New discovery solves problem of anti-inflammatory substance

March 3, 2014, Karolinska Institutet
Jesper Z. Haeggström is a Professor of Molecular Eicosanoid Research at Karolinska Institutet in Stockholm, Sweden. Credit: Karolinska Institutet

There have been great expectations regarding the production of a drug to block the enzyme LTA4 hydrolase, which plays a key role in the body's inflammatory response. However, in clinical trials, such molecules have proven to be only moderately effective. Now, researchers at Karolinska Institutet have successfully refined their understanding of why previous substances have been less effective – and in so doing have produced a molecule that gets around the problem. Consequently, there is once again hope of a new anti-inflammatory drug based on the principal of blocking LTA4 hydrolase, which could provide relief in diseases such as COPD, the vascular disease arteriosclerosis and chronic eczema.

The LTA4 hydrolase has two functions. One is to produce LTB4, which contributes to the . The other is to inactivate the tripeptide Pro-Gly-Pro, which is formed during degradation of connective tissue and which also contributes to . In the first pathway, the enzyme LTA4 hydrolase evokes an inflammatory process, while it contributes to healing in the second.

"It could be considered remarkable that the same enzyme has two activities that are completely opposite. But this is more understandable if you look at it over time: in the first stage, the enzyme creates inflammation at the site of an injury, thus attracting , and in the second stage it contributes to healing by inhibiting the inflammation," says Jesper Z. Haeggström, Professor of Molecular Eicosanoid Research in the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.

Previous attempts to produce an anti-inflammatory drug that blocks LTA4 hydrolase have knocked out both of these functions. This is probably why the effects have so far been only moderate. Using x-ray crystallography to study LTA4 hydrolase, Jesper Z. Haeggström and his colleagues have been able to demonstrate that the formation of LTB4, which contributes to the and the inactivation of Pro-Gly-Pro, takes place at different parts of the enzyme's active site – the part of the enzyme used for biochemical communication.

They have used this information to produce a molecule that inhibits LTA4 hydrolase from producing LTB4, while the inactivation of Pro-Gly-Pro is maintained. This means that LTA4 hydrolase acts as an anti-inflammatory in both pathways; awakening new hopes of producing a drug that acts on this enzyme.

In the long-term, the researchers believe that a drug based on their molecule could be used to treat COPD (chronic ), arteriosclerosis and various types of inflammatory skin disease such as chronic eczema. The study has been financed by the Swedish Research Council, the EU, VINNOVA, Stockholm County Council and Dr. Hans Kröner Graduiertenkolleg.

Explore further: Scientists discover new way to tackle inflammatory diseases

More information: 'Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase and development of an epoxide hydrolase selective inhibitor', Alena Stsiapanava, Ulrika Olsson, Min Wan, Thea Kleinschmidt, Dorothea Rutishauser, Roman Zubarev, Bengt Samuelsson, Agnes Rinaldo-Matthis and Jesper Z. Haeggström, PNAS, online early edition 3-7 March 2014. www.pnas.org/cgi/doi/10.1073/pnas.1402136111

Related Stories

Scientists discover new way to tackle inflammatory diseases

February 27, 2014
Researchers at the University of Sheffield have found a potential new way to treat common and largely incurable inflammatory conditions like chronic obstructive pulmonary disease (COPD).

Impaired recovery from inflammation linked to Alzheimer's disease

February 14, 2014
(Medical Xpress)—New research from Karolinska Institutet shows that the final stage of the normal inflammatory process may be disrupted in patients with Alzheimer's disease. A study published in the journal Alzheimer's ...

Alcohol-breakdown molecule may play a role in breast cancer development

February 11, 2014
(Medical Xpress)—New research looking at the biological process involved in breast cancer development has strengthened the argument for a potential link between alcohol consumption and the disease.

Beta-catenin alters T cells in lasting and harmful ways

February 26, 2014
Activation of beta-catenin, the primary mediator of the ubiquitous Wnt signaling pathway, alters the immune system in lasting and harmful ways, a team of Chicago-based researchers demonstrate in the February 26, 2014, issue ...

Research associates pro-inflammatory molecules with early death in HIV patients

January 16, 2014
A study led by researchers at Boston University School of Medicine (BUSM) provides new insight into the impact that pro-inflammatory molecules have on early death in HIV patients who abuse alcohol. The findings, published ...

Recommended for you

Chronic inflammation causes loss of muscle mass during aging

January 12, 2018
People start losing muscle mass at the age of 40—about some 10 percent of the total muscle mass for each 10-year period, which may lead to fall-related injuries, slowing metabolism and reduced quality of life. Today, very ...

Breathing exercises help asthma patients with quality of life

December 13, 2017
A study led by the University of Southampton has found that people who continue to get problems from their asthma, despite receiving standard treatment, experience an improved quality of life when they are taught breathing ...

Study highlights the need for research into prevention of inflammatory bowel disease

December 7, 2017
Countries in Africa, Asia, the Middle East and South America have seen a rise in incidence of inflammatory bowel disease as they have become increasingly industrialised and westernised, a new study has found.

Air pollution can increase asthma risk in adults, even at low levels

November 24, 2017
Living close to a busy road can be bad for your respiratory health if you are middle aged, new Australian research has found.

Evidence found of oral bacteria contributing to bowel disorders

October 20, 2017
(Medical Xpress)—An international team of researchers has found evidence that suggests certain types of oral bacteria may cause or exacerbate bowel disorders. In their paper published in the journal Science, the group describes ...

New compound discovered in fight against inflammatory disease

September 22, 2017
A 10-year study by University of Manchester scientists for a new chemical compound that is able to block a key component in inflammatory illness has ended in success.

0 comments

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.