Biocombinatorial Approaches for Drug Finding

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Bit scores are shown in red if they equal or more and in white if they equal or less. The self-hits in the diagonal line were omitted for clarity. There are a total of 15, biosynthetic and tailoring enzymes identified from the 2, bacterial gene clusters Table 1.

Surprisingly, nonmodular enzymes showed an extraordinary abundance 8, compared with others with multiple domains Fig. Nearly every domain type was found as a nonmodular enzyme Fig. Some modification domains of aminotransferase and polyketide cyclase were found almost exclusively as separate proteins.

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Once again, many of the nonmodular enzymes are also present in hybrid clusters, such as the AT proteins from trans-AT clusters Fig. A total of 15, enzymes were found in 2, gene clusters in bacteria. These enzymes were grouped according to the number of their domains. The nonmodular enzymes showed high levels of abundance 8, compared with other multidomain enzymes.


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Most of the nonmodular enzymes are found together with multidomain enzymes in gene clusters. However, one fifth of them 1, occurred in close genomic vicinity with each other and form into gene clusters Fig. Our data mining located a total of The majority , Although these type II-like gene clusters were found in multiple lineages of bacteria Dataset S4 , many of the NRPS clusters are from proteobacteria and appear to be related to siderophore biosynthesis.

For example, a total of 16 putative brucebactin gene clusters, in which the condensation, adenylation, and carrier domains are presented as separated proteins, were found from sequenced Brucella genomes. Examples of gene clusters comprised of nonmodular enzymes. A total of gene clusters formed mostly by nonmodular enzymes were found in bacteria.

Examples of two hybrid gene clusters and a putative acinetobactin biosynthesis gene cluster are shown. The ABC transport system proteins are indicated in blue, other tailoring enzymes in light green, and hypothetical proteins in gray. Our analysis showed that the domains of NRPS and type I PKS display gradient organizations among gene clusters, from fully dissociated nonmodular enzymes to a highly modular mode in massive multidomain enzymes.

For example, the iron-chelating siderophore acinetobactin biosynthesis gene clusters in Acinetobacter baumannii were found with many nonmodular enzymes and grouped as type II-like gene clusters in this study Dataset S4. The mono- and didomain enzymes of these gene clusters can be mapped to the six-domain VibF in the vibriobactin biosynthesis gene cluster Recently, the well-conserved tandem heterocyclization domains were also found in the siderophore serratiochelin gene clusters These siderophores share one or more 2,3-dihydroxyphenymethyloxazoline-acyl groups, which is synthesized by the domains of modular VibF in Vibrio cholerae 29 , and also likely by similar domains but organized as SchF1, -2, and -3 in Serratia 28 and BsaD, -A, and -B in A.

Although the biosynthesis of parabactin in Paracoccus denitrificans is still unknown, its 2-hydroxyphenymethyloxazoline-acyl group appears to be synthesized by the shown modular enzyme Fig. Gene clusters with similar domains were also detected from strains of Pseudomonas , Marinomonas , Halomonas , and Agrobacterium , which may also produce siderophores with similar structures Fig. The first condensation domain C1 of VibF was missing from some gene clusters, likely due to its dispensability in biosynthesis Phylogenetic analysis of condensation domains C2 from siderophore biosynthetic enzymes with gradient-domain organizations.

The neighbor-joining tree was constructed by MEGA5. These siderophore biosynthetic pathways share an unusual pair of tandem heterocyclization domains and others with similar composition but in gradient organizations, which are congruent with the phylogeny of the C2 domains. These domains are responsible for the biosynthesis of the 2,3-dihydroxyphenymethyloxazoline-acyl group, which is synthesized by the double heterocyclization H domains from a 2,3-dihydroxybenzoate and an l -threonine that is activated by the adenylation A domain, and fused by the condensation C domain C2 with other substrates.

The activated l -threonine and the derived group are both tethered by the peptidyl carrier PCP domain. A neighbor-joining tree was constructed based on the C2 domains of VibF in V. The phylogeny of the C2 domains is congruent with the gradient-domain organizations of these siderophore biosynthetic pathways. Nonribosomal peptides and polyketides account for a significant portion of known natural products, which are the major source of drug candidates Recent studies showed the rich sources of nonribosomal peptides and polyketides in bacterial lineages of myxobacteria 18 , pseudomonads 32 , cyanobacteria 17 , and streptomycetes In this systematic study, we have demonstrated that NRPS and type I PKS biosynthetic pathways are widely distributed in bacteria and found sporadically in archaea and eukarya Fig.

