Sunday, February 27, 2011

Greener chemical reaction for pharmaceutical production awarded $50,000 in development funding from GreenCentre Canada

A key chemical process used by the pharmaceutical industry has the potential to become less expensive and more energy efficient, thanks to a green chemistry discovery at the University of British Columbia.

Dr. Laurel Schafer, a professor of chemistry at UBC, has created a method and a compound that affects a crucial chemical reaction in drug production. Current methods of producing this reaction are costly because they are energy-intensive and require multiple steps that generate waste. 

Dr. Schafer's technology reduces extra steps, is energy-efficient and reduces waste byproducts. It also uses less expensive reagents, substances that react with other substances to produce chemical products.

Recognizing the green promise in Dr. Schafer's work, GreenCentre Canada has awarded Dr. Schafer $50,000 in Proof of Principle funding to pursue further development of her technology.

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The lock shapes the key: Mystery about recognition of unfolded proteins solved

Proteins normally recognize each other by their specific 3-D structure. If the key fits in the lock, a reaction can take place. However there are reactions at the onset of which the key does not really have a shape. German chemists at the Technische Universitaet Muenchen and the Max Planck Research Unit for Enzymology of Protein Folding (Halle/Saale) have now shown how this might work. Their results will appear in PNAS this week.

Interactions between proteins are of fundamental importance for a number of processes in virtually every living cell. However, in order for the proteins to carry out any , they must first assume their specific three-dimensional shape. A number of reactions have been described in recent years, where one of the interaction partners does not assume its active structure until the actual binding process commences. It was still a great mystery, though, how the binding partners could actually recognize such unstructured proteins.

Scientists led by Professor Thomas Kiefhaber (TUM) posed the question of whether local properties are sufficient for the recognition to take place or whether the unstructured binding partner first had to assume a specific . Possible candidates were regularly structural elements such as coiled ?-helices or ß-pleated sheets, in which internal hydrogen bonds are formed.

In collaboration with Professor Gunter Fischer's research group at the Max Planck Research Unit for Enzymology of Protein Folding Halle/Saale, the scientists developed a novel method for observing the formation of individual hydrogen bonds in the course of a binding process.

The model system was the enzyme ribonuclease S, which in its active form comprises the S-protein and an ?-helical S-peptide. While the S-protein has a defined three-dimensional shape, the S-peptide on its own is initially unfolded. The scientists attempted to determine whether the S-protein recognizes the unstructured S-peptide or a small fraction of peptide molecules in their helical conformation. To this end, the oxygen atoms in the peptide bonds were replaced by sulfur atoms via chemical synthesis, causing individual hydrogen bonds to become destabilized.

Time-based measurements of the binding process of the altered peptide have now shown that the in the S-peptide, and as such in the ?-helical structure, do not form until after the bonding to the S-protein. Thus, they cannot play a role in the recognition process. Protein-protein recognition in this case takes place via hydrophobic interaction of the S-protein with two spatially clearly defined areas of the unstructured S-peptide.

These results are of fundamental importance for understanding the mechanism of protein-protein interactions. In the future, this method can be used to examine in detail the structure formation in proteins in other systems, as well.

More information: Mapping backbone and side-chain interactions in the transition state of a coupled protein folding and binding reaction, Annett Bachmann, Dirk Wildemann, Florian Praetorius, Gunter Fischer, and Thomas Kiefhaber PNAS, Early Edition, Publikation Online in der Woche vom 14.02.2011, http://www.pnas.or … s.1012668108

Provided by Technische Universitaet Muenchen

Warring molecules keep the colon cancer-free

 By Jill Jess A molecular battle is going on inside your colon, and University of Kansas researchers want neither side to win.

KU associate professor of molecular biosciences Kristi Neufeld and her graduate student Erick Spears study how a molecule, a protein called APC, suppresses colon cancer. In a recent article in the , they explain how a drug might someday treat the disease by blocking the action of one of APC’s molecular opponents.

