From Studies Of A Rare Human Mutation To New Approaches To Herbicides Or Antibiotics

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 different manner, producing a nearly inactive enzyme.

This type of change is unprecedented in the scientific literature, causing it to be of great interest to those who study protein structure. The fact that this change arises from a single amino acid substitution, affecting the smallest building block of protein structure, is of additional interest to evolutionary biologists. The finding suggests ways that small changes at critical points in protein sequences can lead to the production of totally new protein complexes.

Perhaps of greatest significance, as described in this and other publications by Jaffe, is the realization that the ability of the human PBGS protein to move between eight-copy and six-copy structures because of a mutation now explains previously mysterious results of experiments concerning the naturally occurring PBGS activity in plants and bacteria. Based on these new insights, it may be possible to develop chemical compounds that specifically shut down plant or bacterial forms of PBGS, providing a novel class of herbicides or antibacterial agents useful in areas as far-flung as treatment of patients or prevention of bacterial infection of specific crops.

Jaffe's co-authors include postdoctoral associate Sabine Breinig, Ph.D., and scientific technician Linda Stith of Fox Chase; Jukka Kervinen, Ph.D., of 3-Dimensional Pharmaceuticals Inc. in Exton, Pa.; Robert Fairman, Ph.D., and Andrew S. Wasson of Haverford College; and Alexander Wlodawer, Ph.D., and Alexander Zdanov, Ph.D., of the National Cancer Institute's Macromolecular Crystallography Laboratory in Frederick, Md.

Fox Chase Cancer Center, one of the nation's first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at http://www.fccc.edu.