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December 10, 2001
Volume 79, Number 50
CENEAR 79 50 pp. 45-55
ISSN 0009-2347
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[Previous Story] [Next Story]CHEMISTRY HIGHLIGHTS 2001

BIOCHEMISTRY. Key developments reported this year in biochemistry, biotechnology, and molecular biology include studies on molecular transporters that help drugs enter cells, proteins with unnatural residues, infinite-affinity antibody-ligand pairs, previously unknown antibody functions, salt-tolerant plants, the mechanisms of action of an important drug and an enzyme, and a series of studies in the areas of carbohydrate chemistry and structural biochemistry.

7950_7926NOTW.photosyn
SUN CATCHER In structure of photosystem I determined by Fromme, Witt, Krauss, Saenger, and coworkers, each lobe of the trimeric complex contains 12 different protein subunits and numerous cofactors.
For drug development purposes, compounds must be polar enough to dissolve in biological fluids and yet nonpolar enough to traverse cell membranes. In work reported initially at the December 2000 Pacifichem meeting in Honolulu (C&EN, Jan. 15, page 49), chemistry professor Paul A. Wender and coworkers at Stanford University developed molecular transporters. The transporters are oligomers of arginine or arginine-like monomers that enable linked compounds to be rapidly and efficiently taken up by cells--even if they couldn't normally enter cells or did so only with difficulty. Wender's team demonstrated the effect with a variety of small-molecule drugs, including cyclosporin A and paclitaxel (Taxol). By using molecular transporters, scientists can now make available for clinical development drug candidates buried in obscurity because of poor cellular uptake, a researcher commented.

Two research groups, working independently, developed improved methods for creating proteins containing unnatural amino acids (C&EN, May 7, page 57). Unnatural amino acid mutagenesis is of interest to scientists as a potential route to novel designer proteins and perhaps even new lifeforms.

The use of stop-codon suppression to incorporate unnatural amino acids into proteins was developed earlier by a group led by Peter G. Schultz, director of the Genomics Institute of the Novartis Research Foundation, La Jolla, Calif., and a chemistry professor at Scripps Research Institute. This year, Schultz and coworkers reported a revised stop-codon suppression method that eliminates a difficult step in the earlier technique--the chemical synthesis of unnatural amino-acid-containing tRNAs [Science, 292, 498 (2001)]. In the new method, genetically modified bacteria are used to biosynthesize the tRNAs instead. The technique is closely related to one reported three years ago by Rolf Furter [Protein Sci., 7, 419 (1998)], but Schultz and coworkers extended it further.

A second new unnatural amino acid mutagenesis strategy was reported by molecular biology and chemistry professor Paul R. Schimmel of Skaggs Institute for Chemical Biology at Scripps; Philippe Marlière, scientific director of Evologic, Evry, France; and coworkers [Science, 292, 501 (2001)]. The researchers coaxed bacteria with a mutant enzyme to replace some natural valine residues in proteins with an unnatural valine analog. Such an approach could eventually lead to the production of novel polypeptide-based biomaterials.

Graduate student Albert J. Chmura, undergraduate Molly S. Orton, and chemistry professor and Bioconjugate Chemistry Editor-in-Chief Claude F. Meares of the University of California, Davis, created antibody-ligand pairs that bind irreversibly and thus exhibit essentially infinite affinity [Proc. Natl. Acad. Sci. USA, 98, 8480 (2001); C&EN, July 23, page 36]. The researchers developed the infinite-affinity systems by engineering complementary reactive groups into specific sites in antibodies and corresponding ligands. The work could lead to new ways to target effector and indicator molecules of various types to specific cells for imaging or therapy.

A collaborative group also discovered that antibodies may have a previously unknown function--catalyzing the formation of hydrogen peroxide from water and singlet oxygen (oxygen in an excited electronic state). Antibody cleanup of singlet oxygen may serve to protect cells from its potentially toxic effects, the researchers speculated. And the production of highly reactive hydrogen peroxide suggested that antibodies may have the ability to kill pathogens directly--in addition to their known role of marking pathogens for destruction. The work was done by chemists Paul Wentworth Jr. and Kim D. Janda, molecular biologist Ian A. Wilson, and President Richard A. Lerner of Scripps Research Institute; theoretical chemist William A. Goddard III of California Institute of Technology; chemistry professor Albert Eschenmoser of the Swiss Federal Institute of Technology, Zurich; and coworkers [Science, 293, 1806 (2001); C&EN, Sept. 10, page 29].