Currently, no drug specifically treats . The vast majority of cases derive from a faulty gene in intestinal that produces a defective APC protein. APC — whose hefty full name is Adenomatous Polyposis Coli — is named after the intestinal polyps it helps prevent. Polyps can turn malignant if not removed by surgery.

“Many researchers are trying to figure out now why this protein is so critical for preventing polyp formation,” Neufeld said. “Mine has been one of those labs.”

Neufeld’s work concerns the health of an astonishingly sophisticated organ. The last part of the digestive system, the colon absorbs water, salt, some nutrients, and keeps symbiotic bacteria in check. Key to its success are stem cells in its lining. These cells reproduce or mature to take different jobs, and then shed when they wear out.

Inside the cells, a governing board of proteins decides whether more cells should reproduce — divide — or take on different jobs — differentiate. Scientists have previously determined that APC always advises differentiation. At the same time, another protein board member pushes for division. It is named Musashi after a renowned samurai swordsman.

APC and Musashi not only have opposite agendas in the colon, Neufeld and Spears now find, but also actively sabotage each other: behind the scenes, APC controls how many Musashi proteins get made and vice versa. When APC is absent, Musashi in a sense shouts louder, causing cells to proliferate out of control and form polyps and tumors.

The health of the colon requires both Musashi and APC. Restoring APC to people who lack a proper copy of its gene is still out of reach. But a designer drug may be able to subdue Musashi.

“Eighty percent of colon cancers will have a nonfunctioning APC . Technology doesn’t allow us to fix that,” Neufeld said. “Keeping Musashi controlled — we can try to do that in another way.”

Next, the team will look for a drug that will inhibit Musashi and will test their hypothesis in mice. The current work was done in cultures of human colon cells.

“Talking to different people, I am struck by how prevalent the disease is,” Neufeld said. “The research that I do is still years away from something that would benefit patients directly. But we’re getting closer. And I do think about how great it would be if something we found in the lab could be translated into a real therapy.”

Provided by University of Kansas


X-rays show why van Gogh paintings lose their shine


This illustration shows how X-Rays were used to study why van Gogh paintings lose their shine. Top: a photo of the painting "Bank of the River Seine" on display at the van Gogh Museum, divided in three and artificially colored to simulate a possible state in 1887 and 2050. Bottom left: microscopic samples from art masterpieces moulded in plexiglass blocks. The tube with yellow chrome paint is from the personal collection of M. Cotte. Bottom right: X-ray microscope set-up at the ESRF with a sample block ready for a scan. Centre: an image made using a high-resolution, analytical electron microscope to show affected pigment grains from the van Gogh painting, and how the color at their surface has changed due to reduction of chromium. The scale bar indicates the size of these pigments. Credit: ESRF/Antwerp University/Van Gogh Museum

Scientists using synchrotron X-rays have identified the chemical reaction in two van Gogh paintings that alters originally bright yellow colors into brown shades.

Scientists have identified a complex chemical reaction responsible for the degradation of two paintings by Vincent van Gogh and other artists of the late 19th century. This discovery is a first step to understanding how to stop the bright yellow colours of van Gogh's most famous paintings from being covered by a brown shade, and fading over time. In the meantime, the results suggest shielding affected paintings as much as possible from UV and sunlight. The results are published in the 15 February 2011 issue of .

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A microsample is taken from the van Gogh painting "Bank of river Seine" on display at the van Gogh Museum in Amsterdam (Netherlands), and then analyzed at the X-rays microscope at the European Synchrotron Radiation Facility in Grenoble (France). Credit: ESRF/van Gogh Museum

The work was carried out by an international team of scientists from four countries led by Koen Janssens of Antwerp University (Belgium), with Letizia Monico, an Italian chemist preparing a Ph.D. at Perugia University (Italy), taking the centre stage in the experiments. As an Erasmus student, she worked for one year in Janssens' research group in Antwerp, and is also the lead author of the two papers. Scientists from the CNR Institute of Molecular Science and Technologies (Perugia, Italy), the CNRS C2RMF (Paris, France), TU Delft (Netherlands) and the van Gogh Museum (Amsterdam, Netherlands) were also part of the team.

