Researchers Reveal Basis for Debilitating Hereditary Disease

Newswise — 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.

"Unless prompt and appropriate treatment is given, hereditary coproporphyria can very quickly turn into a life-threatening medical emergency," said C. S. Raman, Ph.D., assistant professor in the Department of Biochemistry and Molecular Biology and senior author of a paper out this week in the Proceedings of the National Academy of Sciences.

Using x-ray crystallography, researchers have generated a three-dimensional image of the enzyme coproporphyrinogen oxidase (CPO) at the atomic level, (resolution of 1.58 angstroms). 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 atomic image of the enzyme teaches us the inner workings of this molecular machine. Particularly, it helps us understand how mutations cause the enzyme to fail, disrupt the heme biosynthesis pathway and culminate in coproporphyrin accumulation," Raman said.

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. 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 the recipient of the Beginning Grant-in-Aid (2005) from the American Heart Association. Co-authors are Borries Demeler, Ph.D., assistant professor of biochemistry at The University of Texas 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.

This study was funded by the Pew Charitable Trusts and the Houston-basedRobert A. Welch Foundation.