Protecting the body against itself

Our ancestors couldn’t get enough fat. The scarcity of food through much of history meant that our genomes evolved to absorb the maximum amount of calories available. Today, with the next meal only as far away as a trip to the corner takeaway, these genes have become a liability, and are helping to fuel the obesity epidemic.

The body’s ancient energy sensing pathway is controlled by an enzyme called AMP-activated protein kinase (AMPK). Simply put, AMPK passes a “make more energy” message to the cell when needed. By doing so, it regulates the burning and storage of fats and sugars, and affects the level of sugars and cholesterol in the blood stream.

Big pharma saw the potential of the enzyme early on and has spent the last 10 years investigating it in search of the pharmaceutical Holy Grail – a drug to activate the AMPK pathway, the so-called ‘fat pill’. Drugs that activate AMPK have been touted as a panacea against Type 2 diabetes, cardiovascular disease, cancer and neurodegeneration including Alzheimer’s disease.

Professor Bruce Kemp, head of SVI’s Protein Chemistry & Metabolism Unit, and the first to purify the protein, is loathe to buy into the hyperbole. “While development of a drug to activate the AMPK pathway may lead to a wonderful vista of metabolic control, there is still a huge amount we don’t know about the enzyme and its mechanisms.” Bruce is most excited about the prospect of using AMPK drugs intermittently to improve metabolic control and enhance exercise capacity.

Bruce admits that his initial work on AMPK was a curiosity-driven side project, part of the bigger picture of trying to understand how a certain family of enzymes, called kinases, work. “While AMPK was first reported in 1973, its true importance was only revealed after we purified it in 1993.”

However, following its purification and sequencing it became apparent that this enzyme formed the crux of metabolic control at the whole animal level through appetite regulation as well as at the cellular level.

Since that time, work in Bruce’s lab has focused on three major questions:

• How AMPK is regulated;
• How the structure of the enzyme influences its function;
• What are the physiological effects of the enzyme at a whole body level.

The group has recently had a breakthrough with its discovery of the mechanism by which the enzyme senses the reduced energy levels in the cell and transmits its message to other cell signallers.

So, while our genes may be stuck in the Stone Age, work in SVI’s Protein Chemistry and Metabolism Unit is looking to the future to unravel the secrets of metabolism.