Discovery of 3D enzyme structure paves the way for development of more stable drugs

In the process of discovery and development of new drugs, knowledge of how drugs are degraded in the body is crucial to ensure that the drug will be fully effective in fighting infection, inflammation or disease. So-called drug metabolism is mediated by enzymes, and occurs mostly in the liver. At the end of August, a team of researchers from UCIBIO@REQUIMTEat the New University of Lisbon published the first 3D structure of the human enzyme aldehyde oxidase (AOX), known to play an important role in the processing of drugs and xenobiotics (chemical substances present in an organism that are not produced naturally by the body). 

This study, funded by FCT and published in the journal Nature Chemical Biologyprovides very detailed information about the structure of the enzyme - at a resolution of ten millionths of a millimeter. This detail allowed us to draw conclusions about how the enzyme processes (metabolizes) drugs, in its active site, and also, surprisingly, revealed an inhibitory site in the enzyme, which can be exploited to delay, or even block, the premature degradation of drugs and thus increase their effectiveness. This is what Teresa Santos-Silva, team member and an FCT Researcher, highlights, "The main results described will allow, in the near future, to develop new inhibitors and design drugs resistant to metabolism by AOX." 

The results of the group led by Maria João Romão, also director of UCIBIO@REQUIMTE, allow the application of in silico studies to predict the ability of the enzyme to metabolize new drugs before they are tested in clinical trials. This possibility significantly increases the success rate of clinical trials. 

Because of the size of the enzyme aldehyde oxidase - it consists of more than 1330 amino acids (the units that make up proteins) - the team used the enzyme's crystal X-ray diffraction technique to determine its molecular structure. This is the same method, in essence, that made it possible to unravel the structure of DNA in the 1950s. In the case of AOX, more than 800 crystals had to be analyzed, after overcoming the hurdle of producing them in sufficient quantity and purity to be analyzed by X-ray diffraction. 

This work was funded mainly by FCT, through Studentships and funding of research projects. The UCIBIO@REQUIMTE has FCT funding, being one of the 11 centers classified as Exceptional in the last evaluation of R&D Units conducted by FCT.

(Image credits: Laboratory of Macromolecular Crystallography, UCBIO@REQUIMTE, New University of Lisbon)