news of the week MARC H 5, 201 2 E D I TED BY W I L L I A M G. SC H UL Z & E MI LY BO NES
residue that activates opening of an epoxide—dramatically change the energetics of the cyclization reaction. The result is formation of a ENZYMOLOGY: Structure, theory six-membered ring. answer question about how an Computational organic unusual biosynthetic step works chemists Robert S. Paton of Oxford University and Kendall N. Houk of UCLA collaborated with Kim and HE FIRST X-RAY crystal structure of a biosyncoworkers by carrying out quantum methetic enzyme and quantum chemical calculachanical simulations that helped determine tions have resolved a long-standing mystery the mechanism. Also adding support to the about how bacteria are able to use a typically slow, new findings is a 1993 proposal by Houk and colseemingly unworkable type of chemical reaction to leagues that a similar mechanism explains theoretically make six-membered rings in polyether antibiotics how a catalytic antibody works. (Nature, DOI: 10.1038/nature10865). The study “gives a glimpse at the inner workings of The study could lead to greater use of similarly disnature’s design,” says synthetic organic chemist and favored reactions in synthetic orbiochemist Igor V. Alabugin of ganic chemistry and in fermentaFlorida State University. In the ALTERED ENERGETICS tion vats to create diverse naturalstudy, Kim and coworkers used Using well-positioned basic (B:) and product-like compounds for drug “a very impressive blend of skills + acidic (H ) residues, Lsd19 catalyzes discovery and other applications. and techniques to solve a diffiformation of five- and six-membered Since 1974, when the first studcult problem,” he says. ether rings in lasalocid A. ies on biosynthesis of the antibiotThe findings show “that when ic lasalocid A were carried out, rethere are two competing reacsearchers have wondered how the tions and one is strongly favored natural product’s six-membered in solution, an enzyme can evolve ether ring forms. In solution, the to preferentially catalyze what type of reaction that forms that would otherwise be the less faring is disfavored, according to vored reaction,” says mechanistic Baldwin’s rules of ring closure, enzymologist David E. Cane of proposed in 1976 by Sir Jack BaldBrown University. “The enzyme win of Oxford University. doesn’t violate the laws of chemA few years ago, pharmaceutiistry. It just has to find a few extra cal chemist Hideaki Oikawa of kilocalories to make the less faHokkaido University, Japan, and vored reaction go faster.” coworkers discovered Lsd19, the Lasalocid A’s six-membered bacterial enzyme that catalyzes cyclic ether is a common structhe epoxide-opening cyclization tural feature in hundreds of other reaction that converts the bionatural products, and the findings synthetic precursor compound could explain how many of them bisepoxyprelasalocid A into are formed in nature. Kim’s group lasalocid A. has already found that seven In the new study, crystalmicroorganisms utilize the new lographer and drug developer mechanism for six-memberedChu-Young Kim of the National ring formation. He believes the University of Singapore and cofindings will lead to new ways to workers have obtained the first favor formation of six-membered crystal structure of Lsd19. rings in a range of polyether The structure shows that prenatural-product-like compounds cisely positioned active-site resiand enhance the ability to credues—a basic residue that deproate analogs with novel forms of tonates a hydroxyl and an acidic bioactivity.—STU BORMAN
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NATURE
UNFAVORED RING ROUTE REVEALED
In lasalocid A biosynthesis, one of Lsd19’s domains (left half of structure) catalyzes fivemembered ring formation, and the other then catalyzes sixmembered-ring cyclization. Stick structures are substrate (left) and product (right) analogs.