Uncovering the secrets of the chemical reaction needed deployment of an impressive arsenal of analytical tools, with synchrotron X-rays at the ESRF in Grenoble (France) providing the final answers. "For every Italian, conservation of masterpieces has always mattered. I am pleased that science has now added a piece to a puzzle that is a big headache for so many museums" says Letizia Monico from University of Perugia.

The experiment reads like a . The scientists employed an X-ray beam of microscopic dimensions to reveal a complex chemical reaction taking place in the incredibly thin layer where the paint meets the varnish. Sunlight can penetrate only a few micrometers into the paint, but over this short distance, it will trigger a hitherto unknown chemical reaction turning chrome yellow into brown pigments, altering the original composition.

Van Gogh's decision to use novel bright colours in his paintings is a major milestone in the history of art. He deliberately chose colours that conveyed mood and emotion, rather than employing them realistically. At the time, this was completely unheard of and, without major innovations in pigment manufacturing made in the 19th century, would also have been impossible.

It was the vibrancy of new industrial pigments such as chrome yellow which allowed van Gogh to achieve the intensity of, for example, his series of Sunflowers paintings. He started to paint in these bright colours after leaving his native Holland for France where he became friends with artists who shared his new ideas about the use of colours. For one of them, Paul Gauguin, he started painting yellow sunflower motifs as a decoration for his bedroom.

The fact that yellow chrome paint darkens under sunlight has been known since the early 19th Century. However, not all period paintings are affected, nor does it always happen at the same speed. As chrome yellow is toxic, artists quickly switched to new alternatives in the 1950s. However, did not have this choice, and to preserve his work and that of many comtemporaries, interest in the darkening of chrome yellow is now rising again.

To solve a chemical puzzle nearly 200 years old, the team around Janssens used a two-step approach: first, they collected samples from three left-over historic paint tubes. After these samples had been artificially aged for 500 hours using an UV-lamp, only one sample, from a paint tube belonging to the Flemish Fauvist Rik Wouters (1882-1913), showed significant darkening. Within 3 weeks, its surface of originally bright yellow had become chocolate brown. This sample was taken as the best candidate for having undergone the fatal chemical reaction, and sophisticated X-ray analysis identified the darkening of the top layer as linked to a reduction of the chromium in the chrome yellow from Cr(VI) to Cr(III). The scientists also reproduced Wouters' chrome yellow paint and found that the darkening effect could be provoked by UV light.

X-rays show why van Gogh paintings lose their shine

This is an image, made using an optical microscope, of the sample taken from ?Bank of the Seine? studied with synchrotron X-rays. The brown layer on top of the paint is varnish, it appears opaque but in reality it lets light through. The brown pigments are invisible to the optical microscope. They are located at the interface between varnish and paint, in a layer less than three micrometers thick. The scale bar at the bottom indicates the size of the sample. Credit: University of Antwerp, Department of Chemistry.

In the second step, the scientists used the same methods to examine samples from affected areas of two van Gogh paintings, View of Arles with Irises (1888) and Bank of the Seine (1887), both on display in the Van Gogh Museum in Amsterdam.

"This type of cutting edge research is crucial to advance our understanding of how paintings age and should be conserved for future generations", says Ella Hendriks of the van Gogh Museum Amsterdam.

Because the affected areas in these multicoloured samples were even more difficult to locate than in the artificially aged ones, an impressive array of analytical tools had to be deployed which required the samples travelling to laboratories across Europe. The results indicate that the reduction reaction from Cr(VI) to Cr(III) is likely to also have taken place in the two van Gogh paintings.

The microscopic X-ray beam also showed that Cr(III) was especially prominent in the presence of chemical compounds which contained barium and sulphur. Based on this observation, the scientists speculate that van Gogh's technique of blending white and yellow paint might be the cause of the darkening of his yellow paint.

