ASU researchers rise to the occasion for yeast study

The common baker’s yeast Saccharomyces cerevisiae not only is a daily dietary staple essential for making bread, beer and wine, but for scientists it’s also provided a bounty of answers to pivotal questions in biology.

Now, a scientific team from the Cold Spring Harbor Laboratory (CSHL), Stony Brook University, and ASU’s Biodesign Institute has found a vital missing link for the regulation of genes essential for cell metabolism.

The team, led by CSHL professor Leemor Joshua-Tor and co-author Stephen Albert Johnston of ASU’s Biodesign Institute, announced a new and unexpected wrinkle in a story they thought they understood about how yeast cells, through the action of genes, adjust their metabolism in response to changes in their sources of food. The team’s findings were published recently in the journal Science.

Adapting to new energy sources

Yeast has proven to be a useful genetic model for researchers when considering subtle influences on gene expression that also are found in higher organisms. Such research has implications for efforts to understand natural processes such as aging and disease states including cancer.

“S. cerevisiae, or common baker’s yeast, can use any number of different types of sugar molecules for energy production,” Joshua-Tor says.

“Importantly, the yeast cell can rapidly respond to changes in its nutritional environment by altering the expression of specific genes that allow it to make use of those different energy sources.”

The study focused on the ability of yeast to metabolize a simple sugar called galactose. Johnston, a professor in ASU’s School of Life Sciences who also directs the Center for Innovations in Medicine at the Biodesign Institute, was one of the first researchers to define the galactose regulatory system.

“The players involved in this process have been known for some time,” Johnston says. “But we did not understand precisely how the components of this particular biochemical pathway worked together.”

The regulation of galactose metabolism depends on three key proteins:

• Gal4p, which turns genes on.

• Gal80p, which blocks Gal4p, thereby turning genes off.

• Gal3p, which overcomes Gal80p to overcome the blocking action of Gal4p – and, thus, turns galactose-metabolizing genes back on.

The team took the step of investigating the architecture of the proteins involved in the pathway, at the level of individual atoms. Using a technique called X-ray crystallography, they discovered a “player” in the molecular cast of characters whose involvement had been overlooked.

The unexpected molecule the team uncovered is called NADP. Johnston and his colleagues found that NADP acted as a key mediator in the GAL4p-GAL80 tug-of-war in turning on galactose genes.

When a yeast cell changes from using glucose (a simple sugar) as a nutritional source to using galactose (a more complex sugar often found in dairy products and vegetables such as sugar beets), NADP is called into action. It “docks” to Gal80p, which acts along with Gal4p, adapts the metabolism of the yeast cell so that it can make use of galactose.

“Importantly, changes in cellular levels of NAD, a close relative of NADP, had previously been linked to a gene circuit that controls aging and longevity in a large number of different organisms, including yeast but also including animals,” says professor Rolf Sternglanz of Stony Brook University in New York, a co-author of the study.

Why the regulatory cascade is important

“It is becoming increasingly clear that the metabolic state of a cell is linked to the expression of its genes in a way that affects biological processes of many kinds, ranging from cancer to aging,” Joshua-Tor says.

The biochemical cascade identified by the team is part of a complex chain of events whose object is regulation of the output of specific genes.
The team’s work helps explain how links in that gene-regulatory chain are constructed.

“Gene-regulatory proteins affect every property of a cell and have long been recognized as possible targets for drugs,” Joshua-Tor says.

“However, these types of proteins have proven resistant to the chemistry of modern drug design. A detailed understanding of how gene regulatory proteins are controlled may offer new and unanticipated opportunities to design drugs that would affect this class of proteins.”

“NADP Regulates the Yeast GAL Induction System” appeared Feb. 22 in Science. The compete citation is as follows: P. Rajesh Kumar, Yao Yu, Rolf Sternglanz, Stephen Albert Johnston, Leemor Joshua-Tor. The paper is available at the Web site www.sciencemag.org/cgi/content/abstract/319/5866/1090.