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Enzymatic Synthesis of Optically Pure (S)-alcohols by Ethylbenzene Dehydrogenase
Jerzy Haber Institute of Catalysis and Surface Chemistry Poland flag Poland
Abstract ID:
Optically pure chiral alcohols are valuable synthons for a range of API and fine chemicals. Biological methods of their synthesis provide a high enantiopurity unmatched by chemical synthetic methods. The method can be used to synthesize the high value sec...
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Chiral alcohols are important building blocks for the synthesis of fine chemicals and pharmaceuticals. Many of them are produced biotechnologically via enantioselective reduction of the respective ketones by various alcohol dehydrogenases. The available enzymes exhibit a wide range in substrate and coenzyme specificities, reaction rates and enantiomeric excesses of the products, and economically feasible processes have been implemented with a number of model enzymes, particularly by coupling the ketone reduction reaction with cost-efficient regeneration techniques for the required NAD(P)H cofactors. However, the process is limited to ketones contained within the substrate range of the used enzymes and their compatibility with the NAD(P)H regeneration process. A fundamentally new process for chiral alcohol production may be derived from the recent discovery that the first enzyme of the anaerobic ethylbenzene metabolic pathway, ethylbenzene dehydrogenase (EbDH), produces (almost) exclusively (S)-alcohols from ethylbenzene and many alternative substrates. This novel process is not limited by equilibrium issue (as oxidation is energetically favorable) and is fastest for compounds which are difficult to reduce with the classical ketone-reduction approach.

EbDH is a periplasmic heterotrimeric molybdenum enzyme of the DMSO reductase family and contains a Mo-bis-molybpdopterin guanine dinucleotide (MGD) cofactor in its active site, which is responsible for the stereospecific hydroxylation of the substrates with water. The extremely large substrate range (up to date 33 alkylatomatic and alkylheterocyclic compounds) and the strongly stereospecific hydroxylation reaction endorse a biotechnological application of EbDH for the production of chiral alcohols. This is a completely novel route to this group of fine chemicals. EbDH offers a very strong region- and stereospecificity combined with a very large substrate range which may even be further extended by the use of similar enzymes from other anaerobic hydrocarbon degraders or by mutagenesis studies on EbDH.

EbDH can be applied for biotechnological conversion assays in an easily obtained “technical grade” that is much more stable than pure enzyme, regarding storage, catalytic longevity and retained activity after immobilization. During the demonstration experiments chiral alcohol concentrations of 0.4 to 0.5 g/L were obtained, which indicates that the process may become economically feasible. The immobilization process does not compromise high reaction enantioselectivity of EbDH observed for homogenous enzyme. Finally our recently developed overexpression system provides much easier (i.e. cheaper) access to the enzyme source.

Competitive advantages

- Novel approach to chiral alcohol synthesis (not blocked by any patents or licenses)

- Complimentary synthetic rout to usual ketone reduction

- Cheap composition of reaction mixture

- Easy separation of product from reaction mixture

- Existing overexpression system for enzyme production

- No GMM in catalyst formulation (immobilized enzyme)

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We are looking for an industrial partner willing to develop our technology into a market ready product.
FEATURED
Last Updated Jun 2016
Technology Type PLATFORM
Phase of Development PRECLINICAL
PRIVATE INSTITUTE