By following the enzymatic activities of a process that breaks down tyrosine, Graham Moran could help provide a path for the development of inhibitors of several diseases.

Moran, an associate professor in the Department of Chemistry & Biochemistry, is working on “4-Hydroxyphenylphyruvate Dioxygenase,” a project that was approved for funding through the Research Growth Initiative. The study looks at the connections between the enzyme and its role as a catalyzing agent in breaking down tyrosine.

The process through which tyrosine, an amino acid, is broken down involves five consecutive enzymes. A deficiency of any one enzyme can lead to disease, Moran said.

For last six years Moran and his research team have demonstrated the mechanism and structure of inhibitors interacting with HPPD and have tried to focus on the connection between the inhibitory mechanism and the catalytic function of the enzyme.

Without the enzyme fumarylacetoacetase, a pathway occurs in which toxic substances build up and produce liver cirrhosis and liver cancer. The disease generally kills the human it appears in before the age of 2, Moran said.

In the second phase, a deficiency of the enzyme homogentisate 1, 2-dioxygenase, produces Alkaptonuria, the symptoms of which include “urine the color of Coca-Cola,” Moran said. Other symptoms of this disease include ears and nose turning a bluish-brown color. Skin pigment accumulates in the joints, which ends up causing chronic arthritis, he said.

The treatment for this disease would not be a sustainable cure, but would suppress the ability for the enzyme to transform into the non-enzymatic and polymer that produces Alkaptonuria.

Hawkinsinuria is the third and least-likely occurring disease manufactured in the catabolism process. This disease causes a “general inability to thrive” in young children and is produced when 4-Hydroxyphenylpyruvate transfers into an uncoupled turnover and enzyme, Moran said.

But molecules designed to act as herbicides can be used in the treatment of these diseases. Inhibition of the second enzyme of the tyrosine break down pathway, 4-hydroxyphenylpyruvate dioxygenase is a viable strategy to treat both type-1 tyrosinemia and alkaptonuria, Moran said. The primary metabolic function of this enzyme in plants is very different from that in mammals. In plants this enzyme is required to produce molecules that aid in photosynthesis whereas in mammals it simply helps modulate that levels of blood tyrosine, Moran said.

“From a medical point of view, if you inhibit the enzyme, you would have killed the plant,” Moran said.

For the project, Moran must write papers in November and February. Funding for earlier portions of the project were awarded by the National Institute of Health and helped fund the project from 2002 to 2006. Moran and his team wrote and published 12 papers during that time span.

As part of the project, a part of the research initiative, Moran received about $130,000 July 1 for funding. However, he said, after the money that can be used for research amounts to about $20,000 to $25,000, he said.

As part of the initiative, researchers who win awards for funding are expected to get funding from outside the university in order to continue the research project.

Funding from the National Institute of Health is “some of the best money you can get,” Moran said, because there generally are no stipulations attached to the award and it is usually given more than other sources of funding.

> Comments