Biochemists solve 3-D structure of cellular ‘fuel gauge’

SAN ANTONIO (April 23, 2008)—Biochemists at The University of Texas Health Science Center at San Antonio have deciphered the three-dimensional, atomic-level structure of an enzyme that acts as a ‘fuel gauge’ sensing when cells are low in energy and signaling it is time to refuel.

The scientists worked out the 3-D contour of the enzyme, called isocitrate dehydrogenase or IDH, by coaxing it to form single crystals and bombarding the crystals with X-rays. The X-ray diffraction pattern was carefully measured and advanced software was used to interpret the resulting diffraction pattern. This technique is called X-ray crystallography and is a specialty of P. John Hart, Ph.D., of the UT Health Science Center San Antonio Department of Biochemistry.

This is the first time IDH structure has been unveiled in an organism above a bacterium, in this case yeast. A rendering of IDH is featured on the cover of the April 18 issue of the Journal of Biological Chemistry (JBC).

“This is a tremendously exciting discovery because IDH is a central player in cells’ energy production,” said JBC article lead author Lee McAlister-Henn, Ph.D., professor and deputy chair of the Department of Biochemistry. She joined the UT Health Science Center in 1992 from Cal-Irvine and has worked on IDH for two decades. Dr. Hart is a co-author of the JBC article.

IDH participates in production of adenosine triphosphate, the most important form of cellular energy. This energy production cycle takes place in mitochondria, which are the factories or power plants located in cells.

“IDH is a key metabolic enzyme and nobody has understood how it works as a fuel gauge,” Dr. McAlister-Henn said. “We will now make mutant forms of IDH to test examples of poor regulation, and ultimately the goal will be to extend studies to human IDH.”

IDH may play a key role in metabolic diseases such as type 2 diabetes, but Dr. McAlister-Henn declined to speculate on what the future clinical implications of the current finding will be.

The Robert A. Welch Foundation, one of the nation’s oldest and largest sources of private funding for basic chemistry research, and the National Institutes of Health’s National Institute of General Medical Sciences funded the research, along with the Office of the Vice President for Research at the UT Health Science Center.

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