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Projects team 'Synthetic enzyme cascades'
Projects and Cooperations

Influences of non-conventional media on bimolecular carboligase reactions catalyzed by thiamine-diphophate (ThDP)-dependent enzymes

(Periode: 1/7/2009 - 31/6/2012)

PhD-studet: Tina Gerhards

Thiamine-diphosphate (ThDP)-dependent enzymes catalyze the carboligation of two aldehydes forming chiral 2-hydroxy ketones. The mixed carboligation of two different aldehydes may yield up to four different products, each as both stereoisomers. The stereo- and chemoselectivity of ThDP-dependent enzymes can be influenced by the environmental conditions (e.g. buffer, pH, T, cosolvent). In this project the influences of different organic solvents and ionic liquids on the chemo- and stereoselectivity of ThDP-dependent lyases are investigated.

Cooperation partners: Dr. M. Bocola (RWTH Aachen University), Dr. E. von Lieres (IBG-1, Forschungszentrum Jülich), Dr. Vicente Gotor-Fernández, University of Oviedo (Spain)

Identification and characterization of enzymes for the synthesis of chiral diols from 2-hydroxy ketones

(Periode: 1/1/2010 - 31/12/2012)

PhD-student: Justyna Kulig

Chiral diols find versatile application as building blocks for chemical catalysts, agrochemicals and pharmaceuticals. The concept of combining two enzyme toolboxes opens access to diversely substituted enantiocomplementary vicinal diols.

In the present project the formation of chiral 1,2-diols is accomplished by the action of two enzyme toolboxes. First, the carboligation of inexpensive aldehydes is catalyzed by thiamine diphosphate (ThDP)-dependent enzymes yielding 2-hydroxy ketones with high chemo- and stereoselectivity. Subsequently these 2-hydroxy ketones are further reduced via NAD(P)H-dependent oxidoreductases, with main focus on the stereoselective reduction of especially bulky-bulky substrates. Promising reactions are optimized via reaction engineering and an appropriate process for the enzymatic 2-step synthesis with cofactor regeneration is evaluated.

Cooperation partners: Prof. W. Kroutil (Karl-Franzens University Graz, AU), Dr. Frank Hollmann (TU Delft, NL), Dr. Kirsten Zeitler (University of Regensburg, D)

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Funded by:

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Development of a biocatalytic production process for (S)-2-hydroxy ketones

(Periode: 1/7/2010 - 31/6/2013)

PhD-student: Álvaro Gómez Baraibar

Chiral 2-hydroxy ketones represent versatile building blocks for organic and pharmaceutical chemistry. They can be obtained by carbo­ligation of cheap aldehyde precursors using thiamine diphosphate dependent enzymes, which are predominantly R-selective. Only recently the access toward (S)-2-hydroxy ketones was opened by conversion of the enantioselectivity using site-directed muta­gene­sis.

The project aims at the optimization and scale-up of the biocatalytic production of selected (S)-2-hydroxy ketones by means of reaction engineering. In order to increase the productivity, important factors influencing the catalytic activity of the respective biocatalyst are determined with the help of computational experimental design. Finally the implementation of different, optimally highly eco-efficient, bioreactors (batch and continuous mode) will be evaluated to achieve high space-time-yields and optimal chemo- and enantioselectivity for the desired chiral (S)-2-hydroxy ketones.

Cooperation partners: Prof. J. Woodley (DTU, DK), Dr. E. von Lieres (IBG-1, Forschungszentrum Jülich, D)

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Funded by:

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Identification and characterization of enzymes for the stereoselective enzymatic synthesis of chiral amino alcohols

(Periode: 1/11/2009 - 31/10/2012)

PhD-student: Torsten Sehl

Chiral 2-amino alcohols are versatile synthons for the synthesis of biologically active compounds and as chiral auxiliaries. A well known example is L-ephedrine, which is prepared via the chemical reductive amination of (R)-phenylacetylcarbinol.

In this project a novel two-step synthesis of 2-amino alcohols such as ephedrine and analogues, catalyzed by the combination of thiamine diphosphate (ThDP)-dependent lyases and omega-transaminases is studied. A toolbox of ThDP-dependent enzymes was assembled to access a broad range of enantio­complementary 2‑hydroxy ketones. In a follow-up reaction the reductive amination of chiral 2-hydroxy ketones, catalysed by omega‑transaminases, will yield chiral 2‑amino alcohols. Therefore a second toolbox of omega-transaminases from different organisms is currently made available and a novel screening assay for omega-transaminase activity based on the consumption of 2‑hydroxy ketones in 96-well plates is established. Promising reactions are scaled-up and analyzed in batch reactions in order to built up a platform of enantiocomplementary and diversely substitute 2‑amino alcohols.

Cooperation partners: Prof. Jörg Pietruszka (University of Duesseldorf, D), Dr. Helen Hailes (University College London, UK), Dr. John Ward (University College London, UK)

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Funded by:

Grafic CLIB

Grafic Department for innovation

Evaluation and optimisation of modular synthetic enzyme cascases by reaction optimisation and solvent engineering

PhD-student: Jochen Wachtmeister

The smart combination of enzymes from different toolboxes will make a broad range of diversely substituted chiral aminoalcohols and diols with high stereoselectivity available. In this project enzymes from different toolboxes will be purified and immobilised and combined to 2-step enzyme cascades in a modular way. Aim of the immobilisation is to remain good enzyme activity after the immobilisation procedure, stably link the enzyme even under activity reducing conditions (e.g. high substrate concentrations or addition of organic solvents) and recycle the catalyst. Those immobilised enzyme modules will than be combined flexibly in order to gain the desired product with destined stereoselectivity. To run the two step synthesis a reactor prototype will be designed.


Cooperation partners: Eric von Lieres (IBG-1, group Modeling & Simulation, D), Marion Ansorge-Schumacher (TU Dresden, D), Antje Spiess (Aachen University, D)

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Further information:

Funded by:

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in frame of the DFG Research Training Group "Bionoco" GK 11 66 at RWTH Aachen.

Process development fot the synthesis of chial diols and aminoalcohols with synthetic enzyme cascades in whole cell approaches

Postdoctoral-fellow: Dr. Andre Jakoblinnert

This Postdoctoral work aims at the synthesis of chiral diols and aminoalcohols with synthetic enzyme cascades in whole cell biotransformations. Special focus is laid on the implementation of neat solvent systems for the synthesis of desired chiral precursors. The potential of this neat solvent approach to reach high space-time-yields and facilitate downstream processing of the gained diastereomers will be evaluated.

Funded by:

Grafic of Helmholtz-Gemeinschaft

in frame of Helmholtz-Young Investigators Group `Synthetic enzyme cascades´