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Biological Chemistry

Science Concentrates

August 16, 2004 | A version of this story appeared in Volume 82, Issue 33

Small molecule shown to activate transcription

The first transcriptional activation domain made from a small organic molecule has been created and tested. Transcriptional regulators play a role in human diseases such as cancer and diabetes. Endogenous transcriptional activators contain a DNA binding domain (blue in figure) linked to an activation domain (red) that recruits RNA polymerase holoenzyme (yellow) and associated transcription factors (green), thus initiating transcription of a gene (black line). Synthetic activation domains have been made from both peptides and RNA, but a small-molecule activation domain had never been achieved. Now, Anna K. Mapp and coworkers Aaron R. Minter and Brian B. Brennan at the University of Michigan, Ann Arbor, have designed and synthesized an isoxazolidine-based agent that activates transcription in an in vitro system at levels similar to those of a natural activation domain [J. Am. Chem. Soc., published online Aug. 7,]. The study "paves the way for the creation of entirely new small-molecule-based transcriptional activators for a variety of mechanistic and medicinal applications," Mapp says.

Selective DNA transport

A DNA-functionalized membrane, made of gold nanotubes and built by chemists at the University of Florida, Gainesville, could give scientists a new tool for DNA separations and genomics research [Science, 305, 984 (2004)]. The system, developed in chemistry professor Charles R. Martin's lab, features a hairpin-shaped DNA molecule covalently attached, via a thiol linkage, to the inner walls of the gold nanotubes that make up the template-synthesized membrane. Martin's group designed the 30-base DNA molecule to assume a hairpin shape by making the six bases at both ends of the strand complementary. These 12 bases come together in a duplex so that the remaining 18 bases in between them form a loop. This hairpin selectively transports specific sequences of DNA through the membrane's golden pores. DNA that perfectly complements the 18-base loop will open up the hairpin and move across the membrane at a rate much faster than the rate of DNA that doesn't match. Under optimal conditions, the system is so specific that it can discriminate against DNA with only a single-base mismatch.

Tracking cholesterol in cell membranes

A method to track changes in the amount of cholesterol in a single cell's plasma membrane has been developed by chemists at Case Western Reserve University. The amount and distribution of cholesterol--a sterol lipid that regulates membrane fluidity and permeability--in the plasma membrane influences processes such as cell-cell communication. James D. Burgess and Anando Devadoss hope their electrochemical method will be useful for studying real-time membrane cholesterol homeostasis and the growth of cholesterol-rich atherosclerotic plaques. The pair electrochemically detects cholesterol in the plasma membrane of a single cell using a platinum microelectrode coated with a lipid bilayer containing the enzyme cholesterol oxidase [J. Am. Chem. Soc., published online Aug. 3,]. Cholesterol in the cell's plasma membrane diffuses into the nearby electrode-supported lipid bilayer, where it is oxidized by cholesterol oxidase. Hydrogen peroxide generated when the enzyme oxidizes cholesterol is detected via electrochemical oxidation at the electrode.

Ulcer-fighting carbohydrate

A sugar chain in human mucus protects stomach cells from the bacteria that cause ulcers [Science, 305, 1003 (2004)]. The discovery is the first example of an antibiotic mammalian glycan and could lead to a drug for treating Helicobacter pylori infection. H. pylori inhabits the guts of about half the human population, but because most human hosts never develop the ulcers or cancer attributable to the potent microbe, scientists have suspected that the body has a natural defense. Jun Nakayama of Shinshu University School of Medicine, in Japan, and Minoru Fukuda at the Burnham Institute, in California, and colleagues suggested that the natural defense might be the branched six-sugar chain capped by alpha1,4-linked N-acetylglucosamine (shown) that is sported by proteins released by deep mucous cells. Indeed, a biosynthesized analog of the glycoprotein blocked the growth of H. pylori. The scientists suspect that the glycan--which structurally resembles cholesteryl-alpha-d-glucopyranoside (CGL), a core component of H. pylori's cell wall--slows down the enzyme that makes CGL, presumably by swamping the enzyme's feedback-inhibition loop.

Photochemical dechlorination

A new catalytic system for dechlorinating chlorinated organic pollutants employs a vitamin B-12 derivative and a ruthenium photosensitizer. Yoshio Hisaeda and coworkers at Kyushu University, Fukuoka, Japan, used the system to catalyze the dechlorination of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] under visible light irradiation [Chem. Commun., published online July 28,]. The catalyst, hydrophobic vitamin B-12, has ester groups in place of the peripheral amide moieties of naturally occurring vitamin B-12. The system exhibits high catalytic efficiency and stability during the dechlorination. The authors postulate that the hydrophobic vitamin B-12, which contains cobalt(II), is reduced to a supernucleophilic Co(I) species by the ruthenium photosensitizer. The Co­C bond of the alkylated complex generated by the reaction of the supernucleophile with DDT is cleaved by photolysis to form a substrate radical and a Co(II) species. The radical reacts with H2 to form, as the main product, a DDT derivative having a CHCl2 group instead of CCl3. The system is simpler and more facile than conventional electrochemical dehalogenation systems, the authors say.




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