Research chemists, chemical hygiene officers, lab safety managers-
Performing Safety Audits] and Hazard Evaluation Reviews ACS Satellite TV Seminar Broadcast Live on June 19,1997,1:00 - 3:00 PM EDT • Learn how to prevent injuries and close calls with Job Hazard Analysis. • See how to audit large research groups with labs in dispersed locations. • Find out who should perform lab audits so that everyone buys into your safety program. • Obtain useful checklists and procedures to help you implement the suggested practices and techniques.
Featured Speakers & Panelists George Whitmyre, safety facilitator, University of Delaware, Chemical Engineering Department David J. Van Horn, former Manager of Research, Safety, Health & Environmental Affairs, Rohm & Haas OSHA inspector
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42 FEBRUARY 17, 1997 C&EN
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Synthetic polymers catalyze DNA cleavage Chemists in South Korea have synthesized carbohydrate polymers that catalyze the hydrolysis of a model phosphodiester and the cleavage of single-stranded DNA. Chemistry professor Man Jung Han and coworkers at Ajou University in Suwon have shown that the rate of phosphodiester hydrolysis and DNA cleavage catalyzed by their synthetic polymer catalysts is up to 1,000 times faster than the uncatalyzed reaction rates. The group made the discovery while investigating polynucleotide analogs [Chem. Commun., 1997,163]. The phosphodiester bridge is an intrinsic component of the backbones of both DNA and RNA. "The hydrolysis of phosphodiesters is very important because it is the key reaction of the cleavage of DNAs and RNAs," Han tells C&EN. According to Michael J. Gait, head of chemistry at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, "This is a remarkable and unprecedented discovery of significant phosphodiester cleavage catalyzed by a carbohydrate polymer." He adds that the reported cleavage rate constant of the model phosphodiester substrate is about one-tenth that of an RNA enzyme (ribozyme) and about one-hundredth that of a protein nuclease. Han's team synthesized the polymers by the reaction of sugar derivatives with maleic anhydride. Four of the polymers have attached ribofuranose rings and one has pyranose rings. Their average molecular weights ranged from 8,400 to 17,000. Three polymers that contain ribofuranose rings with neighboring hydroxyl groups in the cis configuration catalyzed both the hydrolysis of ethyl /Miitrophenyl phosphate and of single-stranded DNA with 30 bases. The other two polymers, which did not contain the vicinal diol group, showed no catalytic activity. This is the "first example either in poly-
KOH
OH -C0 2 CH 3
-C0 2 CH 3 Fax
Synthetic ribofuranose polymer
American mer or biological chemistry" of such catalytic activity, says Han. The polymers show standard enzyme kinetics with the phosphodiester substrate. "This has not been previously observed with synthetic polymer catalysts," he says. Han suggests that the polymers form active sites in which the furanose rings with the vicinal cis diol groups are located and where the phosphodiester substrates are accommodated. "The diol groups form hydrogen bonds with the two oxygen atoms of the phosphate so as to activate the phosphorus atoms to be attacked by a nucleophile, the water molecule," postulates Han. According to Gait, the length of the polymer required to bind the substrate is large. "This suggests the catalytically active structure may be complex," he says. "Therefore, it is unclear if these polymers will find practical value. However, their novelty will undoubtedly inspire further structural and mechanistic studies." Peter J. Sadler, a chemistry professor at the University of Edinburgh, Scotland, points out that DNA hydrolysis is more difficult than RNA hydrolysis, which can be catalyzed by ribozymes. "Synthetic molecules that can catalyze the hydrolysis of DNA are of great interest in studies of DNA chemistry and also as potential pharmaceuticals," observes Sadler. "It will be interesting to see whether any base specificity can be introduced by appropriate design of the synthetic polymers and to unravel the mechanism involved." Ronald R. Breaker, assistant professor of biology at Yale University, considers that "it is surprising to find that simple homopolymers of ribofuranose derivatives can cleave DNA, a molecule that is noted for its stability to hydrolytic degradations." RNA, the distant cousin of these polymers, can cleave DNA with great precision and efficiency, but such ribozymes are also quite large and need intricately folded tertiary structures for activity, he notes. Breaker's group recently unveiled new classes of catalytic DNAs made by combinatorial techniques. In the presence of a metal ion, the DNA molecules catalyze their own oxidative self-cleavage (C&EN, Feb. 3, page 33). "Will these new polymers form structures like those made by protein and nucleic acid enzymes?" asks Breaker. "Perhaps these modified ribofuranose monomers could be used to diversify the chemical makeup of RNA to produceribozymeswith new catalytic activities," he suggests. Michael Freemantle
Chemical Society Presents Intensive Four-Day Short Courses Providing Hands-On Experience with State-ofthe-Art Techniques and
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FEBRUARY 17, 1997 C&EN 4 3
