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Breaking the Mold
New FAS Model Proposed by CHORI Scientist Confirmed

Although the actual crystal structure was achieved by a dedicated group at the Swiss Federal Institute of Technology, it decisively puts to rest any remaining controversy over Dr. Smith’s proposed structure of FAS.

“The difference between the models is in the way the subunits fold together,” explains Dr. Smith. “In simple terms, the old model envisioned the two subunits as oriented head-to-tail in a fully extended conformation. It turns out it’s actually head to head, and coiled. That’s what we deduced from our biochemical studies. And that’s what the structure shows on the front of Science.”

Because the FAS actually contains all seven enzymes required for the biosynthetic pathway integrated into very long, flexible polypeptide, its structure has been particularly difficult to capture through crystallography. Instead, scientists have used biochemical approaches to deduce the FAS structure, which was how Dr. Smith discovered that the old model, first developed about 25 years ago, was wrong.

“By looking at the interactions of the differently mutated subunits,” says Dr. Smith, “we were able to deduce how the protein is organized, and how the domains cooperate to make fatty acid. It was this approach that resulted in the new model we proposed.”

While Dr. Smith’s proposed model had been generally accepted in the field, the influence of the old model has proved continually pervasive. In fact, as recently as February of this year, an historical retrospective on FAS research was published in a leadinig journal - which included the old structure as the established model. Thanks to the Swiss team, it will be the last such published article.

“It’s just a shot in the arm for the whole field, I think,” says Dr. Smith.
Nevertheless, the structure does have its limitations. Although the electron density maps were derived at a resolution of ~5A, the resolution was not actually high enough to see individual amino acids. Instead, Ban and colleagues utilized high resolution crystal structures from homogolous counterparts in the bacterial world.

“They then tried to fit the crystal structures of the individual bacterial enzymes into the overall fold they could see from their low resolution structure,” explains Dr. Smith, and in fact, they were able to fit five out of the seven domains. While this overlay confirms Dr. Smith’s proposed FAS structure overall, the crystal as pictured on the cover of Science represents more of a model than an exact reproduction.

“The best thing, of course, is that this actually validates the last ten years of work we’ve done,” says Dr. Smith, “but we really do need a higher level resolution structure of actual human FAS.”

Without it, the research can’t progress to the next level – targeted pharmaceutical development for FAS inhibitors that could be used to treat obesity or even cancer.

“There’s still plenty more work to do,” Dr. Smith says.

It's work he and his colleagues aim to do, with current research already underway to crystallize mutant enzymes his group has been developing that may prove to be more susceptible to x-ray crystallography techniques than the naturally occurring enzyme.

For the moment however, they can pause in a little quiet satisfaction.

Monday, May 16, 2011 11:33 PM

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