Joe Caspermeyer, Media Relations Manager & Science Editor
(480) 727-0369 | joseph.caspermeyer@asu.edu
March 4, 2008
A spoonful of sugar: Scientists discover regulatory details for metabolic gene network
The common baker’s yeast (Saccharomyces cerevisiae) is not only a daily dietary staple essential for making bread, beer and wine, but for scientists, has also provided a bounty of answers to pivotal questions in biology.
Now, a scientific team from the Cold Spring Harbor Laboratory, Stony Brook University and the Biodesign Institute at Arizona State University has found a vital missing link for the regulation of genes essential for cell metabolism.
The team, led by CSHL Professor Leemor Joshua-Tor, PhD, and co-author Stephen Albert Johnston, PhD, of ASU’s Biodesign Institute, announced a new and unexpected wrinkle in a story they previously 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 are also 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,” noted Dr. Joshua-Tor, a structural biologist. “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. Biodesign’s Johnston was one of the first researchers to define the galactose regulatory system.
“The players involved in this process have been known for some time. But we did not understand precisely how the components of this particular biochemical pathway worked together,” said Johnston, a professor in ASU’s School of Life Sciences who also directs the Center for Innovations in Medicine at the Biodesign Institute.
The regulation of galactose metabolism depends on three key proteins: Gal4p, which turns genes on; Gal80p, which blocks Gal4p, thereby turning genes off; and 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 previously had been overlooked.
The unexpected molecule the team uncovered is called NADP. Johnston and colleagues found that NADP acted as a key mediator in the GAL4p/GAL80 tug of war in turning galactose genes on. 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,” said 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 impacts biological processes of many kinds, ranging from cancer to aging,” said Joshua-Tor. The biochemical cascade identified by the team is part of a complex chain of events whose object is the regulation of the output of specific genes.
The team’s work help explain how links in that gene-regulatory chain are constructed. “Gene-regulatory proteins impact every property of a cell and have long been recognized as possible targets for drugs,” said Joshua-Tor. “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 impact this class of proteins.”
“NADP Regulates the Yeast GAL Induction System” appears in the journal Science. The compete citation is as follows: P. Rajesh Kumar, Yao Yu, Rolf Sternglanz, Stephen Albert Johnston, Leemor Joshua-Tor. The paper is available online at: http://www.sciencemag.org/cgi/content/abstract/319/5866/1090
Compiled from ASU and CSHL news sources
The Biodesign Institute at Arizona State University is focused on innovations that improve health care; provide renewable sources of energy and clean our environment; outpace the global threat of infectious disease; and enhance national security. Using a team approach that converges the biosciences with nanoscale engineering and advanced computing, the goal is to find solutions to complex global challenges and accelerate these discoveries to market. For more information, visit www.biodesign.asu.edu
CSHL is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.
For more information, visit www.cshl.edu
