May 2012

Eicosanoid research of yesteryear and now

JBC & MCP news

 

 

journal_news_jbcandmcp_v2 
E.J. Corey (left) and Robert B. Woodward (right) with Samuelsson at a conference in Uppsala, Sweden.

Eicosanoids are signaling molecules involved in a number of major biochemical pathways, such as inflammation and immunity. Two recent articles, one in the Journal of Biological Chemistry and the other in Molecular & Cellular Proteomics, focus on these molecules from different angles and together give a comprehensive view of how research in this field started and has grown over time. Prostaglandins, prostacyclins, thromboxanes and leukotrienes are types of eicosanoids. They are produced from the oxidation of essential omega-3 or omega-6 fatty acids.

In his JBC Reflections article, Bengt Samuelsson at the Karolinska Institute in Sweden describes the journey his laboratory embarked on in the 1960s to understand the fundamental biochemistry of eicosanoids (1). At least 10 drugs currently on the market are based on initial findings made by Samuelsson’s group and its collaborators. The work also garnered Samuelsson the Nobel Prize in physiology or medicine in 1982 along with Sune Bergström at Karolinska and John Vane at the William Harvey Research Institute at St. Bartholomew’s Hospital Medical College.

Samuelsson’s group discovered an enzyme that catalyzed the conversion of arachidonic acid into a molecule called PGG2. The team named the enzyme cyclooxygenase. Researchers later discovered that a variant of cycolooygenase called COX-2 was expressed during inflammation. The pharmaceutical industry developed COX-2 inhibitors to fight inflammation, such as Celebra and Vioxx (although Vioxx had to be taken off the market.

Samuelsson’s group also discovered thromboxane A2 and found that it plays a role in blood vessel injury by causing platelet aggregation and constriction of smooth vascular muscle. Later, researchers found that low doses of aspirin inhibited the formation of thromboxane A2. Based on that finding, millions of people now take daily doses of baby aspirin to prevent heart attacks and strokes. The discovery of leukotrienes by Samuelsson’s group led to the development of several drugs for treatment of asthma and rhinitis. One of these, Singulair, has been Merck´s bestselling product for several years, with sales around $5 billion.

Samuelsson’s body of work clearly shows how basic research can have a tremendous impact on public health. But, as Samuelsson concludes in his article, his contributions demonstrate “the power of research that is not targeted to a specific disease but rather focuses on understanding the structures and functions of the molecules constituting the human body.”

The MCP article highlights how modern -omics technologies can reveal connections between different molecular pathways. The laboratory of Edward Dennis at the University of California, San Diego, has studied the activation of phospholipase A2, which causes the release of arachidonic acid. Arachidonic acid then leads to the production of eicosanoids, which are metabolites. Dennis’ group previously had quantified these metabolites and correlated their levels with transcriptomic changes of 28 genes. “However, it was clear that the missing link between the transcript and the metabolite was the protein,” says Dennis.

To get a handle on the proteins, the Dennis group teamed up with the group of Ruedi Aebersold at the Swiss Federal Institute of Technology in Zurich. They applied multiple reaction monitoring mass spectrometry, a quantitative method that let them measure the amounts of the proteins involved in eicosanoid production (2). For example, Dennis says they were able to show that the protein expression of COX-2 closely follows the same trajectory as its transcript expression. The work by Dennis and colleagues is one of the first integrations of various -omic analyses, which allow researchers to better understand how seemingly isolated biochemical pathways are connected. Dennis explains -omics techniques have advanced to the point at which researchers can carry out an integrated study of genomics, proteomics and metabolomics. Dennis says, “This has been a long time in coming but is essential to fully understand the complex interplay between the genes, the proteins and the metabolites that the proteins make.”

REFERENCES
  1. 1. Samuelsson, B. J. Biol. Chem. 287, 10070 – 10080 (2012).
  2. 2. Sabido, E. et al. Mol. Cell. Proteomics, DOI: 10.1074/mcp.M111.014746.

Rajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer for ASBMB Today and the technical editor for the Journal of Biological Chemistry.


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