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

In the process of discovering and developing new drugs, understanding how drugs are broken down in the body is crucial to ensuring that the drug is fully effective in fighting infection, inflammation, or disease. Drug metabolism is mediated by enzymes and occurs mainly in the liver. At the end of August, a team of researchers from UCIBIO@REQUIMTE, at Universidade Nova de Lisboa, 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 naturally produced by the organism). 

This study, funded by FCT and published in the journal Nature Chemical Biology, provides very detailed information on the structure of the enzyme—at a resolution of ten millionths of a millimeter. This detail has allowed conclusions to be drawn about how the enzyme processes (metabolizes) drugs at its active site and, surprisingly, has revealed an inhibitory site in the enzyme that can be exploited to slow down or even block the premature degradation of drugs, thereby increasing their effectiveness. This is highlighted by Teresa Santos-Silva, a member of the team and an FCT researcher: "The main results described will allow, in the near future, the development of new inhibitors and the design of drugs resistant to metabolism by AOX." 

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

Due to the size of the aldehyde oxidase enzyme—it consists of more than 1,330 amino acids (the units that make up proteins)—the team used X-ray diffraction of enzyme crystals to determine its molecular structure. This is essentially the same method that was used to unravel the structure of DNA in the 1950s. In the case of AOX, it was necessary to analyze more than 800 crystals, after overcoming the barrier of producing them in sufficient quantity and purity to be analyzed by X-ray diffraction. 

This work was mainly funded by FCT, through Studentships research project funding. UCIBIO@REQUIMTE is funded by FCT and is one of 11 centers classified as Exceptional in the latest evaluation of R&D units carried out by FCT.

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