Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

04.08.2003


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 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.

Contact: Karen Carter Mallet, k_carter@fccc.edu

Karen Carter Mallet | EurekAlert!

More articles from Life Sciences:

nachricht Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel

nachricht Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>