Scientists map important immune system enzyme for the first time

March 30, 2018, Canadian Light Source
Crystal structure of the host enzyme, Acyloxyacyl Hydrolase (AOAH), in complex with lipopolysaccharide (LPS) shown in grey sticks, which is a potent bacterial toxin. The figure shows one of the six fatty acid chains of LPS swung out and positioned in AOAH active site ready to be clipped off, rending LPS immunologically inert. This enzymatic function of AOAH is crucial for recovering from immune tolerance which generally follows gram-negative bacterial infection. Credit: Bhushan Nagar

Biochemists from McGill University are getting a good look at just how a specific enzyme that is part of the human immune system interacts with a certain group of bacteria that are described as gram-negative.

Researchers around the world "have been studying the enzyme, known as AOAH, for more than 30 years. This is the first time anyone has been able to see exactly what it looks like," according to Bhushan Nagar, an associate professor of biochemistry at McGill University in Montreal.

More than that, the 3-D images captured a moment in time which shows just how AOAH inactivates a toxic molecule that is commonly part of various . The research was conducted at the Canadian Light Source.

Numerous types of gram-negative bacteria exist throughout the environment. While some are harmless, many cause a variety of human illnesses, says Nagar. For example, several species such as E. coli and Salmonella, cause food borne illness. Others cause infections such as pneumonia, meningitis, or gonorrhea.

Some types of gram-negative bacterial infections are demonstrating drug resistance and are increasingly difficult to treat, making understanding how the human immune system interacts with them even more important.

When an infection develops, it generally triggers inflammation through a toxic component of the outer shell of gram-negative bacteria, called lipopolysaccharide (LPS) – also commonly referred to as an endotoxin.

"Inflammation is a protective response by the immune system when fighting infections," says Nagar.

It's what causes fever, aches, swelling and sometimes redness on the skin. But there is a fine balance. Too much inflammation can cause a person to become sicker and even die, while too little won't help kill off the bacteria causing the infection. The immune system controls this problem by dampening inflammation after the initial acute response. That way, the doesn't cause excessive damage.

After the is cleared, the system needs to reset itself so it will be prepared to fight new infections. This job falls into the hands of the AOAH enzyme. With the gram-negative bacterium, it was found that the AOAH targets, binds to, and removes two specific regions on LPS, rendering it ineffective and causing the system to reset.

The researchers were able to see the images by using a crystallized sample of AOAH bound to a portion of the LPS. The results allowed for a detailed look at the molecular structure of AOAH and clearly showed which parts of its surface interacted with the toxin.

"We could actually see the molecular mechanism the enzyme uses to clip off parts of LPS to inactivate it," says Nagar.

The findings were published in the Proceedings of the National Academy of Sciences earlier this year.

The images provide a map to the AOAH enzyme and opens the door to other directions of research. Some forms of AOAH are associated with certain diseases such as asthma and chronic sinusitis. Knowing its full structure will help researchers better understand what its disease-causing variations are like and could provide details needed to develop new treatments for infections or approaches to prevent them.

Explore further: Researchers discover a 'security chief' that sounds the alarm against infections

More information: Alexei Gorelik et al. Crystal structure of the mammalian lipopolysaccharide detoxifier, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1719834115

Related Stories

The importance of asymmetry in bacteria

October 17, 2017

New research published in Nature Microbiology has highlighted a protein that functions as a membrane vacuum cleaner and which could be a potential new target for antibiotics.

Specially designed protein fights several species of bacteria

December 13, 2017

As resistance to existing antibiotics increases, new approaches to serious bacterial infections are needed. Now researchers at Lund University in Sweden, together with colleagues at the University of Massachusetts Medical ...

Recommended for you

New theory shows how strain makes for better catalysts

April 20, 2018

Brown University researchers have developed a new theory to explain why stretching or compressing metal catalysts can make them perform better. The theory, described in the journal Nature Catalysis, could open new design ...

Machine-learning software predicts behavior of bacteria

April 19, 2018

In a first for machine-learning algorithms, a new piece of software developed at Caltech can predict behavior of bacteria by reading the content of a gene. The breakthrough could have significant implications for our understanding ...

Spider silk key to new bone-fixing composite

April 19, 2018

UConn researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

GLUT5 fluorescent probe fingerprints cancer cells

April 19, 2018

Determining the presence of cancer, as well as its type and malignancy, is a stressful process for patients that can take up to two weeks to get a diagnosis. With a new bit of technology—a sugar-transporting biosensor—researchers ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.