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From Cutting Edge to Classic
CHORI Scientist Included in Classics Publication

CHORI senior scientist Stuart Smith, PhD, of CHORI’s Center for the Prevention of Obesity, Cardiovascular Disease & Diabetes, was recently included in a special issue of the Journal of Mammary Gland Biology and Neoplasia devoted to an historic review of the mammary gland field from 1945 to 1980. A 1980 publication of Dr. Smith’s was reprinted as a seminal contribution to the field.

"I was quite thrilled over it, I have to admit. It came as a complete surprise, but it's really lovely at this stage of my career to find that something I did such a long time ago was considered worthy of being called a Classic."

While Dr. Smith and colleagues shook up the scientific airwaves more recently by characterizing the extraordinary structural changes in fatty acid synthase (FAS) that are required for catalysis in a study that graced the cover of the February 2009 issue of Nature Structural and Molecular Biology, Dr. Smith began his career in the mammary gland field.

"My interest in that field started in my post-graduate years," says Dr. Smith. "My PhD thesis was actually on milk fat synthesis."

For decades, both dairy researchers and breast cancer researchers have been interested in mammary gland biology and the mechanism of production and secretion of milk. Milk fat and its biosynthesis was of particular interest because it contains shorter chain-length fatty acids than any other fat that is stored in the body making it more easily absorbed by the immature gut.

As Dr. Smith explains, "The main question I wanted to investigate was how this unique fat in milk was made and secreted. At the time, we suspected that there might be a unique FAS that was only present in breast tissue."

In fact, after nearly a decade of painstaking research in the 1970s that was summarized in the 1980 paper, Dr. Smith and his then colleagues discovered that the FAS in breast tissue wasn't any different than the FAS in the rest of the body. Instead, Dr. Smith discovered a different enzyme, named thioesterase II, that was responsible for altering the products of FAS uniquely in the mammary gland. The discovery of thioestserase II was a defining moment for both the mammary gland field and Dr. Smith, whose interest shifted from the mammary gland to FAS.
"Realizing that the versatility of FAS allowed it to make both short and long chain-length fatty acids was intriguing and led me address the question of how FAS works. What does it look like? How do its multiple structural elements cooperate with each other?"
"The study reproduced in this classics issue really started off my career, and got me focused on solving the mechanism and structure behind FAS," says Dr. Smith.

Of course another 30 years would go by before before the three-dimensional structure of FAS was solved and Dr. Smith and collaborators were able to identify the dynamic conformational changes required for catalysis, adding what will no doubt become a classic of its own to the scientific literature.

"Looking back it still seems relatively surprising that it would have taken that long to from where we were then to where we are now - it just turned out that, because of its gigantic size and extreme flexibility, it was an incredibly difficult protein to work with," says Dr. Smith.

In spite of the long haul between then and now, Dr. Smith isn't slowing down a bit, switching his research focus now to a newly discovered mitochondrial FAS. Dr. Smith's current research projects address the question of why we have two pathways for fatty acid synthesis and how important the mitochondrial FAS pathway is in supporting mitochondrial function and cellular metabolism.

"It looks like there is a second system for making FAS that is located in the mitochondria, and this is of particular interest because we've begun to realize that a lot of human diseases seem to have defective mitochondrial functions as at least one of their components," explains Dr. Smith who, if he keeps up with his own standards, may just keep adding more classics to the FAS field.


Tuesday, May 17, 2011 8:19 AM

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