n e w s of t h e w e e k
Carbenes may be key to enzyme's power Carbene intermediates in a nonpolar en vironment may explain how one of the world's most powerful enzymes works, say chemists at the University of Califor nia, Los Angeles. Orotidine monophosphate decarbox ylase is the most proficient enzyme known. It catalyzes a simple but impor tant reaction, decarboxylation of oroti dine 5/-monophosphate to uridine 5'monophosphate, a key ingredient in nu cleic acid biosynthesis. The rate constant for reaction with the enzyme is 1023 times greater than for the uncatalyzed reaction. Scientists have been seeking to explain how the enzyme achieves such accelera tion. The fact that cofactors or metal ions aren't involved makes the problem even more intriguing. No crystal structure exists yet for the enzyme, but that hasn't stopped the search for answers. Now, using quantum mechanical the ory, National Institutes of Health post doctoral fellow Jeehiun K. Lee and chem istry professor Kendall N. Houk predict the mechanism involves a carbene inter mediate. It "represents a previously un recognized mode of enzymatic activity" for the enzyme, they write in Science [276,942(1997)]. The astounding proficiency of the en zyme was first shown experimentally in 1995 by Richard V. Wolfenden, a bio chemistry professor at the University of North Carolina, Chapel Hill. The UCLA chemists, Wolfenden says, "suggest an energetically plausible mechanism by which the reaction might be catalyzed in a nonpolar microenvironment." Lee and Houk's proposed mechanism for "this central biological reaction should influence the design of inhibitors and im prove the understanding of the environ ment at the enzyme's active site," says chemistry professor Peter Beak at the Uni versity of Illinois, Urbana-Champaign, who had proposed a different mechanism for the enzyme in 1976. On the basis of theoretical calcula tions, Lee and Houk suggest that proton transfer from the amino group of lysine93 of the enzyme to the oxygen at posi tion 4 of the substrate occurs simulta neously with decarboxylation, yielding a carbene. "It is ironic that a carbene would be the key intermediate involved in the catalyzed reaction," Houk tells C&EN, because carbenes usually are un12 MAY 12, 1997 C&EN
When oxygen at position 4 (arrow at left) in orotidine S-monophosphate is protonated by lysine-93 in a nonpolar cavity of the enzyme, decarboxylation occurs simultaneously (center) to produce a resonance-stabilized carbene (right).
stable. But in this case, explains Lee, the carbene is stabilized by resonance. To study the reaction, Lee used a high-end, reliable level of quantum me chanical theory to calculate very accu rately the energetics of the uncatalyzed reaction. Then she tested various catalyt ic mechanisms, including solvent effects. What the researchers found about sol vent effects is "of even more general in terest," Lee notes. Because the enzyme's proton donor, protonated lysine, is a weak acid, protonation—and the accom panying carbene formation that results in the dramatic acceleration of the reac tion—occurs only in an environment of low polarity. Water is too polar for catal ysis by such weak acids to occur, Lee's work shows. That means the enzyme pocket where the reaction occurs must be nonpolar, says Houk. "In a nonpolar cavity, unusu al and unanticipated things happen," he adds. Lee will continue to examine such solvent effects to explain how enzymes work after she joins Rutgers University,
Lee: resonance stabilizes carbene
New Brunswick, N.J., as an assistant pro fessor of chemistry this fall. Lee and Houk are "courageous calculational chemists" for going beyond "pro viding a correlation or analysis of estab lished chemical fact to making a predic tion about a complex biological reaction," says Beak. "It will be interesting to see whether their novel mechanism withstands the challenge of structural analysis," adds Wolfenden. Maureen Rouhi
ICI buys Unilever's specialty chemicals units Britain's ICI, the seventh largest global chemical producer, plans to acquire the specialty chemicals businesses of AngloDutch firm Unilever for $8 billion. The acquisition "will create a formida ble new force in specialty chemicals," ICI Chairman Ronnie C. Hampel said in announcing the deal last week. The agreement, which ICI expects will be completed by the middle of the year, re quires regulatory approval and consent from a shareholders meeting, expected to be held June 16. To help pay off the debt it will take on to fund the Unilever acquisition, ICI will sell its 62% shareholding in ICI Aus tralia and use that money, along with money from the planned sale of its titani um dioxide unit. The Unilever businesses included in the deal are National Starch & Chemical, Bridgewater, Ν J., which makes adhesives, resins, and specialty chemicals and starch es; Quest International, Naarden, the Neth erlands, a fragrances and flavors producer; Unichema International, Gouda, the Neth erlands, a specialty oleochemicals manu facturer; and Crosfield, Warrington, En gland, which makes inorganic silica- and alumina-based compounds.
