CSHL scientists discover new details of a gene-regulatory network governing meta

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CSHL scientists discover new details of a gene-regulatory network

governing metabolism

NADP molecule regulates a cascade enabling yeast cells to adjust

metabolic state

http://www.eurekalert.org/pub_releases/2008-02/cshl-csd022208.php

Metabolism is a central feature of life – a myriad of biochemical

processes that, together, enable organisms to nourish and sustain

themselves. Scientists at Cold Spring Harbor Laboratory (CSHL) are in

the forefront of efforts to demonstrate how the regulation of genes

governs fundamental life processes, including metabolism.

Such research, performed on simple model organisms like yeast cells,

has implications for efforts to understand natural processes such as

aging and disease states including cancer.

This week a team at CSHL led by Professor Leemor -Tor, Ph.D.,

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 February 22 in

the journal Science.

Adapting to New Energy Sources

" S. cerevisiae, or common baker's yeast, can use any number of

different types of sugar molecules for energy production, " noted Dr.

-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. "

This much, notes Dr. -Tor and colleagues, has been understood

for years. " 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

ston, a professor at the Biodesign Institute at Arizona State

University and a co-author of the study.

It was Dr. -Tor's team at CSHL that 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 is called NADP. The team discovered that 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 a protein called Gal80p, which acts

along with a gene regulating-protein called Gal4p, to adapt 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 Dr. -Tor. 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.

Not only does 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 Dr. -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 Science on

February 22. The compete citation is as follows: P. Rajesh Kumar, Yao

Yu, Rolf Sternglanz, Albert ston, Leemor -Tor. The

paper is available online at:

http://www.sciencemag.org/cgi/content/full/319/5866/1090

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.