Analyzing poppies to make better drugs

A team of researchers from the University of Calgary has uncovered new information about a class of plant enzymes that could have implications for the pharmaceutical industry. In a paper published in the Journal of Biological Chemistry, the scientists explain how they revealed molecular details of an enzyme class that is central to the synthesis of many widely used pharmaceuticals, including the painkillers codeine and morphine.  

The team used the Canadian Light Source at the University of Saskatchewan and the SLAC National Accelerator Laboratory to better understand how the enzyme behaves, which is crucial for unleashing its potential to make novel medicines. “Until this study, we didn’t know the key structural details of the enzyme. We learned from the structure of the enzyme bound to the product how the methylation reaction locks the product into a certain stereochemistry. It was completely unknown how the enzyme did that before we determined this structure,” corresponding author Dr. Kenneth Ng explained.

Stereochemistry is an important concept when it comes to safety and efficacy in drug design. A molecule can have a few different arrangements—similar to how your left hand is a mirror image of your right hand. These arrangements can lead to very different effects.

>Read more on the Canadian Light Source website

Image: group photo of some of the researchers involved with this project. From left to right: Ken Ng (Professor and corresponding author), Jeremy Morris (PhD graduate and second author), Dean Lang (PhD student and first author), and Peter Facchini (Professor, CSO of Willow Biosciences and senior author).

A new generation of anti-malaria drugs


Malaria is endemic to large areas of Africa, Asia and South America and annually kills more than 400,000 people, a majority of whom are children under age 5, with hundreds of millions of new infections every year. Although artemisinin-based drug combinations are available to treat malaria, reports from Southeast Asia of treatment failures are raising concerns about drug resistance spreading to Africa. Fortunately, there is hope on the horizon because there are several new antimalarial drug candidates undergoing clinical testing as well as other promising drug targets that are under investigation.
An international research team has for the first time determined the atomic structure of a protein kinase called PKG in Plasmodium parasites that cause malaria—a finding that potentially will help create a new generation of anti-malarial drugs and advance fundamental research. PKG[i] plays essential roles in the developmental stages of the parasite’s complex life cycle, so understanding its structure is key to developing malaria-fighting therapies that specifically target PKG and not other human enzymes, according to researcher Dr. Charles Calmettes.

>Read more on the Canadian Light Source website

Image: PKG crystal.

Analyzing the world’s oldest woddy plant fossil

Scientists investigate the early evolution of tissue systems in plants.

Mapping the evolution of life on Earth requires a detailed understanding of the fossil record, and scientists are using synchrotron-based technologies to look back—way, way back—at the cell structure and chemistry of the earliest known woody plant. Dr. Christine Strullu-Derrien and colleagues used the Canadian Light Source’s SM[1] beamline at the University of Saskatchewan to study Armoricaphyton chateaupannense, an extinct woody plant that is about 400 million years old. Their research focused on lignin, an organic compound in the plant tracheids, elongated cells that help transport water and mineral salts. Lignin makes the cells walls rigid and less water permeable, thereby improving the conductivity of their vascular system.
Strullu-Derrien, a scientific associate at the Natural History Museum in London, England and the Natural History Museum in Paris, France, had described A. chateaupannense some years ago and returned to it for this project.
“Studies have been done previously on Devonian plants but they were not woody,” she said. “A. chateaupannense is the earliest known woody plant and it’s preserved in both 2D form as flat carbonaceous films and 3D organo-mineral structures. This allows for comparison to be done between the two types of preservation,” she said.
Although the fossils used in the study were collected in the Armorican Massif, a geologically significant region of hills and flatlands in western France, Strullu-Derrien said early Devonian woody plants have also been found in New Brunswick and the Gaspé area in Quebec “although these are 10 million years younger than the French one.”

>Read more on the Canadian Light Source website

Image: A, photograph of Armoricaphyton chateaupannense preserved in 2D as carbonaceous thin films. B, SEM image of a transverse section of an axis of a specimen of A. chateaupannense preserved in 3D showing the radially aligned tracheids.

The future of fighting infections

Scientists analyze 3D model of proteins from disease-causing bacteria at the CLS.

Millions of people are affected by the Streptococcus pneumoniae bacterium, which can cause sinus infections, middle ear infections and more serious life-threatening diseases, like pneumonia, bacteremia, and meningitis. Up to forty percent of the population are carriers of this bacterium.
Researchers from the University of Victoria (UVic) used the Canadian Light Source (CLS) at the University of Saskatchewan to study proteins that the pathogen uses to break down sugar chains (glycans) present in human tissue during infections. These proteins are key tools the bacterium uses to cause disease.

