Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Odd biochemistry yields lethal bacterial protein

23.01.2013
While working out the structure of a cell-killing protein produced by some strains of the bacterium Enterococcus faecalis, researchers stumbled on a bit of unusual biochemistry. They found that a single enzyme helps form distinctly different, three-dimensional ring structures in the protein, one of which had never been observed before.

The new findings, reported in Nature Chemical Biology, should help scientists find new ways to target the enterococcal cytolysin protein, a "virulence factor that is associated with acute infection in humans," said University of Illinois chemistry and Institute for Genomic Biology professor Wilfred van der Donk, who conducted the study with graduate student Weixin Tang.


One enzyme shapes the components of a bacterial protein into rings with right-handed (D) and left-handed (L) stereochemistries.

Credit: Graphic by Weixin Tang

Enterococcus faecalis (EN-ter-oh-cock-us faye-KAY-liss) is a normal microbial inhabitant of the gastrointestinal tracts of humans and other mammals and generally does not harm its host. Some virulent strains, however, produce cytolysin (sigh-toe-LIE-sin), a protein that, once assembled, attacks other microbes and kills mammalian cells.

"The cytolysin protein made by Enterococcus faecalis consists of two compounds that have no activity by themselves but when combined kill human cells," van der Donk said. "We know from epidemiological studies that if you are infected with a strain of E. faecalis that has the genes to make cytolysin, you have a significantly higher chance of dying from your infection." E. faecalis contributes to root canal infections, urinary tract infections, endocarditis, meningitis, bacteremia and other infections.

Enterococcal cytolysin belongs to a class of antibiotic proteins, called lantibiotics, which have two or more sulfur-containing ring structures. Scientists had been unable to determine the three-dimensional structure of this cytolysin because the bacterium produces it at very low concentrations. Another problem that has stymied researchers is that the two protein components of cytolysin tend to clump together when put in a lab dish.

Van der Donk and Tang got around these problems by producing the two cytolysin components separately in another bacterium, Escherichia coli (esh-uh-REE-kee-uh KOH-lie), and analyzing them separately.

"The two components are both cyclic peptides, one with three rings and the other with two rings," van der Donk said. "Curiously, a single enzyme makes both compounds."

In a series of experiments, the researchers found that one ring on each of the proteins adopted a (D-L) stereochemistry that is common in lantibiotics (see image, above). But the other rings all had an unusual (L-L) configuration, something van der Donk had never seen before.

Scientists had assumed that the enzyme that shaped enterococcal cytolysin, a lantibiotic synthetase, acted like a three-dimensional mold that gave the ring structures of cytolysin the exact same stereochemistry, van der Donk said.

"But we found that the enzyme, enterococcal cytolysin synthetase, makes the rings with different stereochemistry," he said. "I don't know of any other examples where one enzyme can make very similar products but with different stereochemistries."

The researchers don't know how the enzyme accomplishes this feat, but found a clue in the sequence of amino acids that make up the protein rings. The chemical characteristics of the three amino acids in the middle of the ring structure and their proximity to another amino acid, a cysteine, determined whether the rings took on a D-L or L-L stereochemistry.

The researchers tested the idea that the amino acid sequence of the cytolysin protein was guiding the stereochemistry by looking at other lantibiotic proteins with similar sequences. So far, every protein they've tested that has the same sequence characteristics conforms to the pattern they discovered, van der Donk said.

Further tests showed that the cytolysin produced in E. coli had the same anti-microbial and cell-killing potency as the E. faecalis variety.

"Knowing the structure of enterococcal cytolysin and having a method to produce it in relatively large quantities will allow scientists to find out how it kills human cells and, in turn, how we might fight against it," van der Donk said.

The National Institutes of Health supported this research. Van der Donk also is a Howard Hughes Medical Institute investigator.

Editor's notes:

To reach Wilfred van der Donk, call 217-244-5360; email vddonk@illinois.edu.

The paper, "The Sequence of the Enterococcal Cytolysin Imparts Unusual Lanthionine Stereochemistry," is available to the media from the U. of I. News Bureau.

Diana Yates | University of Illinois
Further information:
http://www.illinois.edu

More articles from Studies and Analyses:

nachricht Rutgers-led innovation could spur faster, cheaper, nano-based manufacturing
14.02.2018 | Rutgers University

nachricht New study from the University of Halle: How climate change alters plant growth
12.01.2018 | Martin-Luther-Universität Halle-Wittenberg

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Researchers invent tiny, light-powered wires to modulate brain's electrical signals

21.02.2018 | Life Sciences

The “Holy Grail” of peptide chemistry: Making peptide active agents available orally

21.02.2018 | Life Sciences

Atomic structure of ultrasound material not what anyone expected

21.02.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>