Yale team sheds light on century-old biochemical mystery

Given plenty of glucose and oxygen, yeast and cancer cells do not burn it all to produce energy but convert much of it to the byproducts ethanol and lactate, respectively.

In the 1920s Nobel laureate Otto Heinrich Warburg asked why these cells were so wasteful of energy. He suggested that this seemingly inefficient cellular use of resources was a root cause of cancer, a hypothesis that has been the subject of research ever since.

Almost a century later, two Yale scientists have used magnetic resonance measurements showing how glucose is metabolized in yeast to answer the puzzle of the “Warburg Effect.” The production of these byproducts is a result of the cell’s need to keep its internal state constant during glucose consumption, they report Aug. 17 in the Proceedings of the National Academy of Sciences.

This biochemical response is an example of homeostasis, a fundamental need of all life forms.

“It’s the cell’s way of saying it has enough to eat,” said Robert Shulman, professor emeritus of molecular biophysics and biochemistry.

In the 1980s, Shulman conducted pioneering studies of metabolism in yeast using magnetic resonance spectroscopy, a method then confined to the study of cells but now used routinely in patients.

More recently, Shulman and co-author Douglas Rothman, professor of diagnostic radiology and of biomedical engineering, reviewed the data applying new methods of analyzing metabolic control. They found key intermediate molecular steps involved in the conversion of glucose to ethanol as well as to ATP, the chief energy source of cells. When these molecular switches that maintained homeostasis were disabled by mutations, the cells died from accumulated excesses of both byproducts and ATP.

This chemical balancing act explains why yeast and likely cancer cells do not convert all available fuel to energy that they could use to divide and flourish.

“Cancer cells have to survive first,” Rothman said.

Shulman and Rothman point out that their results open a new direction for cancer researchers — identifying metabolic homeostasis mechanisms and targeting them for treatment.

“By taking another look at the in vivo data available from magnetic resonance experiments, I think we can revitalize research efforts in a host of areas,” Shulman said.

Primary funding for the research came from the National Institutes of Health.

(Illustration by Michael S. Helfenbein. Image via Shutterstock.)