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 An evolutionary heads-up – The brain size advantage
22.05.2015 | Veterinärmedizinische Universität Wien

nachricht Endocrine disrupting chemicals in baby teethers
21.05.2015 | Goethe-Universität Frankfurt am Main

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Basel Physicists Develop Efficient Method of Signal Transmission from Nanocomponents

Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.

Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...

Im Focus: IoT-based Advanced Automobile Parking Navigation System

Development and implementation of an advanced automobile parking navigation platform for parking services

To fulfill the requirements of the industry, PolyU researchers developed the Advanced Automobile Parking Navigation Platform, which includes smart devices,...

Im Focus: First electrical car ferry in the world in operation in Norway now

  • Siemens delivers electric propulsion system and charging stations with lithium-ion batteries charged from hydro power
  • Ferry only uses 150 kilowatt hours (kWh) per route and reduces cost of fuel by 60 percent
  • Milestone on the road to operating emission-free ferries

The world's first electrical car and passenger ferry powered by batteries has entered service in Norway. The ferry only uses 150 kWh per route, which...

Im Focus: Into the ice – RV Polarstern opens the arctic season by setting course for Spitsbergen

On Tuesday, 19 May 2015 the research icebreaker Polarstern will leave its home port in Bremerhaven, setting a course for the Arctic. Led by Dr Ilka Peeken from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) a team of 53 researchers from 11 countries will investigate the effects of climate change in the Arctic, from the surface ice floes down to the seafloor.

RV Polarstern will enter the sea-ice zone north of Spitsbergen. Covering two shallow regions on their way to deeper waters, the scientists on board will focus...

Im Focus: Gel filled with nanosponges cleans up MRSA infections

Nanoengineers at the University of California, San Diego developed a gel filled with toxin-absorbing nanosponges that could lead to an effective treatment for skin and wound infections caused by MRSA (methicillin-resistant Staphylococcus aureus), an antibiotic-resistant bacteria. This "nanosponge-hydrogel" minimized the growth of skin lesions on mice infected with MRSA - without the use of antibiotics. The researchers recently published their findings online in Advanced Materials.

To make the nanosponge-hydrogel, the team mixed nanosponges, which are nanoparticles that absorb dangerous toxins produced by MRSA, E. coli and other...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International symposium: trends in spatial analysis and modelling for a more sustainable land use

20.05.2015 | Event News

15th conference of the International Association of Colloid and Interface Scientists

18.05.2015 | Event News

EHFG 2015: Securing health in Europe. Balancing priorities, sharing responsibilities

12.05.2015 | Event News

 
Latest News

Mesoporous Particles for the Development of Drug Delivery System Safe to Human Bodies

22.05.2015 | Materials Sciences

Computing at the Speed of Light

22.05.2015 | Information Technology

Development of Gold Nanoparticles That Control Osteogenic Differentiation of Stem Cells

22.05.2015 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>