Product Profiles of Promiscuous Enzymes Can be Altered by Controlling In Vivo Spatial Organization

Author:

Cheah Li Chen12ORCID,Liu Lian3,Plan Manuel R.3,Peng Bingyin1245ORCID,Lu Zeyu14ORCID,Schenk Gerhard16ORCID,Vickers Claudia E.12457ORCID,Sainsbury Frank127ORCID

Affiliation:

1. Australian Institute for Bioengineering and Nanotechnology The University of Queensland St Lucia QLD 4072 Australia

2. CSIRO Future Science Platform in Synthetic Biology Commonwealth Scientific and Industrial Research Organisation (CSIRO) Dutton Park St Lucia QLD 4102 Australia

3. Metabolomics Australia (Queensland Node) The University of Queensland St Lucia QLD 4072 Australia

4. ARC Centre of Excellence in Synthetic Biology Queensland University of Technology Brisbane QLD 4000 Australia

5. School of Biological and Environmental Science Queensland University of Technology Brisbane QLD 4000 Australia

6. School of Chemistry and Molecular Biosciences The University of Queensland St Lucia QLD 4072 Australia

7. Centre for Cell Factories and Biopolymers Griffith Institute for Drug Discovery Griffith University Nathan QLD 4111 Australia

Abstract

AbstractEnzyme spatial organization is an evolved mechanism for facilitating multi‐step biocatalysis and can play an important role in the regulation of promiscuous enzymes. The latter function suggests that artificial spatial organization can be an untapped avenue for controlling the specificity of bioengineered metabolic pathways. A promiscuous terpene synthase (nerolidol synthase) is co‐localized and spatially organized with the preceding enzyme (farnesyl diphosphate synthase) in a heterologous production pathway, via translational protein fusion and/or co‐encapsulation in a self‐assembling protein cage. Spatial organization enhances nerolidol production by ≈11‐ to ≈62‐fold relative to unorganized enzymes. More interestingly, striking differences in the ratio of end products (nerolidol and linalool) are observed with each spatial organization approach. This demonstrates that artificial spatial organization approaches can be harnessed to modulate the product profiles of promiscuous enzymes in engineered pathways in vivo. This extends the application of spatial organization beyond situations where multiple enzymes compete for a single substrate to cases where there is competition among multiple substrates for a single enzyme.

Funder

Human Frontier Science Program

Australian Research Council

Commonwealth Scientific and Industrial Research Organisation

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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