Ferritin-like Superfamily

“…By contrast, the low sequence similarities across this superfamily make it practical to generate sequencebased phylogenies only across subsets of the superfamily. Consequently, superfamilies such as this are missed by efforts to marry structural information with sequence-based phylogenies for superfamilies in or beyond the twilight zone of sequence similarity (20 -30% pairwise sequence identity) (20,21). We summarize briefly how these databases and phylogenies inform current classification of the ferritin-like superfamily.…”

Engineering of Flexible Loops in Enzymes

“…The evolution of enzymes involves sequence changes that are frequently localized at loop regions and thus reveal their role in protein evolution and in the diversification of numerous enzyme families and superfamilies. 3 Over the past few years, a surge of interest from the scientific community has brought the study of loopstheir flexibility and impact on enzyme functionto the forefront of biocatalysis. Most of the activity in this field so far has centered on the role of surface and lid loops that cover the active site and their functional role in substrate and cofactor binding, protein− protein interaction, and stability.…”

Evolutionary history of redox metal-binding domains across the tree of life

“…It has been suggested that an ancestral pool of peptide modules may have given rise to the first protein folds that were dispersed into different superfamilies (2)(3)(4). Some of these peptide modules are part of the limited set of building blocks (i.e., the "redox enzyme construction kit") that gave rise to many oxidoreductases (5).…”