New chemical tools to modify and study biomolecules

July 02, 2019

Understanding the structure and metabolism of cells and living organisms is essential for the development of new drugs and diagnostics. The availability of chemical tools that allow scientists to edit biomolecules, like proteins, with atom-level resolution have greatly contributed to the progress of chemical biology.

Proteins are macromolecules constructed from a set of twenty chemically different amino acids. One key approach to modify proteins is to react with the sulfur atom in the amino acid cysteine. However, current methods are still problematic in terms of efficiency, selectivity, and stability of the final product (the "adduct").

Now, the labs of Jérôme Waser and Beat Fierz at EPFL's Institute of Chemical Sciences and Engineering have developed a new method for modifying cysteines on peptides and proteins. The method uses a group of highly reactive organic molecules, the ethynylbenziodoxolones (EBXs). What makes EBXs highly reactive is that they contain an iodine atom bound to three substituent groups. This non-natural situation leads to high reactivity in these so-called "hypervalent iodine" reagents.

For the first time, the researchers were able to generate a simple biomolecule-EBX adduct while keeping their reactive iodine group in the final molecule. The reaction can be easily performed by a non-expert under standard physiological conditions.

The end product are protein-hypervalent iodine reagent chimeras that can act as dual attachment points for two new chemical groups, opening up new opportunities for the study of biological processes.

"One new functionality can be introduced via 'click-chemistry', a well-established reaction in chemical biology," says Waser. "Using a palladium catalys, another selective modification can be achieved at the reactive iodine atom- what we would call a 'biorthogonal' functionality, as it does not exist in nature." Introducing such exotic reactive groups into biomolecules is currently one of the most important tools in chemical biology, as it allows the study of biological processes without interfering with them.

The scientists demonstrated the potential of the method by introducing a diverse set of chemical groups into biomolecules. For example, the scientists used the dual handle to attach a fluorescent dye and a photoprotecting group into a neuropeptide simultaneously. Combining them improves the dye's photostability, and enables high-resolution, single-molecule imaging of molecular interactions.

Beyond peptides, they further modified small proteins, and even large protein-DNA complexes, so-called nucleosomes. As nucleosomes organize the genome, labeling them with fluorescent dyes can help track them to decipher how nature regulates gene expression.

"What we developed here is a new method for modifying proteins based on fundamental studies of chemical reactivity," says Fierz. "We have already used it to modify of histones, and carried out fluorescence experiments on living cells. With these examples, we have set the foundation for a better understanding of biological processes."
Romain Tessier, Javier Ceballos, Nora Guidotti, Raphael Simonet-Davin, Beat Fierz, Jerome Waser. Doubly Orthogonal Labeling of Peptides and Proteins. CHEM 02 July 2019. DOI: 10.1016/j.chempr.2019.06.022

Ecole Polytechnique Fédérale de Lausanne

Related Amino Acids Articles from Brightsurf:

Igniting the synthetic transport of amino acids in living cells
Researchers from ICIQ's Ballester group and IRBBarcelona's Palacín group have published a paper in Chem showing how a synthetic carrier calix[4]pyrrole cavitand can transport amino acids across liposome and cell membranes bringing future therapies a step closer.

Microwaves are useful to combine amino acids with hetero-steroids
Aza-steroids are important class of compounds because of their numerous biological activities.

New study finds two amino acids are the Marie Kondo of molecular liquid phase separation
a team of biologists at the Advanced Science Research Center at The Graduate Center, CUNY (CUNY ASRC) have identified unique roles for the amino acids arginine and lysine in contributing to molecule liquid phase properties and their regulation.

Prediction of protein disorder from amino acid sequence
Structural disorder is vital for proteins' function in diverse biological processes.

A natural amino acid could be a novel treatment for polyglutamine diseases
Researchers from Osaka University, National Center of Neurology and Psychiatry, and Niigata University identified the amino acid arginine as a potential disease-modifying drug for polyglutamine diseases, including familial spinocerebellar ataxia and Huntington disease.

Alzheimer's: Can an amino acid help to restore memories?
Scientists at the Laboratoire des Maladies Neurodégénératives (CNRS/CEA/Université Paris-Saclay) and the Neurocentre Magendie (INSERM/Université de Bordeaux) have just shown that a metabolic pathway plays a determining role in Alzheimer's disease's memory problems.

New study indicates amino acid may be useful in treating ALS
A naturally occurring amino acid is gaining attention as a possible treatment for ALS following a new study published in the Journal of Neuropathology & Experimental Neurology.

Breaking up amino acids with radiation
A new experimental and theoretical study published in EPJ D has shown how the ions formed when electrons collide with one amino acid, glutamine, differ according to the energy of the colliding electrons.

To make amino acids, just add electricity
By finding the right combination of abundantly available starting materials and catalyst, Kyushu University researchers were able to synthesize amino acids with high efficiency through a reaction driven by electricity.

Nanopores can identify the amino acids in proteins, the first step to sequencing
While DNA sequencing is a useful tool for determining what's going on in a cell or a person's body, it only tells part of the story.

Read More: Amino Acids News and Amino Acids Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to