They used the Canadian Macromolecular Crystallography Facility (CMCF) at the CLS to determine the three-dimensional structure of a specific protein, an enzyme, that the bacterium produces to figure out how it interacts with and breaks down glycans.

>Read more on the Canadian Light Source website

Image: The 3D structure of an enzyme from the disease-causing bacterium Streptococcus pneumoniae.

Preventing heart attacks

Scientists have taken an important step towards finding a potential cure for the disease that causes strokes and heart attacks in seniors and increases the mortality rate of diabetic and chronic kidney disease patients.
Researchers from the University of McGill and SickKids Toronto in collaboration with Universite de Montreal developed a simplified laboratory model that mimics the formation of mineral deposits that harden arteries and leads to these devastating conditions.
They used the Canadian Light Source (CLS) at the University of Saskatchewan to understand the type of minerals that formed and how they develop on the arteries.
“The goal in developing our lab model is that it would help us understand the mineralization process. We can then mimic what happens, and use it to test hypotheses on why the minerals are forming and also test some drugs to find something that can stop it,” said lead researcher Dr. Marta Cerruti.
Her six-member team is focused on the poorly understood process of how minerals form and grow on elastin, a protein on artery walls that provides the elasticity needed for blood flow to the heart, said Cerruti, an associate professor in Materials Engineering at McGill.
The hypothesis is that calcium phosphate-containing minerals form inside the walls of arteries and then calcify into a bone-like substance that narrows arteries and causes them to lose elasticity crucial for blood flow.

>Read more on the Canadian Light Source website

Image: Marta Cerruti (left) and Ophelie Gourgas in a laboratory using a Raman machine.

Using reed waste for sustainable batteries

With the changing climate, researchers are focusing on finding sustainable alternatives to conventional fuel cells and battery designs. Traditional catalysts used in vehicles contribute to increasing carbon dioxide emissions and mining for materials used in their design has a negative impact on the environment. Prof. Shuhui Sun, a researcher from the Institut National de la Recherche Scientifique (INRS) in Montreal, and his team used the Canadian Light Source (CLS) at the University of Saskatchewan to investigate an Iron-Nitrogen-Carbon catalyst using reed waste.

They hope to use the bio-based materials to create high-performance fuel cells and metal-air batteries, which could be used in electric cars. “An efficient oxygen electrocatalyst is extremely important for the development of high-performance electrochemical energy conversion and storage devices. Currently, the rare and expensive Pt-based catalysts are commonly used in these devices. Therefore, developing highly efficient and low-cost non-precious metal (e.g., Fe-based) catalysts to facilitate a sluggish cathodic oxygen reduction reaction (ORR) is a key issue for metal air batteries and fuel cells,” said Qilang Wei, the first author of the paper.

>Read more on the Canadian Light Source website

Preventing colorectal cancer and stillbirths

Characterizing a tiny protein—determining its shape and what it does—was the first step taken by Dr. Kirsten Wolthers and her colleagues in their effort to learn more about a very common molecule that is implicated in a wide range of human ailments.
Wolthers used the Canadian Light Source (CLS) at the University of Saskatchewan to study flavodoxin. This protein is produced by all sorts of bacteria and some algae, she explained, including the bacteria associated with influenza, H. pylori, E. coli and even appendicitis.
Of particular interest to the associate professor from the University of British Columbia is the flavodoxin produced by Fusobacterium nucleatum, an oral bacteria found naturally in the human mouth that plays a role in periodontal disease and gingivitis.
“What makes it so interesting is that what’s been emerging in the last 10 years or so are links between F. nucleatum and colorectal cancer and pre-term or stillbirths,” she said. In some studies, mice given oral F. nucleatum have shown a higher-than-normal incidence of pre-term births. Because flavodoxin is known to be essential for the lifecycle of the bacteria, it is seen as a potential target for a controlling growth of the bacterium.

> Read more on the Canadian Light Source website

Image: Dr Kirsten Wolthers working in a laboratory.

