Fluorescent Eel Protein UnaG Leads to New Liver Test

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Atsushi Miyawaki, a molecular biologist at the RIKEN Brain Science Institute in Wako, Japan, named a new fluorescent protein discovered in an eel UnaG, after the Japanese unagi, popular with sushi lovers worldwide.  UnaG is the first fluorescent protein found in vertebrates. UnaG binds with bilirubin, which activates the fluorescence of the UnaG. This has lead to a new liver test that can help save lives worldwide.

Previously, before UnaG  was found in eels, there was a long-held notion among scientists that fluorescent proteins only were found in simple organisms, like jellyfish.

Fluorescent proteins do not produce light themselves, but glow when illuminated. The 2008 Nobel Prize in Chemistry was awarded for the discovery and development of such molecules. They are used to tag proteins or to track how genes are expressed.

The molecules have been engineered to produce light in a variety of hues and brightnesses. Those fluorescent proteins discovered until now in nature all came from non-vertebrates, mainly microbes, jellyfish, and corals.

Though Miyawaki named the fluorescent eel protein and how it works, through binding with bilirubin, the first clues to the eel protein’s existence came in 2009 when Seiichi Hayashi and Yoshifumi Toda, food chemists studying nutrients in eel at Kagoshima University in Japan, were tracking lipid transport into oily eel tissue.

They reported that eel muscle fluoresced naturally glowing green when a blue light is shone on it. The two food chemists then isolated a few fragments of the protein responsible.

This was what first attracted Miyawaki’s attention to the fluorescent protein in the unagi eels. Before this, Miyawaki  had identified and also engineered new properties into fluorescent proteins from jellyfish and corals.

The team,  by analyzing the structure of UnaG, discovered a novel mechanism of fluorescence enabling bilirubin to bind to UnaG. This binding is what activates its light emission. They have since used this knowledge to develop a superior new test for bilirubin.

They believe that the test will be important in the early detection of liver problems and may become the global clinical standard, especially in developing countries where child liver health remains a major issue.

Bilirubin is a breakdown product of blood hemoglobin, and it’s toxic if present in excess in the body. An excess of bilirubin causes characteristic yellow skin and eye color conditions seen in newborn babies, jaundice and kernicterus.

UnaG, in addition to assess liver function, can also be used to test for the loss of red blood cells in anemia.

The unagi eel species is endangered, but Miyawaki and the other researchers believe that the discovery of the medical importance of UnaG may encourage legislation to conserve the species.

Miyawaki said that he and his team believes that UnaG provides “an unexpected foothold into several important but currently obscure areas of human health, including bilirubin metabolism and muscle physiology during endurance exercise.” He is referring to the unagi’s long-distance migration lifecycle. They’re born in and grown up in inland rivers and later swim far into the sea to spawn.

He was also surprised at the impact that “basic science” can sometimes have on human health. He stated:  “From a simple eel, we found a new path to the clinic.”

Robert Campbell, a protein engineer at the University of Alberta in Edmonton, Canada, said: “I don’t think anyone would have thought that eels would have such a bright fluorescent protein.”

UnaG is in a class of its own. “It’s totally different” from other fluorescent proteins, he said. “There’s not anything you can point to that’s the same.”

Besides being unusual in that UnaG’s fluoresence is activated when it binds with bilirubin, is also unusual because, unlike GFP, it fluoresces brightly even when oxygen levels in cells are low. According to Campbell, this could be useful for visualizing anaerobic areas inside cancerous tumors.

Written by: Douglas Cobb

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