Tag: 3D structure

Understanding bacteria’s role in transforming steroids to pharmaceuticals

Understanding bacteria’s role in transforming steroids to pharmaceuticals

Identifying 3D structure of enzymes by University of Guelph researchers key first step in harnessing alterations for disease treatments.

For decades, pharmaceutical companies have been using bacteria found in soil and water to chemically convert steroids into effective treatments for human diseases. One example is cortisol, which is used to treat asthma and skin rashes. But how bacteria convert steroids is not fully understood.

Now a research team from the University of Guelph has taken a significant step forward in answering that question. Using the Canadian Light Source (CLS) at the University of Saskatchewan, Dr. Stephen Seah and colleagues have determined the 3D structures of steroid-transforming enzymes from Proteobacteria (also called Pseudomonadota), a large, diverse family of gram-negative bacteria named after Proteus – the shape-shifting Greek sea god.Video: Understanding bacteria’s role in transforming steroids to pharmaceuticals

Studying the 3D structure of these enzymes, which Seah says would be impossible without the ultrabright X-ray source of the CLS, is key to understanding how this Proteobacteria chemically transforms steroids – such as bile acids – which are typically resistant to being changed.

Seah and his colleagues found that the bacteria have evolved to transform steroids as a means to obtain carbon and energy for their own growth. However, he says, these transformations can be harnessed to chemically alter steroids into compounds that we can use for disease treatments; a discovery that will help advance future pharmaceutical development.

“If we understand the process, we can manipulate other bacteria to produce novel compounds that may have medicinal properties,” says Seah. “I think my work helps fill in this gap of knowledge.” The team’s research findings were published recently in both the Journal of Biological Chemistry and Biochemistry.

This new research, says Seah, also opens the door to exploring the potential of other enzymes in bacteria to change the chemical structure of steroids. “In other words, one could create steroids with diverse chemical structures using the many steroid-modifying enzymes that bacteria produced to alter naturally occurring steroids,” he says. “Some of these modified steroids may have therapeutic properties.”

Read more on the CLS website

Image: Protein structure

Credit: CLS

Developing new drugs for superbugs like MRSA

Developing new drugs for superbugs like MRSA

The team is using bright beams at the Canadian Light Source (CLS) at the University of Saskatchewan to image how potential antibiotic-enhancing drugs interact with a molecule vital for building the cell wall of bacteria.

Staphylococcus aureus (the “SA” part of MRSA) has a thick protective cell wall that can make it difficult for some antibiotic drugs to attack it. That wall is an attractive target for drugs. If a therapeutic can weaken or break the wall, then the bacteria will die.

One protein that makes an attractive target for drugs is called UppS. It is involved in assembling part of the lipid scaffold on which the wall is built. Attacking UppS could weaken the wall and make the bacteria more susceptible to existing antibiotics, says Sean Workman, a postdoctoral researcher in the Department of Biology at the University of Regina.

“By slowing down the function of UppS we can make the bacteria more sensitive to other drugs,” he says.

Eric Brown, a professor in the Department of Biochemistry and Biomedical Sciences at McMaster University, went looking for drugs that could target the early steps in the creation of the cell wall and found clomiphene, an already-approved fertility drug that could interfere with UppS. He and his colleagues then used the same techniques to find several new molecules that could do the same thing, two of which – MAC-0547630 and JPD447 – seemed to be worth a closer look.

Read more on the CLS website

Image:UppS protein crystals used to obtain high resolution diffraction data.

Credit: Canadian Light Source

Universal mechanism of regulation in plant cells discovered

Universal mechanism of regulation in plant cells discovered

In pioneering work, a German-Japanese research team at BESSY II has been able to determine the 3D structure of a metalloprotein that plays an important role as a catalyst in all plant cells. This involves the DYW deaminase domain of what is referred to as the RNA editosome. The DYW domain alters messenger RNA nucleotides in chloroplasts and mitochondria and contains a zinc ion whose activity is controlled by a very unusual mechanism. The team has now been able to describe this mechanism in detail for the first time. Their study, published in Nature Catalysis, is considered a breakthrough in the field of plant molecular biology and has far-reaching implications for bioengineering.

