Tracing back enzyme evolution

A model of the enzyme cyclohexadienyl dehydratase. It's ancestry has now been revealed.
A model of the enzyme cyclohexadienyl dehydratase. It’s ancestry has now been revealed.

Scientists have succeeded in tracing the evolution of an important enzyme, uncovering a pathway back to the long-extinct protein from which it sprang.

The research, led by Ben Clifton from the Australian National University, represents the first time the molecular evolutionary processes that govern the emergence of enzymes have been revealed.

The work will assist other research into both understanding the characteristics of existing enzymes, and the synthesis of new ones.

“Previous studies on enzyme evolution have shown how it is possible for new enzymes to evolve from existing enzymes – but we still knew very little about how enzymes evolved in the first place,” says co-author Colin Jackson.

In a paper published in the journal Nature Chemical Biology, the research team details the ancestral line that resulted in the emergence of an enzyme called cyclohexadienyl dehydratase, which is involved in transporting substances around the body.

To do this, they employed a technique called “ancestral protein reconstruction”. The approach involves reconstructing historic biomolecules, and then experimentally characterising their properties.

Summarising research in the area in 2017, scientists from the University of Chicago explained that the strategy “has proven to be a powerful means for discovering how historical changes in sequence produced the functions, structures, and other … characteristics of modern proteins.”

By tracing the evolution of the foundation proteins through time, it is possible to determine roles played by forces such as optimisation, constraint and blind chance.

“Understanding the evolutionary processes that create new enzymes is important because we can then mimic those processes to design or engineer enzymes for our own purposes in the biotechnology or pharmaceutical industries,” explains Clifton.

The team found that in the case of cyclohexadienyl dehydratase, the foundation protein had undergone a series of mutations, which optimised the emergent enzyme’s capacity to function.

The findings were broadly in line with conclusions arising from a related field called computational enzyme design, in which proteins are intentionally created to catalyse reactions not found in nature.

The field, though promising, is still in its infancy, and the insights arising from the work of Clifton’s team will be of significant benefit. 

“The big problem we face when engineering enzymes is first understanding of how they work, and how they can gain new functions,” says Jackson.

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