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Chapter 30 : Assembly of Peptide Antibiotics on Modular Protein Templates

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Abstract:

Nonribosomal peptide synthetase (NRPS) domains and associated enzymes represent the molecular toolbox used by nature for the assembly of structurally complex peptides. In order to exploit this toolbox for the biosynthesis of novel peptide antibiotics, one needs to understand the mechanism of each catalytic domain as well as the interplay between domains and modules that facilitates the assembly of a productive biosynthetic template. One hallmark of nonribosomal peptide antibiotics is the presence of D-amino acids, often in substantial abundance. This chapter focuses on how nature utilizes catalytic building blocks for the assembly of biosynthetic templates for structurally complex peptide antibiotics. The following examples from species were selected because their entire set of genes is known. The tyrocidine system is particularly well understood with respect to variants of the product that exhibit amino acid substitutions. Although the pathway of the DAla incorporation is only partially characterized, conclusions can be drawn from the corresponding genes and enzymes in . First, DAla is activated as alanyl adenylate by the D-alanyl-D-alanine carrier protein ligase Del and then transferred to the DAla carrier protein Dcp. The first experiments to demonstrate the general feasibility of engineering hybrid NRPSs were AT minimal module swaps in various positions of the surfactin biosynthetic operon. NRPSs produce an abundance of bioactive peptides with wide structural diversity. The manifested natural modularity makes them promising targets for the construction of hybrid synthetases.

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 1
FIGURE 1

The multiple carrier thiotemplate mechanism illustrated on the biosynthetic template of tyrocidine A. (A) Three NRPSs encoded by the genes act in concert for the stepwise assembly of the cyclic decapeptide. (B) The synthetases are composed of one, three, and six modules, respectively, which can be further subdivided into functional domains. Substrates are recognized and adenylated by action of A domains and subsequently covalently tethered to the thiol group of cofactor 4'-Ppant, which has been posttranslationally introduced onto each Τ domain. In analogy to fatty acid and polyketide biosynthesis, these carrier domains serve as an anchor of the various peptidyl intermediates. C domains catalyze peptide bond formation and chain translocation between the nascent peptidyl-S-Ppant intermediates and the downstream monomeric aminoacyl-S-Ppant. At positions 1 and 4, Ε domains convert -Phe moieties into the -isomer, and a terminal Te domain acts as a cyclase and releases the final product, tyrocidine (C).

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 2
FIGURE 2

Domain organization of NRPS modules. (A) The simplest NRPS template feasible is constituted of three different types of module: an initiation module (domain structure: A + T) for the activation of the first amino acid, elongation modules (CAT) for every additional monomeric building unit to be activated and incorporated into the nascent peptide chain, and a termination module (CATTe), which catalyzes the final elongation step, as well as product release. (B) Optional tailoring domains can integrate in NRPS modules, in order to modify the activated monomers and to further functionalize the synthesized peptide product. PKS modules resemble NRPS modules, and additional domains may be integrated to catalyze optional reduction steps or Ν methylation. Abbreviations: A, adenylation domain; ACP, acyl-carrier protein; AT, acyl transferase domain; C, condensation domain; Cy, cyclization domain; DH, dehydratase domain; E, epimerization domain; ER, enoylreductase domain; -formyltransferase domain; Kr, ketoreductase domain; KS, ketosynthase domain; -methyltransferase domain; Ox, oxidoreductase domain; R, reductase domain; T, thiolation domain (synonymous with PCP, peptidyl carrier protein); and Te, thioesterase domain.

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 3
FIGURE 3

Priming of NRPS modules by designated Ppant transferases. The conversion of an inactive apo Τ domain (intimated by gray balls) into functional HS-Ppant holo form is catalyzed by a cognate Ppant transferase such as Sfp, which directs the nucleophilic attack of the hydroxyl group of an invariant serine residue to the β-phosphate of CoASH.

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 4
FIGURE 4

Key reactions catalyzed by NRPS modules. (A) Paralleling the first activation step of aminoacyl tRNA synthetases, an A domain selects the cognate amino acid from the pool of available substrates and reversibly generates the corresponding aminoacyl adenylate. (B) The activated aminoacyl moiety is then covalently tethered to the sulfhydryl group of cofactor Ppant of the paired holo Τ domain. (C) Peptide bond formation and chain translocation occurs under catalytic control of a C domain, which catalyzes the nucleophilic attack of the monomeric aminoacyl-S-Ppant onto the nascent peptidyl chain situated at the immediately upstream holo Τ domain. Organization of these essential domains within NRPS modules is shown in Fig. 2 .

