By Admin at 15 Feb 2016, 16:25 PM

Researchers from Griffith University's Institute for Glycomics have succeeded in a world first. They’ve used X-ray crystallography to create a 3-D image of a bacterial heparanase, a protein involved in cancer spread.

Heparanase degrades heparan sulfate, a sugar molecule. In humans, a functionally identical human enzyme is intricately involved in cancer, but no one knew exactly what the enzyme structure looked like – that is, until now.

The newly created 3-D structure provides “intimate atomic-level detail” of heparanase, which will give researchers a more detailed focus for future research into how to best target the enzyme.

In humans, the enzyme is naturally regulated in healthy cells but is produced in excessive quantities in cancers. It is associated with angiogenesis (the development of new blood vessels, which my promote cancer growth), inflammation and increased metastatic potential.

Heparanase is able to degrade sugars in the molecules surrounding cells (the extra-cellular matrix), which makes it easier for cancer to grow and spread.

Now that the structure has been revealed – a discovery 10 years in the making – researchers will focus on developing an anti-cancer drug to target it. Professor Mark von Itzstein, director of the Institute for Glycomics, told Science Daily:

"We have successfully crystallized and determined the structure of the enzyme by X-ray crystallography, making it the first reported heparanase X-ray crystal structure in the world … This tells us exactly where substrates bind in the catalytic domain and we explored this region by mutating certain amino acids that kill the activity so that we can understand how the enzyme works.

The bacterial and human heparanase share identical substrate preference and catalytic machinery, thus enabling our heparanase structure to be used in the drug discovery process in targeting the human enzyme."

Structural and functional analysis of the bacterial heparanase is expected to further the discovery of “structure-guided anti-cancer and anti-angiogenesis inhibitor discovery, particularly mechanism-based inhibitor discovery,” according to von Itzstein.

Researchers from the University of York have also succeeded in building a 3-D structure of human heparanase. The enzyme is a key target in emerging anti-cancer treatments. Multiple anti-heparanase compounds are currently in advanced clinical trials, and the 3-D model is expected to further such drug development. Study author Professor Gideon Davies told Science Daily:

"The 3-D structure of human heparanase will allow the design and application of novel therapeutic agents based upon the intimate details of its structure. All groups worldwide will now be able to benefit from understanding of its 3-D shape and interaction with sugars."

Sources:
Nature Chemical Biology December 2015
Nature Structural and Molecular Biology December 2015
Science Daily November 2, 2015
Science Daily November 18, 2015

Post a comment

Make me anonymous

CAPTCHA
Below question is to prevent automated spam submissions.

* Math Question:

2 + 1 =

Solve this math problem and enter the result. E.g. for 1 + 3, enter 4.

You must provide a response to the reCaptcha challenge.