How enzyme promiscuity and horizontal gene transfer contribute to metabolic innovation

Abstract

Promiscuity is the coincidental ability of an enzyme to catalyze its native reaction and additional reactions that are not biological functions in the same active site. Promiscuity plays a central role in enzyme evolution and is thus a useful property for protein and metabolic engineering. This review examines enzyme evolution holistically, beginning with evaluating biochemical support for four enzyme evolution models. As expected, there is strong biochemical support for the subfunctionalization and innovation–amplification–divergence models, in which promiscuity is a central feature. In many cases, however, enzyme evolution is more complex than the models indicate, suggesting much is yet to be learned about selective pressures on enzyme function. A complete understanding of enzyme evolution must also explain the ability of metabolic networks to integrate new enzyme activities. Hidden within metabolic networks are underground metabolic pathways constructed from promiscuous activities. We discuss efforts to determine the diversity and pervasiveness of underground metabolism. Remarkably, several studies have discovered that some metabolic defects can be repaired via multiple underground routes. In prokaryotes, metabolic innovation is driven by connecting enzymes acquired by horizontal gene transfer (HGT) into the metabolic network. Thus, we end the review by discussing how the combination of promiscuity and HGT contribute to evolution of metabolism in prokaryotes. Future studies investigating the contribution of promiscuity to enzyme and metabolic evolution will need to integrate deeper probes into the influence of evolution on protein biophysics, enzymology, and metabolism with more complex and realistic evolutionary models. Enzymes lactate dehydrogenase (EC 1.1.1.27), malate dehydrogenase (EC 1.1.1.37), OSBS (EC 4.2.1.113), HisA (EC 5.3.1.16), TrpF, PriA (EC 5.3.1.24), R‐mandelonitrile lyase (EC 4.1.2.10), Maleylacetate reductase (EC 1.3.1.32).

Enzyme promiscuity and evolution in light of cellular metabolism

“…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.…”

Conserved Metabolic and Evolutionary Themes in Microbial Degradation of Carbamate Pesticides

“…Apart from HGT, adaptations at molecular and cellular level play an important role in the evolution and optimisation of degradation traits. At the molecular level, enzyme promiscuity is a major factor that paves way for the evolution of enzymes that carry out novel reactions ( Glasner et al, 2020 ). Certain enzymes might show broad substrate specificity and act on novel compounds to convert them into less toxic intermediates.…”

Evaluating the Potential of Applying Machine Learning Tools to Metabolic Pathway Optimization

“…In particular, deep learning approaches have played an important role in dissecting the often convoluted signals from the genome in assigning gene function to sequence information [21][22][23][24][25], and is poised to help identify more enzyme candidates with suitable functions in a metabolic engineering project. The latter comes about due to enzyme promiscuity where some enzymes could be repurposed for other functions [26,27]. Usually, enzymes with the highest activities and performance are desired.…”