"Our next experiments are already in the pipeline. Obviously, we want to understand which conditions favour the reduction of chromium, and whether there is any hope to revert pigments to the original state in paintings where it is already taking place.", summarises Koen Janssens from University of Antwerp.

Note to Editors: the crime scene investigation

The techniques used by the scientists included X-ray diffraction along with various spectroscopies employing infrared radiation, electrons and X-rays at the universities of Antwerp and Perugia, and at two synchrotrons (ESRF and DESY).

"I am not aware of a similarly big effort ever having been made for the chemistry of an oil painting", says Joris Dik, Professor at Delft Technical University.

In the decisive step, two techniques were combined using a single X-ray beam at the ESRF: X-Ray fluorescence (XRF) and X-Ray absorption near-edge spectroscopy (XANES). For the XRF, the microscopic beam size (0.9 x 0.25 µm2) made possible to separate the study of degraded and unaffected areas, and the XANES technique proved the speciation of chromium, i.e. the reduction from Cr(VI) to Cr(III).

"Our X-ray beam is one hundred times thinner than a human hair, and it reveals subtle chemical processes over equally minuscule areas. Making this possible has opened the door to a whole new world of discovery for art historians and conservators," says Marine Cotte, an ESRF scientist also working at CNRS/Musée du Louvre.

The reduction of chromium that had been observed in the artificially aged sample from the atelier of Rik Wouters was finally confirmed in both microsamples from the van Gogh .

The study was completed with a nanoscopic investigation of the discoloured paint using electron energy loss spectroscopy at the University of Antwerp, which confirmed the results and showed that the newly formed Cr(III) compounds were formed as a nanometer-thin coating of the pigment particles that constitute the paint.

More information: L. Monico et al., Degradation Process of Lead Chromate in Paintings by Vincent van Gogh Studied by Means of Synchrotron X-ray Spectromicroscopy and Related Methods. 1. Artificially Aged Model Samples and 2. Original Paint Layer Samples, Analytical Chemistry 15 February 2011.

Provided by European Synchrotron Radiation Facility

Venom of marine snails provide new drugs

 Baldomero Olivera studies chemical compounds found in the venoms of marine cone snails, a potential source of powerful, yet safe and effective drugs. He will discuss the development of Prialt - an FDA-approved drug for intractable, chronic pain - and the potential for new drugs during a free public lecture at the University of Utah.

The conventional picture of a snail is a slow-moving, plant-eating, shelled animal found in gardens. However, in the marine environment, there are more than 100,000 species of snails. About 100 different species have evolved to become venomous predators that specialize in hunting fish. These fish-hunting Conus harpoon fish with a hypodermic needle-like tooth that injects paralyzing made up of 100 chemical components.

"The long-range goal is to use these toxins as an entrée for studying key molecules in the central ," Olivera says.

The fact that the poisons can be synthesized and categorized easily will enable researchers to learn more about parts of the nervous system affected by the Conus toxins.

The precise mechanism that accounts for the biological activity of most peptides present in cone snail venoms has not yet been determined. A major challenge in the next few years is to clarify the molecular mechanisms through which the different peptides in Conus venom elicit their profound behavioral effects.

The natural form of Prialt - a drug for severe pain approved in 2004 by the U.S. Food and Drug Administration - was discovered in Olivera's lab in 1979 by J. Michael McIntosh, then an incoming freshman at the University of Utah and now a professor of psychiatry and research professor of biology. The drug was isolated from the fish-hunting cone snail Conus magus, or magician's cone, which is only 1.5 inches long.

Prialt is injected into the fluid surrounding the spinal cord to treat chronic, intractable pain suffered by people with cancer, AIDS, injury, failed back surgery or certain nervous system disorders.

Olivera was named a distinguished professor of biology at the University of Utah in 1992. He is the author of more than 250 scientific publications. In 2006, he was appointed a Howard Hughes Medical Institute Professor. He was elected to the Institute of Medicine in 2007 and to the National Academy of Sciences in 2009.