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Chapter 13 : Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics

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Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, Page 1 of 2

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Abstract:

A large percentage of the peptidic natural products that have antibiotic activity are produced by nonribosomal peptide synthetases (NRPSs). The NRPSs catalysts have organizational analogies to the type I polyketide synthases (PKSs) as multidomainal catalysts organized into modules, with multiple modules collected in one or more protein subunits. These include the L-aminoadipyl-L-cysteinyl-D-valine (ACV) tripeptide precursor to the β-lactam families of antibiotics, the channel-forming tyrocidine and gramicidin S, and the topical antibiotic bacitracin. The ACV synthetase has three modules in a polypeptide of 450 kDa, while the heptapeptide scaffold of vancomycin or chloroeremomycin is assembled by three subunits with three, three, and one module, respectively. The enzymatic transformation of the acyclic ACV tripeptide to the bicyclic β-lactam structure of penicillins is catalyzed by a single nonheme Fe enzyme, isopenicillin N synthase (IPNS), that reduces cosubstrate O by four electrons to two molecules of water. In the chloroeremomycin cluster there are three hemeproteins, ORFs 7 to 9, and there are two homologs in the bahlimycin cluster that are implicated in genetic knockouts as the cross-linking catalysts. These putative cytochrome P450s could generate the phenolic radicals in the side chains of the heptapeptide substrates to initiate the cross-linkings. In most of the lipopeptide NRPS clusters sequenced to date, the acyltransferase responsible for N-acylation of the N-terminal amino acid does not map with the biosynthetic cluster and little is known about specificity. In the case of mycosubtilin, the first five domains of the MycA subunit are dedicated to construction of the C-β-NH-acyl group.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Figures

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Untitled

Structural motifs in the catalytic and carrier domains of nonribosomal peptide synthetases.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.1
Figure 13.1

Examples of antibiotics made on nonribosomal peptide synthetase assembly lines.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.2
Figure 13.2

NRPS assembly line organization: the three modules of ACV synthetase.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.3
Figure 13.3

Core domains of an NRPS elongation module: C-A-PCP and conversion of Apo PCP to Holo PCP domains by posttranslational phosphopantetheinylation.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.4
Figure 13.4

Two steps of NRPS adenylation domain catalysis: selection and activation of amino acid as tightly bound aminoacyl-AMP; aminoacyl group transfer to generate the covalent aminoacyl--PCP intermediate.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.5
Figure 13.5

Representative nonproteinogenic amino acids selected for chain incorporation by NRPS A domains.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.6
Figure 13.6

C domain action in NRPS catalysis: peptide bond condensation and elongation via peptidyl chain transfer to the downstream PCP domain.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.7
Figure 13.7

(A) A-PCP two-domain chain initiation modules; (B) C-A-PCP-TE fourdomain chain termination modules and three different pathways of chain termination.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.8
Figure 13.8

Domain function in the ACV synthetase assembly Line: (A) action of the E domain to make D-Val--PCP; (B) chain termination by the TE domain through deacylation of a tripeptidyl--Ser-TE acyl enzyme intermediate.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.9
Figure 13.9

Thirty genes clustered for chloroeremomycin biosynthesis.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.10
Figure 13.10

A 24-domain, seven-module assembly line for the heptapeptide backbone of chloroeremomycin or vancomycin synthetase.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.11
Figure 13.11

The NRPS assembly line of tyrocidine synthetase.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.12
Figure 13.12

Bacitracin chain release by intramolecular macrolactamization by the TE domain of bacitracin synthetase: making the Lys-Asn isopeptide bond.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.13
Figure 13.13

Action of the cyclization domain of bacitracin synthetase to create the thiazoline ring from Cys-Leu.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.14
Figure 13.14

Double cyclization of ACV to the -lactam skeleton of penicillins by isopenicillin N synthase.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.15
Figure 13.15

Expansion of the five ring of penicillins to the six ring of cephalosporins by expandase (deacetoxycephalosporin C synthase).

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.16
Figure 13.16

X-ray structure of IPNS with active-site iron and bound ACV substrate.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.17
Figure 13.17

Proposed mechanisms for the formation of the first ring (-lactam) by IPNS.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.18
Figure 13.18

Formation of the second ring of penicillins by IPNS with reduction of the ferryl intermediate.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.19
Figure 13.19

Ring expansion by DAOCS with reduction of the ferryl intermediate.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.20
Figure 13.20

The tandem action of CarA-C to generate the carbapenem nucleus.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.21
Figure 13.21

Three oxidative transformations by CAS during construction of clavaminate.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.22
Figure 13.22

Rigidifying cross-links connect the aryl side chains in the vancomycin family of antibiotics.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.23
Figure 13.23

Proposed phenoxy radical cyclization mechanisms for hemeprotein-mediated cross-linking in the vancomycin family.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.24
Figure 13.24

Three regiospecific glycosyltransferases for tailoring of the aglycone in chloroeremomycin maturation.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.25
Figure 13.25

Lipopeptides made by nonribosomal peptide synthetase assembly lines.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.26
Figure 13.26

-Acylation machinery at the N terminus of the mycosubtilin synthetase assembly line.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.27
Figure 13.27

NRP-PK hybrids: bleomycin, pristinamycin IIA, and rifampin, a member of the rifamycin family.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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Image of Figure 13.28
Figure 13.28

NRP and PK modules in the (A) rifamycin and (B) bleomycin assembly lines.

Citation: Walsh C. 2003. Enzymatic Assembly Lines for Nonribosomal Peptide Antibiotics, p 194-219. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch13
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