Revolutionary discovery in leukemia research

Leukemia affects over 6,000 Canadians per year. A team of researchers used the Canadian Light Source (CLS) at the University of Saskatchewan to discover a new way to kill leukemia cancer cells. When the scientists hyperactivated the “garbage disposal systems” of leukemia cells, it caused the cancer to die.
The researchers believe this finding will transform the direction of cancer therapy by focusing on a protein that was previously believed to be impossible to target. Their study was featured on the cover of the journal Cancer Cell.
“It was a major advancement to visualize the structural biology through crystallography facilities at CLS and to prove conclusively that ONC201 binds and hyperactivates ClipP proteases to induce cell death,” said co-author Dr. Aaron Schimmer from the Princess Margaret Cancer Centre and the University of Toronto.

>Read more on the Canadian Light Source website

Image: Interface of two heptamer rings in an apparently closed conformation of human mitochondrial ClpP.

Helping people to hear

Using advanced techniques at the Canadian Light Source (CLS) at the University of Saskatchewan, scientists have created three-dimensional images of the complex interior anatomy of the human ear, information that is key to improving the design and placement of cochlear implants.
“With the images, we can now see the relationship between the cochlear implant electrode and the soft tissue, and we can design electrodes to better fit the cochlea,” said Dr. Helge Rask-Andersen, senior professor at Uppsala University in Sweden.
“The technique is fantastic and we can now assess the human inner ear in a very detailed way.”
The cochlea is the part of the inner ear that looks like a snail shell and receives sound in the form of vibrations. In cases of hearing loss, cochlear implants are used to bypass damaged parts of the ear and directly stimulate the auditory nerve. The implant generates signals that travel via the auditory nerve to the brain and are recognized as sound.
By imaging the soft and bony structures of the inner ear with implant electrodes in place, Rask-Andersen said the researchers were able to discover what the auditory nerve looks like in three dimensions, and to learn how cochlear implant electrodes behave inside the cochlea. This is very important when cochlear implants are considered for people with limited hearing.

>Read more on the Canadian Light Source website

Image: the inner ear

Scienstists make breakthrough in creating universal blood type

Enzymes in the human gut can convert A blood type into O.

Half of all Canadians will either need blood or know someone who needs it in their lifetime. Researchers from the University of British Columbia have made a breakthrough in their technique for converting A and B type blood into universal O, the type that is most needed by blood services and hospitals because anyone can receive it.
In a paper published in Nature Microbiology, Stephen Withers and a multidisciplinary team of researchers from the University of British Columbia show how they successfully converted a whole unit of A type blood to O type using their system.  They were able to remove the sugars from the surface of the red blood cells with help from a pair of enzymes that were isolated from the gut microbiome of an AB+ donor.
The Canadian Light Source (CLS) at the University of Saskatchewan (UofS) played a critical role in understanding the structure of a previously unknown enzyme that was part of this pair. The researchers were unable to identify what this unique enzyme looked like from the gene sequence they had.  Crystallography, done at the CLS, was crucial for the researchers to understand how this enzyme works and why it had a particular affinity for the A type blood.

>Read more on the Canadian Light Source website

Improving engine performance and fuel efficiency

A study conducted in part at the Canadian Light Source (CLS) at the University of Saskatchewan suggests reformulating lubricating oils for internal combustion engines could significantly improve not only the life of the oil but the life of the engine too.
Dr. Pranesh Aswath with the Department of Materials Science and Engineering at the University of Texas at Arlington and his research colleagues focused on the role soot plays in engine wear, and its effect on the stability of engine oil.
He described the research as “one piece of a broader story we’re trying to write” about how the reformulation of engine oils can reduce emissions, decrease wear and increase the longevity of engines.
Soot is a carbon-based material that results from incomplete combustion of fuel in an internal combustion engine, he explained. The soot ends up in crankcase oil where it is trapped by additives, but that leads to reduced engine efficiency and a breakdown of lubricating oil.

>Read more on the Canadian Light Source website

Keeping nuclear power safe

Nuclear energy is clean, powerful, affordable, and zero-emission. A new study uses the Canadian Light Source (CLS) at the University of Saskatchewan to help ensure that waste from nuclear power plants remains safe and secure for thousands of years to come.
The project, led by Dan Kaplan and Dien Li, researchers at the Savannah River National Laboratory in South Carolina, looks at storing iodine, which is generated during uranium use, including in nuclear power generation.
Among the challenges of iodine management is its slow rate of decay—it has a half-life of 16 million years. Iodine is volatile and highly mobile in the environment, making containment critically important in nuclear waste management.
Currently, nuclear waste disposal sites use Ag-zeolite to sequester iodine from nuclear waste streams, which is then encased in concrete to prevent leaching.

