Methylobacterium extorquens – a microbial cell factory for production of chemicals from methanol

Bild Forschungsprojekt

Methanol represents an attractive, very flexible feedstock for industrial biotechnology. It is efficiently synthesized via syngas from cheap natural gas and other fossil resources, but can also be derived from renewables such as wood or biogas. As a biotech feedstock, methanol does not interfere with the use of arable land for food and nutrition, and being a liquid it is easier to supply and control in bioprocesses than gaseous substrates such as syngas, methane, CO2 or H2. The host organism of our methylotrophic cell factory is Methylobacterium extorquens which assimilates methanol via the serine cycle, whereas the ethylmalonyl-CoA pathway (EMCP) is necessary for glyoxylate regeneration during growth on methanol. Intermediates of the EMCP include acetoacetyl-CoA and dicarboxylic acid CoA esters usually not found in primary metabolism of conventional host strains and represent starting intermediates for the synthesis of e.g. dicarboxylic acids and terpenoids.

Chiramet – Chiral building blocks produced from the biomass conversion product methanol

Period: 01.07.2017 - 31.06.2020
Partner: Westfälische Wilhelms-Universität (Münster, DE)

Chiracon GmbH (Luckenwalde, DE)

Insilico Biotechnology AG (Stuttgart, DE)

Max-Planck-Institut für terrestrische Mikrobiologie (Marburg, DE)

Funder: BMBF
Project Manager: Laura Pöschel, Dr. Markus Buchhaupt
Research Group: Industrial Biotechnology

Production of ethylmalonyl-CoA pathway derived dicarboxylic acids mesaconic and (2S)-methylsuccinic acid from methanol by Methylobacterium extorquens

Period: 01.01.2012 - 31.12.2014 
Partner: ETH Zürich, Stiftelsen SINTEF, Rijksuniversiteit Groningen (RUG), PROMAR AS, Universität Bielefeld, INSA Toulouse, Insilico Biotechnology AG
Funder: EU
Project Manager: Dr. Markus Buchhaupt
Research Group: Biochemical Engineering

There is a high need for sustainably producible chemical building blocks being applicable e.g. as monomers for novel bioplastics. The ethylmalonyl-CoA pathway (EMCP) harbors several CoA-esters such as ethylmalonyl-, methylsuccinyl- or mesaconyl-CoA whose free dicarboxylic acid derivatives potentially present promising synthons for chemical industry. The EMCP in Methylobacterium extorquens offers the possibility to produce these new building blocks directly from the cheap and non-food competing C-source methanol.

Suitable thioesterases for production of different EMCP-derived dicarboxylic acids were identified by in vitro assays and their expression levels in M. extorquens optimized. Productivities of different strains were compared and increased by different metabolic engineering and medium optimization strategies. A current focus of this project is the identification of acid reuptake and utilization mechanisms. Altogether we aim to establish the biotechnological production of unconventional dicarboxylic acids from methanol with high efficiency.

Engineering Methylobacterium extorquens for production of the sesquiterpenoid α-humulene

Period: 01.01.2012 - 31.12.2014       
Partner: ETH Zürich, Stiftelsen SINTEF, Rijksuniversiteit Groningen (RUG), PROMAR AS, Universität Bielefeld, INSA Toulouse, Insilico Biotechnology AG
Funder: EU
Project Manager: Dr. Markus Buchhaupt
Research Group: Biochemical Engineering

Over the last 10 to 15 years, metabolic engineering of microbes has become a versatile tool for high-level de novo synthesis of terpenoids, with the sesquiterpenoids armopha-1,4-diene, farnesene and artemisinic acid as prime examples. However, almost all cell factory approaches towards terpenoids to date have been based on sugar as the raw material, which is mainly used as a food resource and subject to high price volatilities.

This project focuses on the de novo synthesis of the sesquiterpenoid α-humulene from the abundantly available non-food carbon source methanol by metabolically engineered Methylobacterium extorquens. We want to make use of the intermediate acetoacetyl-CoA, which is part of the central metabolism of the organism but also the starting metabolite of the terpene-producing mevalonate pathway. Expression of this pathway together with prenyltransferase and a plant α-humulene synthase resulted in production of this model terpenoid. The use of a tightly controlled expression system and fine tuning of the translation rates of specific mRNAs allowed the production of 1.6g/L humulene in a bioreactor.

This project demonstrates the potential of M. extorquens as a future platform strain for the production of high-value terpenoids from the alternative carbon source methanol.




Laura Pöschel

Tel.: +49 69 / 75 64-611

Dr. Markus Buchhaupt

Tel.: +49 69 / 75 64-629    



F. Sonntag, M. Buchhaupt, J. SchraderApplied Microbiology and Biotechnology 98(10) (2014) 4533–4544

F. Sonntag, J. E. Müller, P. Kiefer, J. A. Vorholt , J.Schrader, M. BuchhauptApplied Microbiology and Biotechnology 99(8) (2015) 3407–3419

F. Sonntag, C. Kroner, P. Lubuta, R. Peyraud, A. Horst, M. Buchhaupt, J. SchraderMetabolic Engineering 32 (2015) 82-94

Buchhaupt & J. SchraderBIOspektrum 21 (6) (2015) 672-67

A. M. Ochsner, F. Sonntag, M. Buchhaupt, J. Schrader, J. A. Vorholt Applied Microbiology and Biotechnology 99 (2) (2015) 517-534

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