The team, led by Stuart L. Schreiber, professor of chemistry and chemical biology and Howard Hughes Medical Institute investigator, used the microarrays to identify compounds that modulate the function of the yeast protein Ure2p [Nature, 416, 653 (2002)]. This protein was already known to be involved in nitrogen metabolism. Using chemical genetics methods, in which small molecules perturb the function of proteins, the researchers established that this protein is also involved in glucose sensing.

The scientists identified a compound, which they dubbed uretupamine, that selectively binds to Ure2p. "The really stunning feature of the small molecule we report is that it modulates only the glucose-sensing function of Ure2p and leaves intact its previously understood nitrogen-sensing function," according to Schreiber.

Schreiber attributes the success in unraveling the pathway to the "time resolution" of chemical genetics methods, in which small molecules perturb proteins to deduce their function. In traditional genetics methods, the gene is removed and the organism develops without it, often compensating in ways that mask the gene's true function.

The Harvard researchers are now applying the small-molecule microarray approach to other components of this glucose-signaling pathway. "We can instantaneously modulate the function of many different components now," Schreiber says. "My hope is that this will soon become one of the best understood signaling networks in biology."

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