New Insight into the Body's 'Clean-Up' Enzymes

Researches with the University of Bristol, in the United Kingdom, recently concluded a new study, in which they took a hard, close look at a specific class of enzymes in the human body. These molecules play an important role in tidying up multiple types of cells.

The discoveries the team made are of great importance for the pharmaceutical industry, which is currently fighting to create better drugs, that are absorbed faster, and which do not build up insdie the human body indefinitely.

As you take a pill, its active ingredients make their way to the gut, where they are absorbed into the bloodstream, and then delivered throughout the entire body. Eventually, they make their way to the cells they are intended to act upon.

But these chemicals must not remain in the body forever. As soon as their beneficial actions are done, they need to be eliminated, and overseeing this process is a type of molecules called enzymes.

In the new study, the UB team looked at a specific class of enzymes, called cytochromes P450, that play a critical role in cleaning up cells of foreign substances and dangerous chemicals.

The group was conducted by UB EU Marie Curie Fellow Dr Julianna Olah, who worked together with professors Jeremy Harvey and Adrian Mulholland, both at the UB School of Chemistry.

One of the things researchers started from was the knowledge that P450 enzymes reside mostly in the liver. They act on drugs inside cells primarily by adding an oxygen group to them. This essentially “tags” the chemicals for removal.

But some substances can interfere with the way the enzymes work. In other cases, adding oxygen to specific chemicals can lead to oxygenated versions of those substances, which may become toxic.

Determining how drug molecules would interact with P450 enzymes is therefore critically important for drug designers. What the UB group did was create a model of the reaction mechanisms that they observed when one variant of the cytochromes enzyme interacted with dextromethorphan.

“Our calculations showed that the outcome of the oxygen transfer process (that is, which part of dextromethorphan oxygen gets added to) is affected by three factors,” professor Jeremy Harvey says.

“The first is the way in which the molecule fits into the enzyme (‘docking’). The second is the intrinsic ability of each part of the molecule to accept oxygen,” the expert goes on to say.

“The third is how much each competing oxygen-delivery process is compatible with the shape of the enzyme pocket where the reaction occurs,” he adds.

“While these first two factors were already known, the third was not. This discovery can help pharmaceutical chemists design new drug molecules with a better understanding of how they will be broken down in the body,” Harvey concludes.

Details of the new research appear in a paper called “Understanding the determinants of selectivity in drug metabolism through modelling of dextromethorphan oxidation by cytochrome P450,” which is published in the esteemed journal Proceedings of the National Academy of Sciences (PNAS).