Enzyme promiscuity and evolution in light of cellular metabolism

Abstract

This Special Issue is composed of 10 reviews that delve into the intricacies behind enzyme promiscuity and evolution, an area that is of increasing interest in the biological research community. In particular, the reviews in this Special Issue explore enzyme promiscuity and evolution in the context of cellular metabolism, as discussed in this introductory Editorial. It is our hope that you enjoy these fascinating and informative reviews and we wish to thank the authors for their compelling contributions to The FEBS Journal. The hallmark of enzymes and the major focus of enzymologists is selectivity, or specificity with respect to substrate and reaction. Nonetheless, it has also been recognized that certain enzymes exhibit broad substrate acceptance and have a priori evolved as such (e.g., detoxifying enzymes). Promiscuity, however, is an altogether different property – the term is used to describe enzymes with completely coincidental activities that have no relation to the normal physiological function of the enzyme and have not been ‘seen’ by natural selection. In recent years, enzyme promiscuity has become a widely studied phenomenon. There are ~ 1400 PubMed entries for ‘enzyme promiscuity’, of which ~ 1000 are from the last decade. A number of reviews have been also been written, mostly in relation to the application of promiscuity in biocatalysis and enzyme engineering. The focus of this Special Issue, however, is enzyme promiscuity and enzyme evolution in the context of cellular metabolism. This Special Issue commences with reviews that lay out the conceptual grounds in relation to enzyme promiscuity and evolution. Shelley Copley [[1]] reviews the dominant mechanism for emergence of new enzymes, via duplication and divergence of preexisting ones. Coincidental, promiscuous activities serve as a starting point and, via mutation and selection, these gradually become the native, physiological function of the new enzyme. Stephen Miller and Spencer Adams [[2]] describe a specific case of duplication and divergence of a fatty acyl-CoA synthetase that led to insect luciferases that were repurposed to generate light by oxidizing luciferin. Margaret Glasner and co-authors [[3]] address another main source of new enzymes – horizontal gene transfer – and how, in combination with promiscuity, this enables the evolution of new metabolic pathways. Promiscuity is the outcome of limited selectivity, the ability of enzyme active sites to accept substrates other than the native, original substrate for which an enzyme evolved, and sometimes to catalyze a different reaction. It stems from the physicochemical and evolutionary constraints under which enzymatic active sites are shaped. Ita Gruic and Dan Tawfik [[4]] analyze these constraints by examining aminoacyl-tRNA synthetases – an enzyme class that has systematically evolved for high selectivity. In his article, William Atkins [[5]] reviews the other extreme – detoxifying, drug-metabolizing enzymes, and transporters that exhibit unusually broad substrate acceptance, as well as high substrate and catalytic promiscuity. The Issue also presents reviews that focus on the cellular and metabolic implications of promiscuity and on specific classes of enzymes. Promiscuity has mostly been examined in the test tube, where enzymes may accept various substrates and generate different products. However, as discussed by Robert Last and Craig Schenck [[6]], the physiological impact of an enzyme and of its promiscuity also depends on when and where in the cell an enzyme is expressed. In the living cell, promiscuity generates side products that are deleterious – so-called damage metabolites. In turn, enzymes that repair this damage have evolved. Thomas Niehaus and Katie Hillmann [[7]] review the area of metabolite repair, which is yielding interesting insight regarding the physiological relevance of promiscuity. The biosynthesis of natural products is evolution's favorite playground. Unlike core metabolism, which has undergone relatively little change since its early emergence, in specialized metabolism, relentless innovation and tinkering resulted in a vast diversity of enzymes and products. Whereas the enzymes of core metabolism are renowned for high catalytic efficiency and selectivity, those in natural products biosynthesis are often sluggish and exhibit broad substrate acceptance as well as high promiscuity. Accordingly, pathways are assembled by the ‘mix and match’ of existing enzymes, as well as by teaching old enzymes new tricks, sometimes in unexpected ways. David Sherman and Amy Fraley [[8]] provided a detailed description of the evolution of biosynthesis of fungal indole alkaloids that teaches us how these biosynthetic pathways assemble. Katherine Ryan and co-authors [[9]] describe one of the most frequently tinkering actions of evolution – emergence of oxygenases, and other unusual pyridoxal phosphate-dependent enzymes. Other unconventional cases of recruitment of enzymes to perform completely new reactions are described by Mikko Metsä-Ketelä and David Fewer [[10]], who also propose a new, general model for the evolution of natural products biosynthesis. Collectively, this Special Issue describes multiple aspects and angles of enzyme promiscuity, principally the physiological and evolutionary aspects. Putting it together and reading these reviews has been inspiring and gratifying – from a fringe, ‘avant-garde’ concept opposed by many, promiscuity has become central to our understanding of enzymes and metabolism. I still recall one listener in a seminar I gave in ca. 2002 who said: ‘Young man, if you ever wish to be tenured in a respectable institute you should stop advocating this promiscuity nonsense’. Well, I guess that this Special Issue says it all. I am grateful to the authors for their scholarly and insightful contributions. I am sure that others will enjoy and benefit from these reviews as much as I have. And, I look forward to the next one.

Topics & Concepts