7950_7939scit3.ce
BOUND In Hurley group's molecular dynamics model of ecteinascidin bound to DNA, the drug's three subunits (yellow, blue, and gray) are positioned in DNA's minor groove, and a guanine residue to which ecteinascidin is attached covalently is shown in red.
REPRINTED WITH PERMISSION FROM CHEMISTRY & BIOLOGY
7950_7935fig3-redux
7950_7935fig3-redux
CHARGED UP These electrostatic maps of a microtubule (top) and its two opposite ends (middle and bottom) were obtained with a parallel focusing technique developed by Baker, Joseph, Holst, McCammon, and Sept. Blue represents areas of positive charge, and negatively charged areas are shown in red.
Typically, plants exposed to high salt concentrations dehydrate and die. But pomology professor Eduardo Blumwald of UC Davis and botany postdoc Hong-Xia Zhang at the University of Toronto created genetically modified tomato plants that flourish on a diet of saltwater, producing fruit that's still healthy looking and tasty [Nat. Biotechnol.,
19, 765 (2001); C&EN, Aug. 13, page 32]. The plants don't mind saltwater because the researchers engineered them to produce high levels of an ion-shuttling transport protein. Extending such salt tolerance to other crops would be a boon to agriculture in regions of the world containing salty irrigation water or salt-damaged soil.

A team led by University of Connecticut plant biologist Roberto Gaxiola also used genetic engineering this year to enhance the salt and drought tolerance of the mustard weed Arabidopsis thaliana [Proc. Natl. Acad. Sci. USA, 98, 11444 (2001)]. In addition to increasing salt tolerance, "research must focus on alternative irrigation practices that optimize the use of water, and also in treatments to optimize its quality," Gaxiola tells C&EN.

And the mechanism of action of ecteinascidin-743, a promising anticancer natural product, was determined this year after nearly a decade of work (C&EN, Sept. 24, page 41). Preliminary clinical trial data indicate that the drug may be an effective treatment for sarcoma (bone or connective tissue cancer) and breast, lung, and ovarian cancers, and the new findings have implications for the development of novel ecteinascidin analogs. Yves Pommier, chief of the Laboratory of Molecular Pharmacology at the National Cancer Institute, and coworkers demonstrated an unprecedented mechanism of action for the drug: They found that it incapacitates the nucleotide excision-repair system in cells [Nat. Med., 7, 961 (2001)]. Similar findings were obtained by professor of medicinal chemistry Laurence H. Hurley of the University of Arizona and coworkers [Chem. Biol., 8, 1033 (2001)].

In findings that could lead to modified aldolases for synthetic applications, chemistry professor Chi-Huey Wong, molecular biology professor Ian A. Wilson, and coworkers at Scripps Research Institute unraveled the first complete mechanism of a Schiff base-forming aldolase [Science, 294, 369 (2001); C&EN, Oct. 22, page 55]. The study showed how a water molecule in the aldolase active site mediates a proton abstraction that leads to formation of a key intermediate, and how a proton shuffling process helps move the reaction along.

Among several important carbohydrate-related studies was one by chemistry professor Samuel J. Danishefsky of Sloan-Kettering Institute for Cancer Research and Columbia University and colleagues Jennifer R. Allen and Christina R. Harris. Vaccines have generally contained only individual antigens. But Danishefsky and coworkers developed an advanced synthetic method for combining multiple carbohydrate antigens in the same molecule [J. Am. Chem. Soc., 123, 1890 (2001); C&EN, March 19, page 40]. In the technique, carbohydrate-based antigen domains are linked to amino acids, and amino acid coupling reactions are then used to form a combined vaccine. The work could lead to a new generation of antipathogen and anticancer vaccines, according to a researcher in the field. Danishefsky and coworkers synthesized the first single molecules displaying multiple carbohydrate antigens last year, but the approach reported this year is more sophisticated and versatile.

