Researchers reveal basis for debilitating hereditary disease

October 07, 2005

HOUSTON - (Oct. 5, 2005) -- 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.
-end-


University of Texas Health Science Center at Houston

Related Enzyme Articles from Brightsurf:

Repairing the photosynthetic enzyme Rubisco
Researchers at the Max Planck Institute of Biochemistry decipher the molecular mechanism of Rubisco Activase

Oldest enzyme in cellular respiration isolated
Researchers from Goethe University have found what is perhaps the oldest enzyme in cellular respiration.

UQ researchers solve a 50-year-old enzyme mystery
Advanced herbicides and treatments for infection may result from the unravelling of a 50-year-old mystery by University of Queensland researchers.

Overactive enzyme causes hereditary hypertension
After more than 40 years, several teams at the MDC and ECRC have now made a breakthrough discovery with the help of two animal models: they have proven that an altered gene encoding the enzyme PDE3A causes an inherited form of high blood pressure.

Triggered by light, a novel way to switch on an enzyme
In living cells, enzymes drive biochemical metabolic processes. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics.

A 'corset' for the enzyme structure
The structure of enzymes determines how they control vital processes such as digestion or immune response.

Could inhibiting the DPP4 enzyme help treat coronavirus?
Researchers and clinicians are scrambling to find ways to combat COVID-19, including new therapeutics and eventually a vaccine.

Bacterial enzyme could become a new target for antibiotics
Scientists discover the structure of an enzyme, found in the human gut, that breaks down a component of collagen.

Chemists create new artificial enzyme
Rajeev Prabhakar, a computational chemist at the University of Miami, and his collaborators at the University of Michigan have created a novel, synthetic, three-stranded molecule that functions just like a natural metalloenzyme, or an enzyme that contains metal ions.

First artificial enzyme created with two non-biological groups
Scientists at the University of Groningen turned a non-enzymatic protein into a new, artificial enzyme by adding two abiological catalytic components: an unnatural amino acid and a catalytic copper complex.

Read More: Enzyme News and Enzyme Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.