Flip a switch and a light comes on, a kitchen appliance whirls, a machine engages. But what is the switch that powers a biological engine--that allows cells to "turn on the juice" to meet their immediate energy requirements?
It's a chemical reaction called protein phosphorylation, discovered by two UW biochemists in the 1950s. Edmond Fischer and Edwin Krebs stumbled upon the interesting reaction as they set out to solve quite another problem in carbohydrate metabolism, which, in fact, they never got around to solving. Perhaps it's just as well. Their discovery of protein phosphorylation was recognized with the Nobel Prize for Medicine in 1992.
Fischer and Krebs discovered that enzymes called phosphorylase and protein kinase make life's power switch work. Protein kinase changes proteins from their inactive to active forms by speeding up the chemical bonding of phosphate to the proteins. This switch turns on and off a variety of biological functions inside the cell, including breakdown of fats and the generation of chemical energy. In fact, the process is fundamental to all cellular activities, including growth and transformations of cells. "It would be difficult, if not impossible, to name any physiological function in which phosphorylation does not play a regulatory role," notes Kenneth Walsh, who holds the E.W. Davie/ZymoGenetics Endowed Chair in the UW Department of Biochemistry (see Blood Coagulation). Today, some 50,000 to 100,000 research papers are published each year based on this serendipitous discovery. Hundreds of different versions of protein kinase molecules have been identified since Krebs and Fischer first identified this class of enzyme.
Protein kinase works by permitting the transfer of a phosphate group (a group of atoms of phosphorous and oxygen) from the energy-rich compound adenosine triphosphate (ATP) to another enzyme, glycogen phosphorylase, activating this enzyme. Then, phosphorylase converts the stored energy of glycogen into a readily available fuel, glucose, a simple sugar, the fuel that our cells burn for energy. This powers up the cell to carry out its functions. When the cell has finished its immediate task, the power is switched off by another set of enzymes, the phosphatases.
Later research based on these original findings has shown that protein phosphorylation also regulates the transmission of messages from hormones and drugs to the biochemical reaction centers inside the cell. Reversible protein phosphorylation affects every cell in the body and plays important roles in immune system response, inflammatory reactions, and neural signaling. These findings by Fischer and Krebs opened up new horizons in research world-wide, and elucidated how the cell responds to chemical signals, including insulin, epidermal growth factor, and platelet-derived growth factor (see Getting to the Heart of Atherosclerosis).
For example, in an emergency, the hormone adrenalin—the "fight or flight" messenger—sends an urgent call to your heart muscle cells to beat faster, to your skeletal muscles to prepare to run or act. A specific protein kinase, crucial to the action of adrenalin and certain other hormones, releases phosphate from ATP. Then, certain secondary messengers , the most common of which is cyclic adenosine monophosphate (cAMP), "contacts" the appropriate protein to pass on the signal or to formulate a cellular response. These second messengers may locate and activate one protein or they may activate many. The process resembles a sort of cellular "telephone tree" or information relay.
These discoveries in basic science have influenced medical research on many levels. Understanding how normal and abnormal cellular activities are controlled may provide clues to the underlying causes of diabetes, cancer, heart disease, and other conditions.
When they made their discovery those 40 years ago, they had no idea it was going to have such broad implications, an observation that leads Krebs to believe strongly that, in this era of budget-cutting and downsizing, non-targeted research should continue to be supported. Says Krebs: "It's a mistake to think we are smart enough to second guess what will be important in the long run."