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Chapter 26 : Heterologous Production of Polyketides in and

Author: James T. Kealey
Content Type: Reference
Publication Year: 2010

Category: Applied and Industrial Microbiology

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Abstract:

This chapter reviews the development of heterologous polyketide production systems in and , providing specific examples of polyketides produced in these hosts to illustrate the utility of the approach. The first section covers , an actinomycete that produces a number of polyketides, most notably the blue pigment actinorhodin. The success with provided motivation to develop heterologous production systems in and , user-friendly organisms for which advanced molecular biology tools and fermentation systems are available. In the second section, the development of an production system is described. Standard transformation methods are employed to introduce expression plasmids into CH999, a strain that contains a chromosomal deletion of the actinorhodin gene cluster encoding the activities required for the synthesis of the aromatic polyketide actinorhodin. The epothilones are mixed polyketides/nonribosomal peptides that have microtubule-stabilizing activities similar to those of the taxanes but are active against Taxol-resistant tumors. Many polyketides, including epothilone and certain analogs of 6-deoxyerythronolide B (6Deb), are produced at low levels in the heterologous production system. The availability of heterologous production systems, together with recent advances in synthetic biology, has accelerated studies of polyketide synthase (PKS) modularity and specificity. With further refinement of the connectivity rules, it is anticipated that virtually any polyketide can be produced in by coexpression of a suitable set of synthetic PKS modules.

Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26
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Heterologous Production of Polyketides in Streptomyces coelicolor and Escherichia coli
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Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26
/content/10.1128/9781555816827.ch26.ch26fig01
FIGURE 1
Module and domain organization of PKSs expressed in and/or : 6-MSAS (A); DEBS (B); DEBS with AT6 replaced with AT2 (malonyl-CoA specific) from RAPS (C); DEBS with KS1 inactivated by a point mutation (D); DEBS with KR2 replaced with dehydratase (DH)/enoylreductase (ER)/KR1 from RAPS, KR5 inactivated by insertion of a stuffer fragment, and AT6 replaced with AT2 (malonyl-CoA specific) from RAPS (E); and epothilone PKS (F). KSy, inactive ketosynthase; TE, thioesterase; NRPS, nonribosomal peptide synthase; MT, methyltransferase; C, condensation; A, adenylation; PCP, peptidyl carrier protein; Ox, oxidase; linker, interpeptide linker that facilitates interaction between the DEBS proteins.
10.1128/9781555816827/f0381-01_thmb.gif
10.1128/9781555816827/f0381-01.gif
Image of FIGURE 1
FIGURE 1

Module and domain organization of PKSs expressed in and/or : 6-MSAS (A); DEBS (B); DEBS with AT6 replaced with AT2 (malonyl-CoA specific) from RAPS (C); DEBS with KS1 inactivated by a point mutation (D); DEBS with KR2 replaced with dehydratase (DH)/enoylreductase (ER)/KR1 from RAPS, KR5 inactivated by insertion of a stuffer fragment, and AT6 replaced with AT2 (malonyl-CoA specific) from RAPS (E); and epothilone PKS (F). KSy, inactive ketosynthase; TE, thioesterase; NRPS, nonribosomal peptide synthase; MT, methyltransferase; C, condensation; A, adenylation; PCP, peptidyl carrier protein; Ox, oxidase; linker, interpeptide linker that facilitates interaction between the DEBS proteins.

Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26
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FIGURE 2
Polyketides heterologously produced in and/or For analogs, arrows indicate the site(s) of functional group modifications with respect to the 6dEB core structure (see the text for details).
10.1128/9781555816827/f0382-01_thmb.gif
10.1128/9781555816827/f0382-01.gif
Image of FIGURE 2
FIGURE 2

Polyketides heterologously produced in and/or For analogs, arrows indicate the site(s) of functional group modifications with respect to the 6dEB core structure (see the text for details).

Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26
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FIGURE 3
Heterologous biosynthetic pathways for (2)-methylmalonyl-CoA introduced into .
10.1128/9781555816827/f0386-01_thmb.gif
10.1128/9781555816827/f0386-01.gif
Image of FIGURE 3
FIGURE 3

Heterologous biosynthetic pathways for (2)-methylmalonyl-CoA introduced into .

Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26
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Tables

Heterologous Production of Polyketides in Streptomyces coelicolor and Escherichia coli
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555816827.ch26-1,webId=/content/author/10.1128/9781555816827.ch26-1,properties={foaf_givenname=James T., foaf_name=James T. Kealey, foaf_surname=Kealey}]]
Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26
/content/10.1128/9781555816827.ch26.ch26tab01
TABLE 1
shuttle vectors and strains
Generic image for table
TABLE 1

shuttle vectors and strains

Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26
/content/10.1128/9781555816827.ch26.ch26tab02
TABLE 2
vectors and strains
Generic image for table
TABLE 2

vectors and strains

Citation: Kealey J. 2010. Heterologous Production of Polyketides in and , p 380-390. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch26

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