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From studies of a rare human mutation to new approaches to herbicides or antibiotics

PHILADELPHIA (July 30, 2003)--The promise of the genomics revolution--the ability to compare important genes and proteins from many different organisms--is that such detailed knowledge will produce new scientific insights that will improve human quality of life. In work on a key human enzyme, PBGS (porphobilinogen synthase), the laboratory of Fox Chase Cancer Center scientist Eileen K. Jaffe, Ph.D., has characterized a rare mutation that results in an unprecedented rearrangement of the enzyme's structure. The discovery provides a key into how tiny genetic changes can have a giant evolutionary impact and may even lead to the development of novel herbicides and antibacterial agents.

The report, "Control of Tetrapyrrole Biosynthesis by Alternate Quaternary Forms of Porphobilinogen Synthase," appears in the September 2003 issue of Nature Structure Biology and as an advance online publication on the journal's web site starting August 3. PBGS is one of a group of enzymes found in every organism from bacteria through plants and humans.

Important roles for PBGS include formation of chlorophyll in plants and the heme component of hemoglobin, the protein that carries oxygen in the blood. A September 1999 report of a routine screen of newborn infants for metabolic defects identified a new mutation in PBGS, termed F12L, that causes the enzyme to lose activity, as reported by Shigeru Sassa, M.D., Ph.D., of Rockefeller University and co-authors in the British Journal of Haematology.

Detailed analysis of this mutation by Jaffe's group has now led to the startling conclusion that the tiny genetic change in F12L results in a drastic structural rearrangement of PBGS. In normal healthy humans, eight separate copies of the PBGS protein associate in a cloverleaf-shaped structure, resulting in an active enzyme complex. In the F12L mutant, however, two of the copies are bumped off, and the remaining six copies of PBGS protein associate in a completely differe
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Contact: Karen Carter Mallet
k_carter@fccc.edu
215-728-2700
Fox Chase Cancer Center
3-Aug-2003


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