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 Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>