A cartoon of a 'ribbon' presentation of the three dimensional structure of endomannosidase. Red regions are alpha helices, green arrows are beta strands. Credit: Spencer Williams/PNAS
Tuesday, 17 January 2012
by Laura Greenhalgh
LONDON: The structure of a unique enzyme in the human body has been identified in a discovery that could lead to treatment against deadly viruses such as HIV and hepatitis C.
Researchers from the University of Melbourne participated in an international collaboration to successfully determine the molecular blueprint of the enzyme endomannosidase, which is involved in synthesising sugar-coated proteins in human cells, and is exploited by viruses to aid their replication.
By describing the structure and activity of the enzyme in unprecedented detail, the new findings published in Proceedings of the National Academy of Sciences pave the way for development of a treatment to prevent viruses from hijacking human cells.
"The implications are quite significant," said Spencer Williams from the University of Melbourne's Bio21 Institute. "Drugs that target the pathway this enzyme is in could be used to stop viruses replicating. And if they can't replicate, then they can't cause disease."
The challenge of HIV, Hepatitis C
Previous efforts to develop treatments have focussed on another group of human enzymes used earlier in the infection process, but these have proved unsuccessful.
"The problem has been that this group of viruses, including HIV, hepatitis C, dengue fever and West Nile virus, are able to bypass the main pathway if inhibited and replicate via a second pathway using endomannosidase. Thus for a treatment to be effective, both pathways need to be blocked," said Williams.
Despite growing knowledge on the location of endomannosidase, scientists remained unable to determine its structure or discover anything about the enzyme's catalytic mechanism. "This endomannosidase bypass pathway has proved a considerable challenge to study," said Gideon Davies, leader of the second research team from the University of York in England.
However, by combining international resources and expertise, the Melbourne and British research teams have for the first time successfully mapped the shape of endomannosidase. In doing so, they also discovered that the enzyme may function via a completely new mechanism.
Unusual endomannosidase
The scientists studied a bacterial version of endomannosidase as a model for the same human enzyme, which they manufactured in sufficient quantities using the bacteria E. coli. They then placed a crystallised form of the enzyme under a powerful X-ray light source and collected the light reflected by individual atoms of the crystal, a state-of-the-art technique known as synchrotron technology.
Using computer software, the researchers then combined the patterns of reflected light to construct a three-dimensional picture of the enzyme. This indicated that endomannosidase contains a barrel-shaped fold in its molecular structure, which houses the enzyme's catalytic centre. The results also indicated the enzyme has some unexpected characteristics.
"It is a surprise in that we expected certain amino acids to be present in specific arrangements, and they were not. As a result we hypothesise that the enzyme is doing its job in an unprecedented new way," said Williams.
The key enzyme
Now the researchers have the molecular blueprint for the enzyme, they can begin to develop drug treatments. "These findings have revealed how we can block the bypass route, stopping the viruses from hijacking human enzymes," said Williams.
This could have significant consequences for the 180 million people infected by viruses like HIV and hepatitis worldwide, and ultimately could benefit an even greater number of people. "We hope that the work will lead beyond viruses and will point the way towards similar treatments for other diseases, including cancer," said Davies.
Commenting on the findings, Keith Stubbs from the University of Western Australia in Perth said, "This research addresses a key enzyme in N-glycan processing that has not been rigorously studied from a structural and biochemical perspective. It now opens the door for further study into how this enzyme is involved in the processing pathway from both a biotechnological and therapeutic perspective."
Williams cautioned that successful treatment may be some way off, but that their latest findings mark a significant breakthrough in this area. "Science moves slowly and in small steps," he said, "but now that we have inhibitors of both pathways we will see if dual inhibition can assist in curing a cell of hepatitis C infection. If this is the case then we will have 'proof-of-concept' that our strategy can be developed further."
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