>Read more on the Canadian Light Source website

Image: Samples of different formulations of cement that were tested for their ability to immobilize radioiodine.

Scientist discover that charcoal traps ammonia pollution

Discovery could have implications for agricultural management and climate change mitigation

Cornell University scientists Rachel Hestrin and Johannes Lehmann, along with collaborators from Canada and Australia, have shown that charcoal can mop up large quantities of nitrogen from the air pollutant ammonia, resulting in a potential slow-release fertilizer with more nitrogen than most animal manures or other natural soil amendments. The results were published Friday in Nature Communications.

Ammonia is a common component of agricultural fertilizers and provides a bioavailable form of the essential nutrient nitrogen to plants. However, ammonia is also a highly reactive gas that can combine with other air pollutants to create particles that travel deep into the lungs, leading to a host of respiratory issues. It also indirectly contributes to climate change when excess fertilizer inputs to soil are converted into nitrous oxide, a potent greenhouse gas.

In Canada, ammonia emissions have increased by 22 per cent since 1990, and 90 per cent are produced by agriculture, particularly from manures, slurries and fertilizer applications. Mitigating this pollutantwithout limiting fertilizers and food growth for our growing world populationis key to a sustainable future.

>Read more on the Canadian Light Source website

Image: Rachel Hestrin (right) on the beamlines at Canadian Light Source with fellow Cornell researcher Angela Possinger.

Rob Norris joins Canadian Light Source

Former provincial cabinet minister Rob Norris is joining the Canadian Light Source at the University of Saskatchewan, as Senior Government Relations Officer.

“Rob brings a unique depth of experience in our parliamentary system, as well as key policy areas, including innovation, post-secondary education, and industry-related research. I have no doubt he will be of enormous help in strengthening our relationships with government stakeholders at every level, and increasing awareness about the valuable contributions our scientists are making,” said Rob Lamb, CLS Chief Executive Officer.

>Read more on the Canadian Light Source website

Image: CLS CEO Rob Lamb, Environmental & Earth Science Manager Chithra Karunakaran and Senior Government Relations Officer Rob Norris talk on the CLS mezzanine.

Discovery may improve cystic fibrosis treatment

A University of Saskatchewan medical research team has made a groundbreaking finding with potential to lead to more effective, longer-lasting and better-tolerated treatments for cystic fibrosis (CF).

“Though we’re still at an early stage for developing new treatments, this is a major discovery of considerable potential relevance to CF patients,” said Dr. Juan Ianowski (PhD), a physiologist at the USask College of Medicine and senior author of a paper on the finding published today in the online Nature Research journal Scientific Reports.
For over 20 years, doctors have treated CF patients with an inhaled concentrated salt solution called hypertonic saline to increase the volume of airway surface liquid (ASL)—a microscopically thin liquid lining that helps remove infected secretions from the clogged chest of a CF patient. The scientific consensus has been that an osmotic reaction drawing water from the blood was responsible for the beneficial increase in ASL from this saline treatment.
But by using synchrotron imaging at the Canadian Light Source (CLS), the national research facility at USask, the nine-member team has concluded that scientists have not completely understood the body’s reaction to the saline treatment.
>Read more on the Canadian Light Source website

Image: Dr. Julian Tam (MD) and Dr. Juan Ianowski (PhD) are researchers with the university’s Respiratory Research Centre.

Understanding the protein responsible for regulating heartbeats

A new research project uses the Canadian Light Source to help researchers understand the protein responsible for regulating heartbeats. Errors in this crucial protein’s structure can lead to potentially deadly arrhythmias, and understanding its structure should help researchers develop treatments. This protein, calmodulin (CaM), regulates the signals that cause the heart to contract and relax in almost all animals with a heartbeat.

“Usually you find some differences between versions of proteins from one species to another,” explains Filip Van Petegem, a professor in the University of British Columbia’s Department of Biochemistry and Molecular Biology. “For calmodulin that’s not the case—it’s so incredibly conserved.”

It also oversees hundreds of different proteins within the body, adjusting a broad array of cellular functions that are as crucial to our survival and health as a steady heartbeat.

>Read more on the Canadian Light Source website

Image: A surface representation of the disease mutant CaM (D95V, red) in complex with the piece of the voltage-gated calcium channel (blue).