Research on cell-control path gains Nobel.

Two U.S. biochemists have won this year's Nobel Prize in Medicine or Physiology for discoveries that led to understanding a process that plays a critical role in cell-protein regulation.

"Their fundamental finding initiated a research area which today is one of the most active and wide-ranging," stated the Nobel Assembly at the Karolinska Institute in Stockholm, Sweden.

Edmond H. Fischer, 72, and Edwin G. Krebs, 74, professors emeritus at the University of Washington in Seattle, will share the $1.2 million prize for work they began in the 1950s and have continued to the present.

Fischer and Krebs made their initial discovery in a study of muscle contraction. They isolated and described a key enzyme in the biochemical process that enables another enzyme within muscle cells to draw energy rapidly from stored body sugars.

This enabling enzyme, one of a class of proteins called protein kinases, later proved to be present in all cell types. Researchers have implicated protein kinases in many critical aspects of cell life, including protein synthesis, cell metabolism, respiration, and hormonal responses to stress. Scientists estimate that as much as 1 percent of the human genetic code holds the programming for protein kinases.

Proteins such as hormones and enzymes perform the essential functions of cell life. In muscle cells, for example, an enzyme called phosphorylase releases stored energy. Biochemists Carl and Gerty Cori won the 1947 Nobel Prize for identifying this muscle enzyme. But a problem remained for biochemists to solve: Just what in muscle cells switches phosphorylase on and off as needed? Fischer and Krebs teamed up in the 1950s to find the answer.

Their solution exposed fertile ground for further biochemical research and ultimately earned Fischer and Krebs their Nobel. The Seattle researchers found that kinases ferry certain chemical subunits, called phosphate groups, from the energy-rich molecule ATP to dormant phosphorylases. The phosphate groups change phosphorylase into an active enzyme, which then breaks down stored sugars to release the energy needed for muscle contraction.

The process works in reverse, too. Krebs and Fischer found that another kind of enzyme, called a phosphatase, strips away phosphate groups, rendering proteins inactive.

This "reversible protein phosphorylation" is a recurrent motif in the complex interplay of proteins that sustains cell life. "Step by step, it has become evident that protein phosphorylation constitutes a fundamental mechanism, influencing all cellular functions," the Nobel Assembly explained in its announcement of the award this week.

Research into the role of phosphorylation has proved medically fruitful. Fischer and Krebs have demonstrated, for example, that the drug cyclosporin blocks the body's immune response to transplanted tissues by interfering with phosphorylation.