All plant cells obtain their energy mainly from two organelles they contain – chloroplasts (responsible for photosynthesis) and mitochondria (responsible for the biochemical cycle of respiration that converts sugars into energy). However, a large number of a plant cell’s genes in its mitochondria and chloroplasts can develop defects, jeopardising their function. Nevertheless, plant cells evolved an amazing tool called the RNA editosome (a large protein complex) to repair these kinds of errors. It can modify defective messenger RNA that result from  defective DNA by transforming (deamination) of certain mRNA nucleotides.

Read more on the HZB website

Image: Around the catalytic centre is a group of molecules, the gating domain, which can occupy two different positions.

Credit: © M. Künsting / HZB

Innovations against COVID-19 outbreak presented to MHESI Minister

Innovations against COVID-19 outbreak presented to MHESI Minister

Adjunct Prof. Dr. Anek Laothamatas, the Minister of Higher Education, Science, and Innovation (MHESI), Thailand, had a visit to the field hospital at Suranaree University of Technology (SUT), Nakhon Ratchasima, on Thursday, 22 April 2021.  On this occasion, the Minister visited an exhibition on innovations created and presented by SLRI to prevent the spread of COVID-19 at SUT Administration Building.  

 In supporting the handling of COVID-19 situation, SLRI researchers created outstanding various innovations.  The first innovation is studying and developing Thai silk mask for use as an alternative to surgical mask.  In this research, SLRI researchers applied synchrotron light to analyze three-dimensional structure of Pak Thong Chai silk and later created the silk mask for use as alternative to surgical mask.  The result showed that the created silk mask was more than 80% efficient at PM 2.5 and 0.3 micron filtration capacity.  The mask was also better than masks made of other fibers using for droplet transmission prevention and it was durable.  The mask development not only helps solving shortage of surgical mask but also increases quality of natural fabric in the region and raises income of community enterprise in Nakhon Ratchasima.

Another innovation created by SLRI is the development of particle permeation test for surgical mask.  A high-speed camera was applied for the test to examine permeation of sneeze and cough droplets through the mask.  The camera can take photos at high frame rate of up to 1,300 frames per second.  In studying permeation of sneeze and cough droplets, the qualified rate is just 200 frames per second to examine droplet permeation through the mask and detect motion occurred during recording and the researchers can examine droplet permeation through surgical masks.  The result showed that the created silk mask was better than a surgical mask at preventing saliva droplet permeation.

Read more on the SLRI website

Battling bad bugs

Battling bad bugs

Scientists fight antibiotic resistance by using synchrotron to study scab disease in potatoes.

In the ongoing war against antibiotic resistant bacteria, a change in battle tactics may prove effective for controlling a common disease of plants and potentially other toxins that affect humans and animals.

Although bacterial toxins cause serious, often deadly diseases, “bacteria aren’t trying to be nasty,” said Dr. Rod Merrill, Professor of Molecular and Cellular Biology at the University of Guelph. “They’re hungry and looking for food, and we’re often the food.” He added that 99 per cent of bacteria are helpful – like gut flora – so the battle is against the remaining one per cent.

The usual approach is to develop antibiotics “that kill the bacteria but not us, or the plant, or the animal,” stated Merrill. However, bacteria mutate quickly, as quickly as every 30 minutes, which leads to antibiotic resistance. “And unfortunately, the pipeline for new antibiotics is empty.”

The approach that Merrill and his research group are pursuing is an anti-virulence strategy – finding or designing small molecules that inhibit the tools bacteria use to colonize the host and create infection. “If we can put a lock on their weapons, they can’t get food and will move on so there’s not the same pressure to mutate. We’re going with this approach because we think it’s time to change up tactics.”

Read more on the CLS website

Image: Scabin crystals

Credit: CLS