Engineering intracellular malonyl-CoA availability in microbial hosts and its impact on polyketide and fatty acid synthesis

Applied Microbiology and Biotechnology, vol. 104, pp. 6057–6065

Abstract

Malonyl-CoA is an important central metabolite serving as the basic building block for the microbial synthesis of many pharmaceutically interesting polyketides, but also fatty acid-derived compounds including biofuels. Especially Saccharomyces cerevisiae, Escherichia coli, and Corynebacterium glutamicum have been engineered towards microbial synthesis of such compounds in recent years. However, developed strains and processes often suffer from insufficient productivity. Usually, tightly regulated intracellular malonyl-CoA availability is regarded as the decisive bottleneck limiting overall product formation. Therefore, metabolic engineering towards improved malonyl-CoA availability is essential to design efficient microbial cell factories for the production of polyketides and fatty acid derivatives. This review article summarizes metabolic engineering strategies to improve intracellular malonyl-CoA formation in industrially relevant microorganisms and its impact on productivity and product range, with a focus on polyketides and other malonyl-CoA-dependent products.Key Points• Malonyl-CoA is the central building block of polyketide synthesis.• Increasing acetyl-CoA supply is pivotal to improve malonyl-CoA availability.• Improved acetyl-CoA carboxylase activity increases availability of malonyl-CoA.• Fatty acid synthesis as an ambivalent target to improve malonyl-CoA supply.

Authors 2

1. Lars Milke

   Forschungszentrum Jülich

   Affiliation as printed

   Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany

2. Jan Marienhagen corresponding Aachen Institute of Biotechnology

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Bioeconomy Science Center (BioSC), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany. j.marienhagen@fz-juelich.de

   Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany. j.marienhagen@fz-juelich.de

   Institute of Biotechnology, RWTH Aachen University, Worringer Weg 3, 52074, Aachen, Germany. j.marienhagen@fz-juelich.de

   Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany