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Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion

I Borodina, J Siebring, J Zhang, Colin P Smith, Geertje Van Keulen, Lubbert Dijkhuizen, Jens Nielsen, Geertje Van Keulen Orcid Logo

Journal of Biological Chemistry, Volume: 283, Issue: 37, Pages: 25186 - 25199

Swansea University Author: Geertje Van Keulen Orcid Logo

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DOI (Published version): 10.1074/jbc.M803105200

Abstract

Streptomycetes are exploited for production of a wide range of secondary metabolites, and there is much interest in enhancing the level of production of these metabolites. Secondary metabolites are synthesized in dedicated biosynthetic routes, but precursors and co-factors are derived from the prima...

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Published in: Journal of Biological Chemistry
ISSN: 0021-9258
Published: Journal of Biological Chemistry 2008
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URI: https://cronfa.swan.ac.uk/Record/cronfa9996
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spelling 2013-09-20T11:41:37.9478315 v2 9996 2012-03-21 Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion 6b2c798924ac19de63e2168d50b99425 0000-0002-6044-1575 Geertje Van Keulen Geertje Van Keulen true false 2012-03-21 BMS Streptomycetes are exploited for production of a wide range of secondary metabolites, and there is much interest in enhancing the level of production of these metabolites. Secondary metabolites are synthesized in dedicated biosynthetic routes, but precursors and co-factors are derived from the primary metabolism. High level production of antibiotics in streptomycetes therefore requires engineering of the primary metabolism. Here we demonstrate this by targeting a key enzyme in glycolysis, phosphofructokinase, leading to improved antibiotic production in Streptomyces coelicolor A3(2). Deletion of pfkA2 (SCO5426), one of three annotated pfkA homologues in S. coelicolor A3(2), resulted in a higher production of the pigmented antibiotics actinorhodin and undecylprodigiosin. The pfkA2 deletion strain had an increased carbon flux through the pentose phosphate pathway, as measured by 13C metabolic flux analysis, establishing the ATP-dependent PfkA2 as a key player in determining the carbon flux distribution. The increased pentose phosphate pathway flux appeared largely because of accumulation of glucose 6-phosphate and fructose 6-phosphate, as experimentally observed in the mutant strain. Through genome-scale metabolic model simulations, we predicted that decreased phosphofructokinase activity leads to an increase in pentose phosphate pathway flux and in flux to pigmented antibiotics and pyruvate. Integrated analysis of gene expression data using a genome-scale metabolic model further revealed transcriptional changes in genes encoding redox co-factor-dependent enzymes as well as those encoding pentose phosphate pathway enzymes and enzymes involved in storage carbohydrate biosynthesis. Journal Article Journal of Biological Chemistry 283 37 25186 25199 Journal of Biological Chemistry 0021-9258 7 7 2008 2008-07-07 10.1074/jbc.M803105200 http://www.jbc.org/content/283/37/25186 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2013-09-20T11:41:37.9478315 2012-03-21T16:17:13.0000000 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine I Borodina 1 J Siebring 2 J Zhang 3 Colin P Smith 4 Geertje Van Keulen 5 Lubbert Dijkhuizen 6 Jens Nielsen 7 Geertje Van Keulen 0000-0002-6044-1575 8
title Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion
spellingShingle Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion
Geertje Van Keulen
title_short Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion
title_full Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion
title_fullStr Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion
title_full_unstemmed Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion
title_sort Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion
author_id_str_mv 6b2c798924ac19de63e2168d50b99425
author_id_fullname_str_mv 6b2c798924ac19de63e2168d50b99425_***_Geertje Van Keulen
author Geertje Van Keulen
author2 I Borodina
J Siebring
J Zhang
Colin P Smith
Geertje Van Keulen
Lubbert Dijkhuizen
Jens Nielsen
Geertje Van Keulen
format Journal article
container_title Journal of Biological Chemistry
container_volume 283
container_issue 37
container_start_page 25186
publishDate 2008
institution Swansea University
issn 0021-9258
doi_str_mv 10.1074/jbc.M803105200
publisher Journal of Biological Chemistry
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://www.jbc.org/content/283/37/25186
document_store_str 0
active_str 0
description Streptomycetes are exploited for production of a wide range of secondary metabolites, and there is much interest in enhancing the level of production of these metabolites. Secondary metabolites are synthesized in dedicated biosynthetic routes, but precursors and co-factors are derived from the primary metabolism. High level production of antibiotics in streptomycetes therefore requires engineering of the primary metabolism. Here we demonstrate this by targeting a key enzyme in glycolysis, phosphofructokinase, leading to improved antibiotic production in Streptomyces coelicolor A3(2). Deletion of pfkA2 (SCO5426), one of three annotated pfkA homologues in S. coelicolor A3(2), resulted in a higher production of the pigmented antibiotics actinorhodin and undecylprodigiosin. The pfkA2 deletion strain had an increased carbon flux through the pentose phosphate pathway, as measured by 13C metabolic flux analysis, establishing the ATP-dependent PfkA2 as a key player in determining the carbon flux distribution. The increased pentose phosphate pathway flux appeared largely because of accumulation of glucose 6-phosphate and fructose 6-phosphate, as experimentally observed in the mutant strain. Through genome-scale metabolic model simulations, we predicted that decreased phosphofructokinase activity leads to an increase in pentose phosphate pathway flux and in flux to pigmented antibiotics and pyruvate. Integrated analysis of gene expression data using a genome-scale metabolic model further revealed transcriptional changes in genes encoding redox co-factor-dependent enzymes as well as those encoding pentose phosphate pathway enzymes and enzymes involved in storage carbohydrate biosynthesis.
published_date 2008-07-07T03:11:29Z
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score 11.012678

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