A new viewpoint on a critical enzyme

Flicking biological switch could hold key to tackling tumours

At the end of 2012 Linda Gilmore and Malcolm Walkinshaw both members of Edinburgh Infectious Diseases in the Institute of Structural and Molecular Biology, published their exciting findings about a key metabolic enzyme – pyruvate kinase.  After screening over 300000 novel compounds they identified a molecule that was able to inactivate the enzyme, opening the door for development of new drugs against deadly infections such as black fever (visceral leishmaniasis).

These original studies also suggested that it might also possible to develop drugs that could reduce or prevent the supply of nutrition to fast growing cells such as tumours, and help lead to new treatments for cancer.  Now Gilmore, Walkinshaw, and their colleagues have made fresh discoveries about pyruvate kinase that show just how this might be possible. 

The new study by Morgan et al shows that pyruvate kinase switches between its dual functions of providing fuel for existing cells and of forming biological material for new cells.  By using x-ray crystallography techniques to examine the structure of the enzyme, Morgan et al found that, in cancer cells, the balance is tipped towards producing new cells and so aiding the growth of tumours.

In tests on human cancer cells in the lab, researchers were able to manipulate the pyruvate kinase to switching its role back to supplying fuel for cells, thus slowing the rate of cancer cell growth.  Further, by adding small molecules, such as the amino acid phenylalanine, that bound to pyruvate kinase at critical sites, the enzyme could be induced to switch from generating energy and instead promoted cell growth and division

Researchers say their findings open up the possibility of developing drugs to monitor and control the growth of cancerous tumours.

The study, which also included researchers from Prof Ted Hupp's group in the Institute of Genetics and Molecular Medicine at the University of Edinburgh, was funded by the Wellcome Trust and the Medical Research Council, and was published in Proceedings of the National Academy of Sciences.

Professor Malcolm Walkinshaw of the University of Edinburgh’s School of Biological Sciences, who led the study, said:

We have effectively shown how to turn on and off the growth of real cancer cells. We hope this finding will advance our understanding of how to tackle this complex and devastating family of diseases.”
 

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