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, knowledge of the way in which drugs are broken down in the body is crucial in order to ensure that the drug is fully effective in fighting infection, inflammation or disease. The so-called metabolism of drugs is mediated by enzymes and takes place mainly in the liver. At the end of August, a team of researchers from UCIBIO@REQUIMTEat the 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 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 has made it possible to draw conclusions about how the enzyme processes (metabolizes) drugs at their active site and, surprisingly, has also revealed an inhibitory site on the enzyme, which can be exploited to slow down or even block the premature degradation of drugs and thus increase their effectiveness. As Teresa Santos-Silva, a member of the team and an FCT researcher, points out, "The main results described will make it possible, in the near future, to develop new inhibitors and design drugs that are resistant to metabolism by AOX." 

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

Due to the size of the aldehyde oxidase enzyme - it is made up of more than 1330 amino acids (the units that make up proteins) - the team used the technique of X-ray diffraction of crystals of the enzyme to determine its molecular structure. This is essentially the same method that made it possible to unravel the structure of DNA in the 50s. In the case of AOX, more than 800 crystals had to be analyzed, 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 and research project funding. UCIBIO@REQUIMTE has FCT funding and is one of the 11 centers classified as Exceptional in the latest evaluation of R&D Units carried out by FCT.

(Image credits: Macromolecular Crystallography Laboratory, UCBIO@REQUIMTE, Universidade Nova de Lisboa)