Researchers uncover pathway that could lead to plant generation of human-like protein

The researchers — led by Lokesh Joshi, an ASU associate professor in the Harrington Department of Bioengineering of the Ira A. Fulton School of Engineering and a member of the Arizona BioDesign Institute — have found a pathway whereby plants can generate human-like proteins. This discovery could lead to an effective means of producing proteins that are medically important and do so with a method that could be effective and less expensive than current methods, Joshi said.

“The discovery has both basic and applied science applications,” Joshi said. “It is a pathway, a set of chemical reactions, that had never been reported before in plants. The discovery will facilitate the use of plants to produce medically important proteins, in their correct form, for human use.”

A paper detailing the research, “Sialylated endogenous glycoconjugates in plant cells,” appears in the December 2003 issue of Nature Biotechnology. In addition to Joshi, authors of the paper are ASU graduate student Miti Shah, visiting professor Kazuhito Fujiyama, and ASU research scientist C. Robert Flynn.

Using plants to make proteins for humans is an idea that has been discussed for some time. But a common problem with plant-produced proteins is that they are often rejected by the human body, which sees them as foreign. As a result, the body’s immune system attacks the substances to rid itself of them.

Researchers had found that the trigger for this action was the lack of specific sugar groups called sialic acids, attached to the sugar chains on protein molecules. When these groups are present on the proteins, the body does not act to rid itself of them. Without the sugar groups, however, the immune system kicks in and the protein (drug) is rapidly cleared away.

“In humans, sialic acids protect the protein,” Joshi said. “They tell our body that this is a self-made protein. If it is not there on a glycoprotein, then our body says it is not a self-made protein and it needs to be removed.”

Joshi and his colleague’s discovery is a complex pathway, or set of chemical reactions, in plants that attach theses sugar groups to the proteins. This pathway, in essence, is common to humans and plants.

“It’s a sialic acid synthesis pathway,” Joshi said. “In humans they are important for the half-life of our proteins and immune system, but we don’t know what their role is in plants. It may be related to a plant’s ability to survive stressful conditions, like a lack of water or nutrients, or it may have a role in plant-pathogen interaction.”

So far, the team has worked on three human proteins — an immune activator called a macrophage activating factor, a type of collagen and a heat shock protein. They have done the work on three plants — tobacco, arabidopsis and alfalfa.

“What we discovered is that there is a very complex set of reactions that exist in plants and no one knows how it got there or what it is doing there, but it is similar to human beings,” Joshi said.

Knowing that the pathway exists, he explained, opens up an avenue that can be used to make the correct glycoproteins for humans by plants. However, the researchers need to enhance other aspects of the process.

“We are seeing about 2 to 3 percent of sialic acids on proteins made in plants. We would like to see 95 percent,” Joshi said. “So we are working on metabolic engineering methods to enhance the levels of enzymes involved in these reactions in the plant to get maximum yield.

The researchers will continue their work on the new pathways, exploiting systems that exist in plants, rather than adding a gene to a plant to make it work in a completely different manner.

“I believe that plants have the genetic makeup to carry out complex human-like reactions,” Joshi explained. “Our approach is to use what exists in the plant system and manipulate that to develop something for human beings. Now we have found the genes in the plants and we are working with those in the lab to regulate them and get more and more sialic acids out of them.”

Sources:
Lokesh Joshi, (480) 965-0655
Lokesh.joshi@asu.edu

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