Researchers Reveal Basis For Debilitating Hereditary Disease

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

Using x-raycrystallography, researchers have generated a three-dimensional imageof the enzyme coproporphyrinogen oxidase (CPO) at the atomic level,(resolution of 1.58 angstroms). The enzyme participates in the sixthstep of an eight-step pathway that generates heme – an essentialmolecule that gives blood its distinctive red color and also helpshemoglobin in red blood cells transport oxygen to tissues.

ThePNAS paper demonstrates for the first time the enzyme's atomicstructure and how mutations in this enzyme specifically disrupt theheme pathway, causing hereditary coproporphyria. The authors review aseries of CPO mutations and their effects on the structure and functionof the enzyme.

"There will be no life without heme, so it isimportant to understand how this molecule is produced and utilized,"Raman said. Hereditary coproporphyria is rare, affecting two in everymillion people, "but rare diseases give you major insights intoextremely complex biological problems."

Porphyrias are disordersof enzymes in the heme synthesis pathway that reduce heme productionand, more importantly, cause accumulation of porphyrins or theirprecursors, Raman explained. In the case of hereditary coproporphyria,inherited mutations in CPO result in accumulation of coproporphyrin inthe liver, leading to disease. In July, British researchers connectedthe madness of King George III to one of the porphyrias.

"Theatomic image of the enzyme teaches us the inner workings of thismolecular machine. Particularly, it helps us understand how mutationscause the enzyme to fail, disrupt the heme biosynthesis pathway andculminate in coproporphyrin accumulation," Raman said.

Excessporphyrins are excreted in the feces and urine. As a result urine frompatients suffering from coproporphyria turns red or purple when exposedto light.

The CPO structure is the third unique structure solvedby Raman's research team, which focuses on heme and nitric oxidesynthesis and signaling pathways.

First author of the paper isDong-Sun Lee, Ph.D., assistant professor of Biochemistry and MolecularBiology at the UT Medical School. He is the recipient of the BeginningGrant-in-Aid (2005) from the American Heart Association. Co-authors areBorries Demeler, Ph.D., assistant professor of biochemistry at TheUniversity of Texas Health Science Center at San Antonio, and EvaFlachsová, Michaela Bodnarová and professor Pavel Martásek, all of theDepartment of Pediatrics, Center of Applied Genomics, First School ofMedicine, Charles University in Prague, Czech Republic.

PNASpapers are either communicated or edited by a member of the NationalAcademies of Science. This paper was communicated by Nobel LaureateFerid Murad, M.D., Ph.D., director of the Brown Foundation Institute ofMolecular Medicine for the Prevention of Human Diseases and holder ofthe John S. Dunn, Sr. Distinguished Chair in Physiology and Medicine atthe UT Medical School at Houston.