Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A Larger Pocket

12.08.2014

 

Reprogramed nonribosomal peptide synthetase incorporates amino acids with reactive sites for “click” chemistry

A single targeted mutation is enough to alter a natural peptide system so that it also incorporates non-natural amino acids into peptides, report Swiss scientists in the journal Angewandte Chemie.

The mutation increases the size of the binding cavity in one domain of the system, which changes the substrate specificity. The researchers are thus able to incorporate amino acids with a specific reactive group that can later be used to easily modify the peptide.

In the search for new pharmaceuticals through the use of combinatorial chemistry and screening processes, researchers are often faced with the task of modifying and varying natural substances—sometimes by adding further molecular components, for example.

Highly specific coupling with molecular markers is particularly important because it allows scientists to monitor the distribution of natural substances in cells and tissues. Coupling reactions that are almost as snapping components together can be carried out by a technique known as “click chemistry”. This method encompasses broadly applicable reactions like those between alkynes and azides, which deliver high yields.

For this technique, the natural substance must first be equipped with such an alkyne or azide group. One way to achieve this would be through the incorporation of amino acids with alkyne or azide side chains into proteins through alteration of their biosynthesis.

However, many interesting natural substances, such as the gramicidin antibiotics, are not formed by way of the classical pathways of protein biosynthesis through the reading of genes and the assembly of amino acids in the ribosomes. Instead, they are made by nonribosomal peptide synthetases, very large multi-enzyme complexes whose individual modules hang together like pearls on a necklace.

These activate the amino acid building blocks and incorporate them into the growing peptide chain. The number, type, and ordering of the individual modules determine the length and composition of the resulting—usually short-chained—peptide. In addition to the usual amino acids, it is also possible to incorporate other, sometimes unusual, individual building blocks, which allows for the formation of an astonishingly large variety of peptides.

Researchers working with Donald Hilvert at the ETH in Zurich exchanged an individual amino acid in one module of the nonribosomal production apparatus for the antibiotic gramicidin S through a mutation. This altered an area known as an A domain, which specifically recognizes and activates the natural amino acid phenylalanine.

The mutation causes the binding cavity to be roomier, so that non-natural amino acids that contain an azide or alkyne group can be activated and incorporated into the peptide chain in place of phenylalanine. The catalytic activity of the overall system is not affected by this change in selectivity.

Because many different nonribosomal synthesis systems contain such A domains, this new method is potentially a general approach for equipping important natural substances with a reactive site for highly specific covalent modification.

About the Author

Dr. Donald Hilvert is Professor of Chemistry at the ETH Zürich. His research group is investigating how enzymes work and evolve and applying this knowledge to the design of new protein-based catalysts. These efforts have been recognized by a number of awards, including the Pfizer Award in Enzyme Chemistry and the Emil Thomas Kaiser Award from the Protein Society.

Author: Donald Hilvert, ETH Zürich (Switzerland), http://www.protein.ethz.ch

Title: Reprogramming Nonribosomal Peptide Synthetases for "Clickable" Amino Acids

Angewandte Chemie International Edition, Permalink to the article: http://dx.doi.org/10.1002/anie.201405281

Donald Hilvert | Angewandte Chemie - Wiley
Further information:
http://pressroom.angewandte.org

Further reports about: ETH Pocket acid acids alkyne amino phenylalanine reactions reactive substances technique

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Tune your radio: galaxies sing while forming stars

21.02.2017 | Physics and Astronomy

Improved Speech Intelligibility and Automatic Speech-to-Text Conversion for Call Centers

21.02.2017 | Trade Fair News

36 big data research projects

21.02.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>