Human O-GlcNAc-hydrolase 3D Structure Determined

The 3-D structure of an enzyme that could provide a crucial step forward in treating neurodegenerative diseases has been revealed by researchers at the University of York and Simon Fraser University.

Earlier work from the same teams focused on a class of diseases called tauopathies, which occur when tau proteins spontaneously group together in the brain. They are associated with Alzheimer’s and other neurodegenerative diseases.

Research has shown that the tau protein can be modified by a sugar, natural to the body, called O-GlcNAc. This sugar can stabilise the protein to block it from clumping together and may thereby prevent disease.

The human enzyme O-GlcNAc-hydrolase, however, is responsible for the removal of this crucial sugar from the protein, making it a prime target in preventing the progression of tau-related dementias.

O-GlcNAc Tau Stabilization

Professor Gideon Davies, from York University’s Department of Chemistry, said:

“Inhibiting the O-GlcNAc-hydrolase enzyme allows scientists to stabilise tau. We have solved the three-dimensional structure of the enzyme in order to aid structure-based drug design. The unusual and complex organisation should help us in the search for new drugs to treat neurodegenerative diseases. Drugs can be designed based on the 3-D structure of this human enzyme, which will ultimately pave the way for new breakthroughs in the treatment of diseases such as Alzheimer’s.”

In order to understand how this clumping of tau could be prevented or reduced by increasing O-GlcNAc, scientists at York investigated the structure of the human enzyme to reveal how it is organized to function in this way.

Professor David Vocadlo, from Simon Fraser University, said:

“In addition to serving as a blueprint for the development of antagonists, this long sought after structure reveals a surprising architecture that may lead to improved understanding of how this important enzyme is regulated in cells. Such insights could lead to more targeted therapeutics for various diseases.”

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, which partially funded the research, said:

“Drug discovery is a bit like designing a key to fit a lock, however, it is important to know the shape of the lock you are working with. This new study describes in detail the shape of O-GlcNAc-hydrolase and paves the way for the design of drugs that can fit this lock. Future studies will need to explore whether drugs that can inhibit this enzyme hold promise for treating Alzheimer’s disease and other dementias, but this is an important step in the right direction.”

Christian Roth, Sherry Chan, Wendy A Offen, Glyn R Hemsworth, Lianne I Willems, Dustin T King, Vimal Varghese, Robert Britton, David J Vocadlo & Gideon J Davies
Structural and functional insight into human O-GlcNAcase
Nature Chemical Biology (2017) doi:10.1038/nchembio.2358