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Discovery of 3D structure of enzyme opens way to designing more stable drugs


Knowing how drugs are processed in the body is an important part of drug design, to avoid degradation of a drug before it acts to fight infection, inflammation or disease. This processing, called metabolism, is mediated by enzymes, and takes place mainly in the liver. In late August, a team of researchers from the Research Unit on Applied Molecular Biosciences (UCIBIO@REQUIMTE) of the Universidade Nova de Lisboa, published the first ever three-dimensional structure of human aldehyde-oxidase (AOX), an enzyme that plays a major role in processing drugs and xenobiotics (chemical substances found in an organism that are not normally naturally produced by that organism). 

This FCT-funded study, published in the leading journal Nature Chemical Biologyprovides an extremely detailed picture of aldehyde-oxidase – at a resolution of 10 millionth of a millimeter, in fact. It gives crucial insight into how the enzyme processes drugs in its active site, but also, surprisingly, revealed an inhibitory site on the enzyme, which may be exploited to delay drug metabolism and thus increase the efficacy of the drug. This possibility is highlighted by Teresa Santos-Silva, a member of the team and an FCT Investigator, their findings, “Our main findings open the possibility, in the near future, to develop new inhibitors of aldehyde-oxidase, as well as more stable drugs that are resistant to degradation by the enzyme.” 

The findings of the group led by Maria João Romão, director of UCIBIO@REQUIMTE, allow in silico studies to be carried out, to predict the enzyme’s ability to metabolise novel drugs before they are taken into clinical trials. This capability significantly increases the success rate of clinical trials. 

Aldehyde-oxidase is a large protein – it has over 1330 aminoacids (the building blocks of proteins). Due to its large size, the researchers used x-ray diffraction of crystals of the enzyme to determine its molecular structure. This is the same method that in the 1950s led to the discovery of the structure of DNA. Over 800 crystals of the enzyme were analysed, once the major barrier of obtaining pure crystals of aldehyde-oxidase, in enough numbers, was overcome. 

Macromolecular Crystallography Team

This study was largely funded by FCT through several project grants and fellowships. UCIBIO@REQUIMTE is an FCT-funded research centre and is one of 11 centres graded as Exceptional in the latest evaluation of R&D units. 

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