science/ technology concentrates
ly increase catalytic activity as the temper ature rises to 100 °C. In effect, the team has created an enzyme that has the ther mal stability of enzymes derivedfrommi Bacterial cell-wall croorganisms that live in extremely hot en precursor synthesized vironments. Contrary to what is generally observed with these "extremozymes," the A powerful tool for discovering antibiotics engineered enzyme did not lose its activi has become easily available with the first ty at lower temperatures [Proc. Natl. total synthesis of a key intermediate in bac Acad. Set. USA, 95, 2056 (1998)]. Work terial cell-wall biosynthesis. Research sci ing with colleagues in both Germany and entist Stephen A. Hitchcock and cowork Norway, Bertus Van den Burg at the Uni ers at Lilly Research Labs, Indianapolis, have versity of Groningen, the Netherlands, in prepared several-hundred-milligram quanti troduced a disulfide bridge into a therties of the intermediate called Park nucleo molysin-like protease from Bacillus steatide (below) \J. Am. Chem. Soc., 120,1916 rothermophilus and, using site-directed (1998)]. The synthesis "provides a practical mutagenesis, substituted six of the en route to substantial quantities of a func- zyme's amino acids. The researchers based their approach on computer modeling and rational design, building on the knowledge HO that the stability of thermolysin (an en HO zyme that cleaves peptide bonds) is con Ο Ο ferred by a small stretch of amino acids and that salt and disulfide bridges im HN prove the stability. Thermal stability of the engineered protein is due to a reduc HO OH tion in entropy in the enzyme's unfolded state, the team says.^ NH xxX 2
I
A- A-
Vy
H0 2 C
ο II Ac=CH 3 C-
cr
NH
Vr
COoH
Heating changes chemistry of magnetic nanoparticles
Zeolites steer steroid photoreduction Photoreduction takes place from the more hindered side of steroids that have been tucked inside the cavities of zeolites, report chemists at Tulane University, New Orleans, and at DuPont Central R&D in Wilmington, Del. (J. Am. Chem. Soc, published Feb. 26 ASAP, http://pubs.acs.org/journals/jacsat). Tulane chemistry professor V. Ramamurthy and coworkers experimented with photo reduction of testosterone acetate and other steroids containing α,β-unsaturated ketones. When they irradiated the steroids in hexane slurries with the zeolite NaY, they unex pectedly found that the carbon-carbon double bond is reduced by addition of hy drogen from the less accessible face of the molecule. No such reaction occurs in hexane alone or with cation-free zeolites. They propose a model in which the least hindered face of the steroid is drawn close to the wall of the sodium-containing zeo lite by interaction of the enone chromophore with the cation, which exposes the more crowded side for reduction.^
Fooling the inflammatory response
In the early stages of inflammation, pro teins called L-selectin on the surface of The chemistry of nanoparticles of the white blood cells bind in bunches to mul spinel ferrite MnFe204 changes dramatical tivalent glycoproteins on the endothelial ly when the tiny crystals are heated, report cells that line blood-vessel walls. Now, re scientists at Georgia Institute of Technolo searchers at the University of Wisconsin, gy in Atlanta and at Oak Ridge National Madison, have found a way to stop the Laboratory in Oak Ridge, Tenn. \J. Am. binding. Their work paves the way for Chem. Soc, 120, 1800 (1998)]. Those new drugs to prevent inflammation and changes, in turn, can affect the magnetic new ways to manipulate the cell-surface properties of the nanocrystals, which are environment [Nature, 392, 30 (1998)]. of interest in applications ranging from Using ruthenium carbene-catalyzed ringmagnetic resonance imaging to magnetic opening metathesis polymerization, Eva J. refrigeration. Georgia Tech assistant pro Gordon, William J. Sanders, and Laura L. fessor of chemistry Z. John Zhang and co Kiessling synthesized a "neoglycopolyworkers studied the oxidation state and mer" that mimics the multivalent compo cation distribution in nanoparticles of nent of natural L-selectin-binding glycopro MnFe204. They found that Mn3+ cations teins. Subsequently, they showed that the are reduced irreversibly to Mn2+ when the synthetic polymer binds L-selectin and in nanoparticles are heated in a vacuum. duces a protease that clips L-selectin off Heating also "drastically" changes the dis the cell. When L-selectin is removed from tribution of the cations in the crystal lat the environment that it needs to function, tice. The variations in magnetic properties the inflammatory response is halted, says that previously were attributed to the size Kiessling. The synthetic polymer's affinity Enzyme engineered of the nanoparticles may instead be due to for L-selectin in solution is low, she notes, their chemistry, the researchers conclude. and as a result, the polymer can dissociate to work at 100 °C "Before we can focus on the effect of size from it, bind to more cell-surface L-selecA European research team has engi on the magnetic properties of nanoparti tins, and initiate another round of cleav neered a bacterial protease that normally cles, we have to understand the crystal age. "In that respect, the polymer func tions somewhat like a catalyst," she says.^ operates optimally at 60 °C to dramatical chemistry," Zhang says.^
tionally complex and formerly inaccessible compound," says John C. Vederas, profes sor of chemistry at the University of Alber ta, Edmonton. According to Hitchcock, the Lilly research was driven by the in creasing resistance of disease-causing bac teria to existing antibiotics, many of which target bacterial cell-wall biosynthesis. The synthetic intermediate now should allow researchers to better understand the mechanism of this resistance and to design new agents to counter it. Before this syn thesis, Park nucleotide could be obtained only by fermentation of several hundred thousand liters of bacterial cell culture. And because of the convergent synthetic approach, in which separately elaborated building blocks are joined together late in the synthesis, it should be possible to pre pare modified intermediates for use in ra tional drug design.^
28 MARCH 9, 1998 C&EN
