Merging Chemical Synthesis and Biosynthesis: A New Chapter in the Total Synthesis of Natural Products and Natural Product Libraries

Kirschning, Andreas; Hahn, Frank

doi:10.1002/anie.201107386

Cited by 161 publications

(94 citation statements)

References 57 publications

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“…Total synthesis of natural products and their analogues, especially for structure-activity relationship (SAR) studies, has often been difficult and cost-ineffective due to their structural complexities 6 . However, given the larger chemical space accessible by total synthesis compared to enzyme-catalysed biosynthesis, a combination of both synthetic routes (also known as semi-synthesis) to generate drug screening libraries has become increasingly common 7 .…”

Section: Introductionmentioning

confidence: 99%

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

Lai¹,

Obled²,

Chee³

et al. 2017

Preprint

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The next frontier in drug discovery could be the semi-synthesis of non-natural, xenobiotic compounds combining both natural product biosynthesis and synthetic chemistry. However, the required tools and underlying engineering principles are yet to be fully understood. One way to investigate non-natural product biosynthesis is to probe the substrate promiscuity of a clinically relevant biosynthesis pathway. Violacein is a bisindole compound produced by the VioABCDE biosynthesis pathway using L-tryptophan as the starting substrate. Previous studies have shown that violacein exhibits antimicrobial properties, and synthetic analogues of violacein might give rise to new targets for therapeutic development to combat antimicrobial resistance. By adding seven types of tryptophan analogues available commercially, 62 new violacein or deoxyviolacein analogues were generated with a synthetic violacein biosynthesis pathway expressed in Escherichia coli, demonstrating the promiscuity of violacein biosynthesis enzymes. Growth inhibition assays against Bacillus subtilis, a Gram-positive bacterium, were carried out to measure growth inhibitory activity of violacein analogues compared to violacein. In addition, we show that four new 7-chloro analogues of violacein or deoxyviolacein can be generated in vivo by combining the rebeccamycin and violacein biosynthesis pathways and purified 7-chloro violacein was found to have similar growth inhibitory activity compared to violacein. Structural studies of VioA revealed active site residues that are important for catalytic activity, and further pathway recombination with VioA homologues in related bisindole pathways may lead to more efficient enzymes that would accept tryptophan analogues more readily.

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Section: Introductionmentioning

confidence: 99%

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

Lai¹,

Obled²,

Chee³

et al. 2017

Preprint

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“…With their complex structures often precluding effective in vitro synthesis, many clinical derivatives of natural products are created by semisynthesis, a process whereby the natural product is chemically modified after isolation from a biological source (4)(5)(6). However, the modular nature of NRPS enzymes offers enticing prospects for targeted modification of products at a biosynthetic level by altering the substrate specificity of individual modules.…”

mentioning

confidence: 99%

Biosynthesis of Novel Pyoverdines by Domain Substitution in a Nonribosomal Peptide Synthetase of Pseudomonas aeruginosa

Calcott

Owen

Lamont

et al. 2014

Appl Environ Microbiol

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dPyoverdine is a fluorescent nonribosomal peptide siderophore made by fluorescent pseudomonads. The Pseudomonas aeruginosa nonribosomal peptide synthetase (NRPS) PvdD contains two modules that each incorporate an L-threonine residue at the C-terminal end of pyoverdine. In an attempt to generate modified pyoverdine peptides, we substituted alternative-substratespecifying adenylation (A) and peptide bond-catalyzing condensation (C) domains into the second module of PvdD. When just the A domain was substituted, the resulting strains produced only wild-type pyoverdine-at high levels if the introduced A domain specified threonine or at trace levels otherwise. The high levels of pyoverdine synthesis observed whenever the introduced A domain specified threonine indicated that these nonnative A domains were able to communicate effectively with the PvdD C domain. Moreover, the unexpected observation that non-threonine-specifying A domains nevertheless incorporated threonine into pyoverdine suggests that the native PvdD C domain exhibited stronger selectivity than these A domains for the incorporated amino acid substrate (i.e., misactivation of a threonine residue by the introduced A domains was more frequent than misincorporation of a nonthreonine residue by the PvdD C domain). In contrast, substitution of both the C and A domains of PvdD generated high yields of rationally modified pyoverdines in two instances, these pyoverdines having either a lysine or a serine residue in place of the terminal threonine. However, C-A domain substitution more commonly yielded a truncated peptide product, likely due to stalling of synthesis on a nonfunctional recombinant NRPS template.

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“…Natural polyketides from diverse microorganisms also deliver novel scaffolds that can be exploited in drug discovery programs by semisynthetic modification and combined chemical and biosynthetic approaches (4,5) and as inspiration for total synthesis and combinatorial chemistry (6,7). A complementary approach is combinatorial biosynthesis, which strives to reengineer biosynthetic pathways to generate novel polyketide scaffolds by one-pot, onestep synthesis via fermentation of recombinant microorganisms.…”

mentioning

confidence: 99%

Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases

Zhou

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Combinatorial biosynthesis aspires to exploit the promiscuity of microbial anabolic pathways to engineer the synthesis of new chemical entities. Fungal benzenediol lactone (BDL) polyketides are important pharmacophores with wide-ranging bioactivities, including heat shock response and immune system modulatory effects. Their biosynthesis on a pair of sequentially acting iterative polyketide synthases (iPKSs) offers a test case for the modularization of secondary metabolic pathways into "build-couple-pair" combinatorial synthetic schemes. Expression of random pairs of iPKS subunits from four BDL model systems in a yeast heterologous host created a diverse library of BDL congeners, including a polyketide with an unnatural skeleton and heat shock response-inducing activity. Pairwise heterocombinations of the iPKS subunits also helped to illuminate the innate, idiosyncratic programming of these enzymes. Even in combinatorial contexts, these biosynthetic programs remained largely unchanged, so that the iPKSs built their cognate biosynthons, coupled these building blocks into chimeric polyketide intermediates, and catalyzed intramolecular pairing to release macrocycles or α-pyrones. However, some heterocombinations also provoked stuttering, i.e., the relaxation of iPKSs chain length control to assemble larger homologous products. The success of such a plug and play approach to biosynthesize novel chemical diversity bodes well for bioprospecting unnatural polyketides for drug discovery.secondary metabolites | fungal genetics

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Merging Chemical Synthesis and Biosynthesis: A New Chapter in the Total Synthesis of Natural Products and Natural Product Libraries

Cited by 161 publications

References 57 publications

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

Biosynthesis of Novel Pyoverdines by Domain Substitution in a Nonribosomal Peptide Synthetase of Pseudomonas aeruginosa

Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases

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