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 5
FIGURE 5

Reactions catalyzed by optional domains. Additional domains have been observed in various biosynthetic systems, which catalyze an in situ substrate modification or alternate modes of initiation and elongation. (A) Alternate modes of initiation are Ν acylation and Ν formylation. While in the first case the corresponding NRPS starts with a CAT elongation module and presumably requires an acyl-S-Ppant ACP donor as an initiator, in the latter an AT initiation module is preceded by an F domain, which depends on cosubstrate formyl tetrahydrofolate. (B) A Cy domain that substitutes the usual C domain in an elongation module effects an alternate mode of elongation, the coupled condensation and heterocyclization. The nucleophilic acceptor can be cysteinyl, seryl, or threonyl-S-Ppant, and the reaction leads to the formation of a thiazoline or oxazoline, respectively. This heterocyclic ring can be further oxidized by an FAD-dependent Ox domain to yield the corresponding thiazole or oxazole. (C) Typical modification reactions of nascent aminoacyl- and pep-tidyl-S-Ppant substrates are epimerization and Ν methylation. While the first reaction affects the nascent aminoacyl or peptidyl-S-Ppant substrate and is catalyzed by an Ε domain, Ν methylation always occurs on stage of the monomeric aminoacyl-S-Ppant and is affected by an Μ domain that depends on S-adenosylmethionine (SAM) as a cosubstrate. The location of optional domains within NRPS modules is shown in Fig. 2 .

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 6
FIGURE 6

Product release. (A) In a bacterial NRPS, a Te domain located at the very end of a C-terminal elongation module usually effects product release. Depending on the particular system, different modes of action of the Te domain have been observed, which are exemplified on a hypothetical tripeptide. The wavy line symbolizes any side chain that contains a nucleophilic moiety XH. (a) Hydrolysis of a peptidyl-S-Ppant intermediate yields the corresponding linear peptide (e.g., ACV [δ-(-α-aminoadipyl)--cysteinyl--valine] [ ]). (b) Head-to-tail condensation gives a cyclic peptide (e.g., tyrocidine [ ]). (c) Condensation of the carboxyl terminus with a nucleophilic side chain amine or hydroxyl leads to a branched-cyclic peptide or lactone (e.g., bacitracin [ ]). (d) Oligomerization and final cyclization gives a polymeric cyclic peptide (e.g., enterobactin [ ]). (B) An alternate, reductive mode of termination is effected by an NAD(P)H cofactor-dependent R domain that formally translocates the generated peptide to a hydride ion, yielding a C-terminal semi-aldehyde ( ).

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 7
FIGURE 7

Biosynthetic gene clusters as revealed by the genome project of MR 168. The organization of the biosynthetic genes for surfactin (A), an as yet unknown mixed NRPS/PKS product (B), fengycin (C), bacillibactin (D), and lipoteichoic acid (E) are shown. Structural genes, promoters, and transcriptional termination loops are indicated as predicted from the genome project (http://genolist.pasteur.fr/SubtiList/) ( ). In panel D, the corrected gene organization is shown as revealed by resequencing ( ). (F) Physical map of MR 168, illustrating the relative localization of the NRPS and PKS clusters.

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Image of FIGURE 8
FIGURE 8

Prospects for the generation of hybrid NRPSs. Different strategies have been used to exploit the natural modularity of NRPS and to recombine domains and modules on the genetic level. Gene segments that encode functional domains and modules are shown to illustrate the practical modifications of an existing NRPS template.

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30
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Tables

Generic image for table
TABLE 1

Domain organization and structure for some antibiotics

Presentation of domain organization is in accordance with the one- and two-letter code ( ): A, adenylation domain; ACP, acyl carrier protein; AL, acyl-CoA ligase; AMT, aminotransferase domain; AT, acyl transferase domain; C, condensation domain; Cy, cyclization domain; E, epimerization domain; KS, ketosynthase domain; T, thiolation (PCP) domain; and Te, thioesterase domain. For clarity of the presentation, PKS domains are separated by a dot; modules are separated by a hyphen.

References dealing with the sequencing and/or cloning of biosynthetic genes.

References dealing with biochemical characterization of biosynthetic gene products.

ΝA, none available.

Citation: Stachelhaus T, Mootz H, Marahiel M. 2002. Assembly of Peptide Antibiotics on Modular Protein Templates, p 415-435. In Sonenshein A, Losick R, Hoch J (ed), and Its Closest Relatives. ASM Press, Washington, DC. doi: 10.1128/9781555817992.ch30

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