A slow and steady march from the barely functional to the peak of perfection—that’s the intuitive view of evolution, whether one is considering the evolution of organisms or the evolution of enzymes. Yet enzymes may defy the common view. In fact, recent work suggests that enzymes evolve their peak activities in short order—years not eons—before they settle into slow declines.

The new work, performed by scientists at New Zealand’s University of Otago, weighed two kinds of evidence. First, it looked at the emergence of enzymes that modern-day bacteria use to break down human-made antibiotics and pesticides. Second, it assessed the fitness of “resurrected” enzymes, that is, reconstructions of ancestral enzymes.

The scientists noted that there are many examples of lightning-fast enzyme evolution. One such example is the phosphotriesterase enzyme from Pseudomonas diminuta, which catalyzes the hydrolysis of a range of synthetic insecticides and chemical warfare agents, none of which were synthesized until the 1940s. The scientists also cited enzymes that evolved rapidly in laboratory studies. For example, a Salmonella enterica strain was deliberately crippled, deprived of a gene that coded for a tryptophan-synthesis enzyme. The strain compensated by modifying a related enzyme. The newly evolved enzyme became an effective substitute in just 500 generations of laboratory evolution.

Impressive though these examples may be, they are not all that surprising. What is surprising, however, is the growing record of reconstructed ancestral enzymes that surpass extant descendants. According to the scientists, ancestral sequence reconstruction (ASR), a technique that combines phylogenetics and biochemistry, has been used to evaluate enzymes such as thioredoxin, nucleoside diphosphate kinase, LeuB, and uricase. The reconstructed enzymes, compared to their extant descendents, show superior kinetic parameters.

The scientists explained how they reconciled their unsurprising and surprising observations in an article that appeared April 29 in the Journal of the Royal Society Interface. The article—”Rapid bursts and slow declines: on the possible evolutionary trajectories of enzymes”—argues that brief periods of strong selection for increased catalytic efficiency are interspersed with much longer periods in which the catalytic power of an enzyme erodes, through neutral drift and selection for other properties such as cellular energy efficiency or regulation.

“We propose that many of the enzymes required for core metabolic processes evolved to peak catalytic performance very early in evolutionary history,” the authors wrote. “We use the analogy of a weak link in metabolism: if a particular biochemical reaction becomes the single rate-limiting step for the growth and replication of a single-celled microorganism, then strong positive selection will be exerted upon the enzyme that catalyzes this step.”

Curiously, enzymes may initially evolve to be far more active than they need to be. Essentially, an evolving enzyme may quickly exceed an activity threshold. At this point, the enzyme is no longer subject to selection, and its catalytic efficiency may begin to decrease, perhaps through either genetic drift or selection for other properties such as stability, regulation of metabolic flux, or energy efficiency.

“Studying the complexities of enzyme evolution not only provides fundamental knowledge about how life emerged from the primordial soup,” said the study’s lead author Wayne Patrick, Ph.D., “but also gives insights into designing proteins with biomedical and biotechnological applications””

Dr. Patrick and his colleagues at the Department of Biochemistry's Laboratory for Enzyme Engineering and Evolution are currently pursuing such applications. Their work includes collaborating with leading biotechnology company LanzaTech, which has a microbe that can grow by using harmful gases from industrial plants such as steel mills and oil refineries. The Otago researchers are engineering enzymes to put into this microbe so it can produce useful raw materials that would otherwise have to be made from petroleum.