Scientists map structure of brain disease molecule

Thursday April 11 2013

"A major breakthrough has been made by researchers seeking treatments for…illnesses such as Parkinson's disease," is the exciting news on the Mail Online website.

This headline is based on early stage research into the structure of an enzyme that has been implicated in the development of brain disorders including Alzheimer’s disease, Parkinson’s disease and Huntington's disease (a genetic condition that causes progressive loss of brain function).

The incidence of Alzheimer’s and Parkinson’s increases with age, and more people are being diagnosed with these conditions as the population ages. This rise, combined with the limitations of current treatment options for these and other ‘neurodegenerative diseases’, makes the search for effective therapies particularly important.

After years of work, scientists have discovered both the structure of this enzyme and a compound that has been shown to block the enzyme’s harmful effects. This makes the enzyme an attractive target for potential drug therapies for these diseases.

The compound that has been found to block the enzyme’s toxic effects is not currently suitable for use as a drug as it is too big to enter the brain. The study of both the compound and the enzyme’s structure should help in the ongoing quest to develop treatments.

Where did the story come from?

The study was carried out by researchers from the University of Manchester, the University of Leicester and other institutions in Portugal, France and Germany. No funding information was reported.

The study was published in the peer-reviewed journal Nature.

The research was covered by the Mail Online website and it provided a measured headline and reported on the study’s findings and implications well.

The 'breakthrough' claim may be overstating how important the findings are, although, in this case, the Mail Online was simply reflecting the researchers' own enthusiasm.

What kind of research was this?

This was laboratory research that sought to determine the structure of an enzyme thought to play a key role in the development of several degenerative brain disorders.

Scientists suspect that a particular ‘molecular pathway’ is involved in the development of conditions such as Huntington’s, Parkinson’s and Alzheimer’s disease.

Molecules produced by this ‘pathway’ (known as ‘metabolites’) have been noted for their effect on the brain. One particular metabolite (an enzyme called kynurenine 3-monooxygenase or KMO, which is produced in certain brain cells) has been previously identified as an attractive target for potential drug therapies for brain disorders.

Previous studies using yeast, fruit fly and mouse models of these conditions suggest that inhibiting the activity of KMO may improve certain symptoms associated with these neurodegenerative diseases.

Although these previous studies have shown that some known chemical compounds can block (inhibit) the activity of KMO, scientists do not know precisely how this occurs on a molecular level.

The current study sought to characterise how the inhibition occurs, and to provide a detailed description of the KMO enzyme in the hope that potentially effective drug compounds can be identified in the future.

This research is at a very early stage in the drug discovery and development process. While a potential drug target has been identified (KMO), scientists have yet to discover compounds or drugs that can interact with that target in a clinically meaningful way.

What did the research involve?

The researchers produced several versions of the enzyme KMO in an attempt to determine its molecular structure, both on its own and when bound to a compound called UPF 648. This compound has been used in previous laboratory and animal studies, and has been shown to inhibit KMO.

Unfortunately, UPF 648 is too large to pass between the blood and the cerebrospinal fluid (because of the blood-brain barrier), which is a vital characteristic for potential drugs directed at the brain.

What were the basic results?

After several attempts, the researchers were able to crystallise KMO on its own, and with UPF 648.

Having generated these ‘crystal structures’ of the enzyme and one of its inhibitors, the researchers hope to be able to screen known compounds with similar molecular structures to identify potential drug compounds that could pass the blood-brain barrier.

How did the researchers interpret the results?

The researchers concluded that discovery of KMO’s crystal structure, both on its own and with a known inhibitor, “is a major breakthrough for new KMO inhibitor design”.


This research represents an exciting development for scientists studying neurodegenerative disorders and those attempting to develop therapies for their treatment.

The researchers say that this new detailed knowledge of KMO’s structure and, in particular, knowledge about the binding of KMO and one of its inhibitors will allow for the development of screens that can sift through collections of chemicals to help identify other compounds that may both bind with KMO and pass the blood-brain barrier.

These new compounds could then be investigated as potential drugs targeting KMO for the treatment of diseases such as Huntington’s, Parkinson’s and Alzheimer’s.

It is important to remember that this is a very early stage of the drug development process. While a potential drug target has been identified, scientists have yet to discover, let alone develop, compounds or drugs that can effectively interact with that target.

This research serves as an important and useful step in the drug discovery process, but there are still many years of research ahead before this new knowledge may lead to drugs for these devastating illnesses.

Analysis by Bazian
Edited by NHS Website