DURHAM, N.C. -- Duke University Medical Center biochemists have reported the detailed function of an enzyme that is a key component of a signaling pathway important for about 30 percent of cancers. Their surprising findings about how the enzyme, called farnesyl transferase (FTase), works could help improve the FTase-inhibiting drugs that pharmaceutical companies are now testing to fight a broad spectrum of cancers.

In an article in the October 10, 2002, Nature, biochemists Lorena Beese, Patrick Casey and Stephen Long reported detailed X-ray crystallographic studies of FTase "frozen" in configurations in which it is attached to the molecules -- called substrates -- on which it acts catalytically. Together, the structures of these configurations produce the equivalent of a stop-motion animation of the enzyme's reaction path. The scientists' work was supported by the National Institutes of Health.

FTase works as a cellular seamstress, connecting a fatty farnesyl molecule to newly built protein enzymes when they emerge from the cell's production machinery. This chemical stitchery adds a molecular "flag" to a new enzyme that signals the cell to send it off on its metabolic mission in the cell.

Ten years ago, Casey and other researchers discovered that among the enzymes that FTase flags to trigger into action is the notorious cancer-causing enzyme Ras. Although Ras usually plays a normal, essential role in the machinery of cell growth when it is under the precise control of the cell's regulatory systems, Ras can mutate to become constantly active and thereby help trigger uncontrolled cancerous cell growth. Mutant Ras enzymes are associated with nearly a third of human cancers, including up to 90 percent of pancreatic cancers, half of all colon cancers and a quarter of all lung cancers.

Thus, pharmaceutical companies including Schering-Plough, Bristol Myers-Squibb and a subsidiary of Johnson & Johnson are now testing drugs that jam FTase to block the
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Contact: Dennis Meredith
dennis.meredith@duke.edu
919-681-8054
Duke University
9-Oct-2002

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