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Researchers Reveal Basis for
Debilitating
Hereditary Disease
Atomic image of enzyme gives major insights into extremely complex biological problems
A research team led by scientists at The University of Texas Medical School at Houston has determined the structure of an enzyme that when defective causes an inherited disease that afflicts sufferers with severe abdominal pain, psychiatric symptoms, skin fragility and light sensitivity.
C. S. Raman, Ph.D.
Using x-ray crystallography, researchers have generated a three-dimensional image of the enzyme coproporphyrinogen oxidase (CPO) at the atomic level. The enzyme participates in the sixth step of an eight-step pathway that generates heme – an essential molecule that gives blood its distinctive red color and also helps hemoglobin in red blood cells transport oxygen to tissues.
The PNAS paper demonstrates for the first time the enzyme’s atomic structure and how mutations in this enzyme specifically disrupt the heme pathway, causing hereditary coproporphyria. The authors review a series of CPO mutations and their effects on the structure and function of the enzyme.
“There will be no life without heme, so it is important to understand how this molecule is produced and utilized,” Raman said. Hereditary coproporphyria is rare, affecting two in every million people, “but rare diseases give you major insights into extremely complex biological problems.”
Porphyrias are disorders of enzymes in the heme synthesis pathway that reduce heme production and, more importantly, cause accumulation of porphyrins or their precursors, Raman explained. In the case of hereditary coproporphyria, inherited mutations in CPO result in accumulation of coproporphyrin in the liver, leading to disease. In July, British researchers connected the madness of King George III to one of the porphyrias.
The CPO enzyme consists of two identical molecules. Here, the surface structure is depicted in the molecule on the right, and its topology is represented in the molecule on the left. One CPO image is a “Featured Image” at the PNAS web site. Courtesy of C. S. Raman
Excess porphyrins are excreted in the feces and urine. As a result, urine from patients suffering from coproporphyria turns red or purple when exposed to light.
The CPO structure is the third unique structure solved by Raman’s research team, which focuses on heme and nitric oxide synthesis and signaling pathways. They also are the first crystal structures to be determined at the Medical School.
First author of the paper is Dong-Sun Lee, Ph.D., assistant professor of Biochemistry and Molecular Biology at the UT Medical School. He is a recipient of a 2005 Beginning Grant-in-Aid from the American Heart Association.
Co-authors are Borries Demeler, Ph.D., assistant professor of biochemistry at the UT Health Science Center at San Antonio, and Eva Flachsová, Michaela Bodnarová and professor Pavel Martásek, all of the Department of Pediatrics, Center of Applied Genomics, First School of Medicine, Charles University in Prague, Czech Republic.
PNAS papers are either communicated or edited by a member of the National Academies of Science. This paper was communicated by Nobel Laureate Ferid Murad, M.D., Ph.D., director of the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases and holder of the John S. Dunn Sr. Distinguished Chair in Physiology and Medicine at the UT Medical School at Houston.
Murad and Raman also hold faculty appointments at the UT Graduate School of Biomedical Sciences at Houston.
By Scott Merville, Public Affairs