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Chapter 12 : Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology
Author:
Christopher Walsh
Content Type: Monograph
Publication Year:
2003
Category: Bacterial Pathogenesis
Book DOI:
10.1128/9781555817886
Chapter DOI:
10.1128/9781555817886.ch12
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Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology, Page 1 of 2
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Abstract:
The chemistry practiced by polyketide synthases (PKSs) is closely parallel to that of fatty acid synthases (FASs), which have been extensively studied for decades to decipher mechanisms and organization and have provided precedents for understanding PKS logic. The four rings of the tetracycline family of antibiotics, such as oxytetracycline and chlortetracycline and also of tetracenomycin and the antitumor antibiotic doxorubicin are produced by type II polyketide synthases along with some partner aromatases and cyclases also expressed in the clusters. In biosynthesis of daunorubicin or doxorubicin, the starter unit is propionyl-CoA and all extender units are malonyl-CoA. In biosynthesis of daunorubicin or doxorubicin, the starter unit is propionyl-CoA and all extender units are malonyl-CoA. After nine condensation cycles a decaketidyl-S-ACP is built up, in which all 10 of the ketone groups are thought to persist without reductive modification in the acyl chain. The first cyclase, TcmN, closes three rings to make TcmF2, and TcmI closes the last ring to give the fused four-ring system analogous to the tetracycline skeleton. The macrolides of the erythromycin class contain 14-membered macrolactone rings while the tylosins have 16-membered rings. Many of the macrolide antibiotics are glycosylated, to provide hydrogen bond interactions with the ribosome 23S rRNA, highlighted by the contacts of the desosamine sugar of erythromycin to A2058. In turn, the genes that encode their biosynthesis are also found clustered with the rest of the antibiotic biosynthesis and resistance genes along with the specific glycosyltransferases.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
Figures
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-pg174
Untitled
Structural motifs in the catalytic and carrier domains of polyketide synthase assembly lines.
10.1128/9781555817886/fig-pg174_thmb.gif
10.1128/9781555817886/fig-pg174.gif
Untitled
Structural motifs in the catalytic and carrier domains of polyketide synthase assembly lines.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-1
Figure 12.1
Building blocks for (A) initiation and (B) elongation cycles by PKS assembly lines.
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10.1128/9781555817886/fig12-1.gif
Figure 12.1
Building blocks for (A) initiation and (B) elongation cycles by PKS assembly lines.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-2
Figure 12.2
(A) Chain elongation and (B) chain termination chemical steps in PKS assembly lines.
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10.1128/9781555817886/fig12-2.gif
Figure 12.2
(A) Chain elongation and (B) chain termination chemical steps in PKS assembly lines.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-3
Figure 12.3
Structure of acyl carrier protein domains from (A) holo ACP domain of Bacillus subtilis FAS, with phosphopantetheinyl prosthetic group shown in ball and stick representation; (B) apo ACP form of S. coelicolor actinorhodin synthetase.
10.1128/9781555817886/fig12-3_thmb.gif
10.1128/9781555817886/fig12-3.gif
Figure 12.3
Structure of acyl carrier protein domains from (A) holo ACP domain of Bacillus subtilis FAS, with phosphopantetheinyl prosthetic group shown in ball and stick representation; (B) apo ACP form of S. coelicolor actinorhodin synthetase.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-4
Figure 12.4
Acyl carrier protein domain: (A) apo to holo conversion by posttranslational priming with phosphopantetheine; (B) loading of holo HS-ACP with acyl groups by transthiolation via AT domain catalysis.
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10.1128/9781555817886/fig12-4.gif
Figure 12.4
Acyl carrier protein domain: (A) apo to holo conversion by posttranslational priming with phosphopantetheine; (B) loading of holo HS-ACP with acyl groups by transthiolation via AT domain catalysis.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-5
Figure 12.5
ACP interactions (A) in type I PKS and FAS, within each module; (B) in type II PKS and FAS, between separate subunits.
10.1128/9781555817886/fig12-5_thmb.gif
10.1128/9781555817886/fig12-5.gif
Figure 12.5
ACP interactions (A) in type I PKS and FAS, within each module; (B) in type II PKS and FAS, between separate subunits.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-6
Figure 12.6
Four stages to the C-C bond-forming chain elongation steps of PKS and FAS assemblies: (A) malonyl- or methylmalonyl-S-ACP formation; (B) decarboxylation to generate the carbon nucleophile; (C) the acyl-S-Cys-KS donor; (D) the product, β-keto-acyl-S-ACP.
10.1128/9781555817886/fig12-6_thmb.gif
10.1128/9781555817886/fig12-6.gif
Figure 12.6
Four stages to the C-C bond-forming chain elongation steps of PKS and FAS assemblies: (A) malonyl- or methylmalonyl-S-ACP formation; (B) decarboxylation to generate the carbon nucleophile; (C) the acyl-S-Cys-KS donor; (D) the product, β-keto-acyl-S-ACP.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-7
Figure 12.7
Three-stage four-electron reduction of the β-keto group: sequential action of KR, DH, and ER domains.
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10.1128/9781555817886/fig12-7.gif
Figure 12.7
Three-stage four-electron reduction of the β-keto group: sequential action of KR, DH, and ER domains.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-8
Figure 12.8
Proposal for incomplete redox adjustment in three cycles of a PKS assembly line.