Compounds derivatized with nonnatural sugar groups have not been easily accessible. But biosynthetic chemist Jon S. Thorson (now at the University of Wisconsin, Madison), structural biologist Dimitar B. Nikolov, and coworkers at Memorial Sloan-Kettering Cancer Center developed a technique called "glycorandomization" that could make it possible to produce such molecules more quickly and conveniently. In the technique, two biosynthetic enzymes that recognize nonnatural sugars as substrates are used to catalyze the synthesis of "glycorandomized" natural-product-like compounds containing nonnatural sugars [Nat. Struct. Biol., 8, 545 (2001); C&EN, June 4, page 11]. The strategy could enable the synthesis of nonnatural versions of natural products with potentially useful new properties.

Polysaccharides are known to play important biological roles. But their detailed function has been hard to study because it's been difficult to turn off polysaccharide production by manipulating the expression of polysaccharide-processing enzymes without simultaneously affecting other biological processes mediated by those enzymes. Graduate student Lara K. Mahal and associate professor of chemistry and molecular and cell biology Carolyn R. Bertozzi at the University of California, Berkeley, and coworkers solved that problem by devising a chemical approach to disrupt a polysaccharide metabolic pathway instead [Science, 294, 380 (2001); C&EN, Oct. 22, page 56]. Essentially, the researchers used an analog of a substrate in a polysaccharide metabolic pathway to interfere with polysaccharide biosynthesis. The study could lead to a better understanding of polysaccharide function, new types of anticancer agents, and new metabolic inhibitors of polysaccharide biosynthesis.

In the area of structural biochemistry, a group of German biochemists, physicists, and crystallographers determined the high-resolution crystal structure of photosystem I, one of two protein complexes where the initial steps of photosynthesis take place. Very few structures of such large membrane-bound complexes have been determined. The achievement is the product of more than a decade of effort by a biophysical chemistry group at the Technical University of Berlin led by Petra Fromme and Horst T. Witt, and a team of crystallographers at the Free University of Berlin headed by Norbert Krauss and Wolfram Saenger [Nature, 411, 909 (2001); C&EN, June 25, page 9]. The trimeric photosystem contains 12 protein subunits per monomer, along with numerous chlorophylls and other cofactors. The structure should help researchers learn how the complex gathers solar energy, transfers it internally, and then uses electron transfer reactions to convert it to the chemical energy that drives almost all life on Earth.

7950_7906nmrprobe
COOL PROBE Sears (left), Ellis (center), and Lipton hold the probe they developed for NMR analysis of zinc metalloproteins. The researchers climbed the foothills of Rattlesnake Mountain, Washington, outside their lab, to take this photo for C&EN.
In another structure study, a collaborative group developed a computational technique for modeling electrical charge distributions in biomolecular structures much larger than those previously accessible. Electrostatic models had been limited to structures of about 50,000 atoms, but the new "parallel focusing" method can be used to map charge distributions in macromolecules, supramolecular complexes, and cell organelles having over a million atoms. The technique was developed by postdoc Nathan A. Baker, assistant professor of biochemistry Simpson Joseph, associate professor of mathematics Michael J. Holst, and chemistry professor and Howard Hughes Medical Institute investigator J. Andrew McCammon of the University of California, San Diego, in collaboration with assistant professor of biomedical engineering David S. Sept of Washington University, St. Louis [Proc. Natl. Acad. Sci. USA, 98, 10037 (2001); C&EN, Aug. 27, page 13].

And a convenient nuclear magnetic resonance (NMR) technique for observing zinc centers of metalloproteins was devised by technical group leader Paul D. Ellis and colleagues Andrew S. Lipton, Garry W. Buchko, Jesse A. Sears, and Michael A. Kennedy of the W. R. Wiley Environmental Molecular Sciences Laboratory at Pacific Northwest National Laboratory [J. Am. Chem. Soc., 123, 992 (2001); C&EN, Feb. 5, page 9]. Previous studies of zinc in metalloproteins typically required a surrogate probe strategy in which zinc was replaced with cobalt or cadmium--which are more easily studied spectroscopically but which don't necessarily faithfully represent the properties of zinc. In the new technique, a metalloprotein is cooled close to absolute zero, enhancing its NMR sensitivity, and a spin-echo procedure is then used to analyze structure and bonding at the zinc site directly.


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