Rice University scientists discover enzyme for precision molecular control

A team of scientists at Rice University has discovered a new enzyme with precision molecular control in directing specific molecules on how to arrange themselves right down to the angle of their individual hydrogen bonds that could lead to the development of better therapeutic options.

The new enzyme, named CtdP, is a part of the Diels-Alderase (DAase) family; a Rice University news release said. It is instrumental in driving the Diels-Alder reaction, a key method for synthesizing essential materials and pharmaceuticals.

The team, led by study co-author Xue Sherry Gao, detected the enzyme's impact on a molecule's spatial structure, also known as stereochemistry, according to the news release. She pointed out that even the smallest chance in stereochemistry could determine whether a compound works as a drug or a poison, highlighting the importance of CtdP.

“Very few DAases work like our enzyme and very strictly synthesize a chemical reaction that is impossible without it,” Xue said in the release. “We hope that our discovery will help develop biocatalysts that enable the production of useful pharmaceuticals in the near future.”

The study, which was published in Nature Chemistry, highlights the Diels-Alder reaction, which was first noted in research by Otto Diels and Kurt Alder and Otto Diels in 1928 and ultimately earned them the 1950 Nobel Prize in Chemistry; according to the release. The reaction is important because it drives the formation of cyclic ring structure that can be found in a number of naturally occurring compounds that have medical applications.

Xue’s team realized that the precision control over the 3D molecular structure can be challenging in Diels-Alder reactions, leading them to look into CtdP, according to the release. They were interested in the idea that a fungal organism could synthesize the 21R-citrinadin A molecule with a single configuration from four options.

Xue set out to uncover how living organisms might demonstrate precise stereochemical control, factoring in just how hard it is to repeat the same result through organic synthesis. The discovery of CtdP proved to be the lynchpin that ensures the required stereochemical control during chemical reaction.

The release noted that the unique mechanism of CtdP makes it different from other DAases. CtdP prepares the substrate and converts nicotinamide adenine dinucleotide phosphate (NADP+) into a reduced form known as NADPH, which is instrumental for driving the Diels-Alder reaction.

The release also noted that the new enzyme also is a driver that rigidly synthesizes a chemical reaction that would not be possible otherwise, and the discovery could ultimately lead to the development of new pharmaceuticals to treat diseases.

Xue is the T.N. Law assistant professor of chemical and biomolecular engineering and assistant professor of bioengineering and chemistry at Rice University, according to the release. She earned the CAREER Award from the National Science Foundation in 2022 for her contributions to the field.

The research was supported by the University of Michigan, the National Institutes of Health and the Robert A. Welch Foundation; with computational resources from the National Science Foundation, the UCLA Institute for Digital Research and Education, the San Diego Supercomputing Center and D.E. Shaw Research; the release said.