Title

Selective hybrid catalysts based on nucleic acids

Principal Investigator

Prof. Dr. Andres Jäschke
Institute of Molecular Biotechnology and Pharmacy
University of Heidelberg
Im Neuenheimer Feld 364
69120 Heidelberg
Germany

Phone: +49 6221-54-4853
Fax: +49 6221-54-6430
E-mail: jaeschke@uni-hd.de

Abstract

Prior the discovery of catalytic RNAs in the early 1980s, proteins were considered by many as the only catalytically active molecules in living matter. Catalytic RNAs or ribozymes in natural systems have predominantly nuclease or nucleotidyl transferase acivity. In other words they catalyze phosphate ester bond cleavage or formation. However, ribozyme engineering, using molecular biology techniques, allows for in vitro selection of active molecules with other catalytically activities. In this way ribozymes able to self-alkylate or catalyzing amide bond formation have been selected [1]. Recently in our group we have selected and characterized a ribozyme catalyzing a Diels-Alder reaction between anthracene and maleimide derivatives [2]. Interestingly this ribozyme is active catalyzing a truly bimolecular reaction, a feature found hardly ever in selected ribozymes which are generally found to be self-modifiers.
In this project we are aiming at extending the range of reactions that can be catalyzed by ribozymes. In particular we will investigate the preparation of hybrid catalysts for organometallic reactions based on conjugates between RNA and transition metal complexes. We are using at present two approaches to this problem:
- noncovalent localization of a metal complex in a known RNA structure
- de novo selection of a hybrid RNA-transition metal catalyst.

The first strategy will be used for the proof of principle using phosphorous donor ligands with a structure that resembles the Diels-Alder product obtained from the ribozyme-catalyzed reaction developed in our laboratories (fig. 1). The Diels-Alderase ribozyme showed in fact product inhibition in the range of 10 µM. We expect that a metal complex prepared with ligands having such bicyclic structure should also be docked within the RNA folds. The occurrence of the reaction in such fashion should be revealed by enantioselective induction in the products. 

In the second strategy we are going to evolve hybrid catalyst either by using the nucleobases as ligands for the transition metal or by attachment of a metal complex to the RNA pool during selection.

I

Figure 1. A phosphoramidite and a phosphite based ligand. The green substructure is necessary for docking of the ligand within the Diels-Alderase ribozyme.

Two model reactions have been selected from literature as suitable test for these hybrid catalysts: 
- Pd, Rh or Ir catalyzed allylic substitution (eq. 1)
- Rh-catalyzed hydrogenation of dehydroamino acid derivatives and of itaconic acid (eq. 2)

(1)

(2)

 

 

Both these reactions have been performed at room or even at lower temperature. They also tolerate water or aqueous organic solvents mixtures as reaction media, conditions that seems good starting point for having compatibility with the presence of RNA.

[1] Wilson, D. S.; Szostak, J. W. Annu. Rev. Biochm. 1999, 68, 611-647.
[2] Stuhlmann, F.; Jäschke, A. J. Am. Chem. Soc. 2002, 124, 3238-3244.


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