10.1128/9781555817886/fig12-8_thmb.gif
10.1128/9781555817886/fig12-8.gif
Figure 12.8
Proposal for incomplete redox adjustment in three cycles of a PKS assembly line.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-9
Figure 12.9
Tetracyclic aromatic polyketide antibiotics generated by type II PKS: tetracycline, oxytetracycline, chlortetracycline, tetracenomycin, and doxorubicin.
10.1128/9781555817886/fig12-9_thmb.gif
10.1128/9781555817886/fig12-9.gif
Figure 12.9
Tetracyclic aromatic polyketide antibiotics generated by type II PKS: tetracycline, oxytetracycline, chlortetracycline, tetracenomycin, and doxorubicin.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-10
Figure 12.10
Modular organization of PKS producing the aromatic tetracyclic antibiotic doxorubicin.
10.1128/9781555817886/fig12-10_thmb.gif
10.1128/9781555817886/fig12-10.gif
Figure 12.10
Modular organization of PKS producing the aromatic tetracyclic antibiotic doxorubicin.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-11
Figure 12.11
The iterative chain elongation cycles of type II PKS and FAS.
10.1128/9781555817886/fig12-11_thmb.gif
10.1128/9781555817886/fig12-11.gif
Figure 12.11
The iterative chain elongation cycles of type II PKS and FAS.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-12
Figure 12.12
Polyketidyl-S enzyme intermediates: (A) daunorubicin synthase; (B) tetracycline synthase; (C) tetracenomycin synthase.
10.1128/9781555817886/fig12-12_thmb.gif
10.1128/9781555817886/fig12-12.gif
Figure 12.12
Polyketidyl-S enzyme intermediates: (A) daunorubicin synthase; (B) tetracycline synthase; (C) tetracenomycin synthase.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-13
Figure 12.13
Bond-forming reactions in the polyketidyl-S-tetracycline synthase acyl enzyme.
10.1128/9781555817886/fig12-13_thmb.gif
10.1128/9781555817886/fig12-13.gif
Figure 12.13
Bond-forming reactions in the polyketidyl-S-tetracycline synthase acyl enzyme.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-14
Figure 12.14
Doxorubicin biosynthesis: (A) C-C bond-forming steps from an enzymebound conformer; (B) DpsF-mediated cyclization of the first three rings; (C) DpsH action and postsynthase tailoring reactions.
10.1128/9781555817886/fig12-14_thmb.gif
10.1128/9781555817886/fig12-14.gif
Figure 12.14
Doxorubicin biosynthesis: (A) C-C bond-forming steps from an enzymebound conformer; (B) DpsF-mediated cyclization of the first three rings; (C) DpsH action and postsynthase tailoring reactions.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-15
Figure 12.15
Modular organization of the synthases for erythromycin and tylosin: (A) the assembly line for the erythromycin aglycone 6-DEB; (B) the assembly line for the 16- membered aglycone tylactone.
10.1128/9781555817886/fig12-15_thmb.gif
10.1128/9781555817886/fig12-15.gif
Figure 12.15
Modular organization of the synthases for erythromycin and tylosin: (A) the assembly line for the erythromycin aglycone 6-DEB; (B) the assembly line for the 16- membered aglycone tylactone.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-16
Figure 12.16
Intermediate-length acyl chains accumulating on the DEBS assembly line.
10.1128/9781555817886/fig12-16_thmb.gif
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Figure 12.16
Intermediate-length acyl chains accumulating on the DEBS assembly line.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-17
Figure 12.17
Release of the mature acyl chain from the last module by the DEBS3 TE domain acting as a cyclase to yield the macrolactone 6-DEB.
10.1128/9781555817886/fig12-17_thmb.gif
10.1128/9781555817886/fig12-17.gif
Figure 12.17
Release of the mature acyl chain from the last module by the DEBS3 TE domain acting as a cyclase to yield the macrolactone 6-DEB.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-18
Figure 12.18
Competition for different macrolactone ring sizes in the pikromycin assembly line: the 14-ring narbonolide and 12-ring 10-deoxymethynolide by cyclization from module 5 or from module 6; note the presence of the C3-keto group in pikromycin.
10.1128/9781555817886/fig12-18_thmb.gif
10.1128/9781555817886/fig12-18.gif
Figure 12.18
Competition for different macrolactone ring sizes in the pikromycin assembly line: the 14-ring narbonolide and 12-ring 10-deoxymethynolide by cyclization from module 5 or from module 6; note the presence of the C3-keto group in pikromycin.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-19
Figure 12.19
Five enzymatic steps to convert 6-DEB to erythromycin A.
10.1128/9781555817886/fig12-19_thmb.gif
10.1128/9781555817886/fig12-19.gif
Figure 12.19
Five enzymatic steps to convert 6-DEB to erythromycin A.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
/content/10.1128/9781555817886.chap12.fig12-20
Figure 12.20
Transformations to produce TDP-D-desosamine and TDP-L-mycarose from TDP-4-keto-6-deoxyglucose in erythromycin assembly.
10.1128/9781555817886/fig12-20_thmb.gif
10.1128/9781555817886/fig12-20.gif
Figure 12.20
Transformations to produce TDP-D-desosamine and TDP-L-mycarose from TDP-4-keto-6-deoxyglucose in erythromycin assembly.
Citation:
Walsh C.
2003.
Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology,
p 174-193.
In
Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555817886.ch12
References
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