Hybrid Peptide–Polyketide Natural Products: Biosynthesis and Prospects toward Engineering Novel Molecules

Du, Liangcheng; Sánchez, César; Shen, Ben

doi:10.1006/mben.2000.0171

Cited by 182 publications

(125 citation statements)

References 81 publications

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“…S3). These analyses demonstrated their close relationship, which might be an outcome of long-term convergent interaction of the two systems and might yield a higher magnitude of structural diversity for the derived hybrid peptide-polyketide compounds that could be exploited as potential biological agents and drug leads (35,36).…”

Section: Discussionmentioning

confidence: 90%

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

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

304

263

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Nonribosomal peptides and polyketides are a diverse group of natural products with complex chemical structures and enormous pharmaceutical potential. They are synthesized on modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzyme complexes by a conserved thiotemplate mechanism. Here, we report the widespread occurrence of NRPS and PKS genetic machinery across the three domains of life with the discovery of 3,339 gene clusters from 991 organisms, by examining a total of 2,699 genomes. These gene clusters display extraordinarily diverse organizations, and a total of 1,147 hybrid NRPS/PKS clusters were found. Surprisingly, 10% of bacterial gene clusters lacked modular organization, and instead catalytic domains were mostly encoded as separate proteins. The finding of common occurrence of nonmodular NRPS differs substantially from the current classification. Sequence analysis indicates that the evolution of NRPS machineries was driven by a combination of common descent and horizontal gene transfer. We identified related siderophore NRPS gene clusters that encoded modular and nonmodular NRPS enzymes organized in a gradient. A higher frequency of the NRPS and PKS gene clusters was detected from bacteria compared with archaea or eukarya. They commonly occurred in the phyla of Proteobacteria, Actinobacteria, Firmicutes, and Cyanobacteria in bacteria and the phylum of Ascomycota in fungi. The majority of these NRPS and PKS gene clusters have unknown end products highlighting the power of genome mining in identifying novel genetic machinery for the biosynthesis of secondary metabolites.biosynthetic gene cluster | data mining | distribution | bioactive compound

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Section: Discussionmentioning

confidence: 90%

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

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

304

263

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“…[14][15][16] In our continued effort Isofuranonaphthoquinones from Streptomyces sp. CB01883 Z Guo et al to study the biosynthesis of hybrid peptide-polyketide natural products, [19][20][21] we sequenced the genome of Streptomyces sp. CB01883 and deleted a gene from a hybrid peptide-polyketide natural product biosynthetic gene cluster to generate the Streptomyces sp.…”

Section: Resultsmentioning

confidence: 99%

New isofuranonaphthoquinones and isoindolequinones from Streptomyces sp. CB01883

Guo

Pan

et al. 2016

J Antibiot

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“…This engineering potential stems from the fact that the individual modules of these enzymes are organized into assembly lines in which the order of modules determines the identity of the polyketide or polypeptide product (1,2). Each domain in the assembly line specifies the incorporation of an individual substrate, because the nascent peptide or polyketide is passed sequentially between domains.…”

mentioning

confidence: 99%

A singular enzymatic megacomplex from Bacillus subtilis

Straight

Fischbach²,

Walsh³

et al. 2007

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

177

168

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Nonribosomal peptide synthetases (NRPS), polyketide synthases (PKS), and hybrid NRPS/PKS are of particular interest, because they produce numerous therapeutic agents, have great potential for engineering novel compounds, and are the largest enzymes known. The predicted masses of known enzymatic assembly lines can reach almost 5 megadaltons, dwarfing even the ribosome (Ϸ2.6 megadaltons). Despite their uniqueness and importance, little is known about the organization of these enzymes within the native producer cells. Here we report that an 80-kb gene cluster, which occupies Ϸ2% of the Bacillus subtilis genome, encodes the subunits of Ϸ2.5 megadalton active hybrid NRPS/PKS. Many copies of the NRPS/PKS assemble into a single organelle-like membraneassociated complex of tens to hundreds of megadaltons. Such an enzymatic megacomplex is unprecedented in bacterial subcellular organization and has important implications for engineering novel NRPS/PKSs. bacillaene ͉ nonribosomal peptide ͉ polyketide ͉ Streptomyces N onribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzymes have received much attention in recent years, in large part because of their potential to be engineered to direct the synthesis of novel compounds with therapeutic value. This engineering potential stems from the fact that the individual modules of these enzymes are organized into assembly lines in which the order of modules determines the identity of the polyketide or polypeptide product (1, 2). Each domain in the assembly line specifies the incorporation of an individual substrate, because the nascent peptide or polyketide is passed sequentially between domains. The structures of many individual NRPS and PKS domains have been solved (3), and the structures of mammalian and fungal isoforms of the PKS-like fatty acid synthases were recently reported (4, 5), bringing into focus a picture of individual enzymatic assembly line architecture. However, much of our current knowledge of NRPSs and PKSs comes from studies in which these proteins are expressed individually in heterologous hosts, leaving much to learn about the quaternary organization and cell biology of these massive enzymes in the context of their native producer organisms.The genome of Bacillus subtilis contains the pks gene cluster, which encodes a hybrid NRPS/PKS (Figs. 1A and 4) that was considered nonfunctional until recently. A recent report has assigned the pks gene cluster to production of bacillaene based on the analysis of an orthologous gene cluster from Bacillus amyloliquefaciens FZB42 called bae (6). In concurrent work, we have solved the structure of bacillaene from B. subtilis and proposed a model for its biosynthesis (28). Bioinformatic analyses of the bacillaene synthase gene cluster reveal features in common with unconventional PKSs from streptomycetes, myxobacteria, and cyanobacteria (see Fig. 4). Examples of these features include three trans-acting acyltransferase (AT) domains that introduce substrates to the assembly line (7) and a six-protein subcluster th...

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Hybrid Peptide–Polyketide Natural Products: Biosynthesis and Prospects toward Engineering Novel Molecules

Cited by 182 publications

References 81 publications

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

New isofuranonaphthoquinones and isoindolequinones from Streptomyces sp. CB01883

A singular enzymatic megacomplex from Bacillus subtilis

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