We have shown the high frequency of these gene clusters in bacteria and fungi and their spreading into specific archaean classes and many eukaryotic phyla. The accumulation of NRPS and PKS gene clusters in some bacteria phyla may partly reflect the biased distribution of sequenced genomes toward pathogens and environmentally important strains Nevertheless, there is no doubt that this distribution will be inevitably expanded, because of the exponential increasing of genome data.

The archaean and eukaryotic NRPSs and PKSs appeared to be acquired from bacteria via horizontal gene transfer according to sequence and phylogenetic analysis in this study Fig. S6 and others 23 , However, more evidence is needed to prove whether they are recently spread from bacteria or are remnants of ancient pathways after genome reduction.

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On the other hand, sequence analysis indicates that the evolution of nonribosomal machineries is consistent with the phylogenetic classifications based on ribosomal sequences Fig. In addition, the plasmid-borne gene clusters Table S1 might be associated with horizontal gene transfer events in bacteria.

A previous study analyzing strains implied that bacterial strains with PKSs usually have genomes larger than 2 Mb We therefore suggest that bacterial strains with genomes fewer than 2 Mb may not be able to sustain these secondary metabolic pathways, perhaps due to the extra metabolic burdens. S2 ; thus, new genomes from these orders would most likely provide novel natural products.

NRPSs and type I PKSs produce distinct groups of natural products with different enzyme systems, despite their common assembly line-like mechanism 7. 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 , Consequently, the structural diversity of these enzyme systems presented here suggests that reclassification of NRPSs and PKSs is needed.

Our analysis showed that these various domain architectures from nonmodular to modular organization are evolutionarily related, indicating their similar enzymology. To obtain reliable information, only completed genomes of bacteria, archaea, fungi, and protist were studied. Repeatedly sequenced genomes were detected by examining the strain codes, and only the newest versions were analyzed. For higher eukaryotic organisms, partial genomes were used because there are no complete genomes available.

Their results were combined, clusters found by antiSMASH were compared with the hits of 2metDB output, and the clusters predicted by both tools were counted.

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The gene clusters were determined as the NRPS type only if the adenylation or condensation domains were present, as the PKS type only if the ketosynthase or acyltransferase domains were found, and the hybrid type if they contained both the PKS and NRPS core domains. The type II-like gene clusters were defined as at least half of the biosynthetic enzymes are nonmodular enzymes and the ratio of detected domain number versus protein number was no more than 1.

We thank Dr. Jouni Jokela for helpful comments on the manuscript. This work was financially supported by Academy of Finland Grants and to K. The authors declare no conflict of interest. This article contains supporting information online at www. Europe PMC requires Javascript to function effectively. Recent Activity. They commonly occurred in the phyla of Proteobacteria, Actinobacteria, Firmicutes, and Cyanobacteria in bacteria and the phylum of Ascomycota in fungi. The snippet could not be located in the article text.

This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Published online Jun 9. PMID: Hao Wang , a, 1 David P. David P. E-mail: if. Edited by Susan S. Copyright notice. See " Reply to Sasso et al. This article has been cited by other articles in PMC. Significance This study demonstrates the widespread distribution of nonribosomal peptide synthetase and modular polyketide synthase biosynthetic pathways across the three domains of life, by cataloging a total of 3, gene clusters from 2, genomes. Keywords: biosynthetic gene cluster, data mining, distribution, bioactive compound.

Abstract Nonribosomal peptides and polyketides are a diverse group of natural products with complex chemical structures and enormous pharmaceutical potential. Table 1. Domain Gene cluster Genome No. Cumulative size, Gb Bacteria 2, 15, 56, Open in a separate window. Discussion Nonribosomal peptides and polyketides account for a significant portion of known natural products, which are the major source of drug candidates Materials and Methods Datasets.

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Gene-Cluster Finding. Tree Building. Heat-Map Construction.

Supplementary Material Supporting Information: Click here to view. Acknowledgments We thank Dr. Footnotes The authors declare no conflict of interest. References 1. Harnessing the biosynthetic code: Combinations, permutations, and mutations. Finking R, Marahiel MA. Biosynthesis of nonribosomal peptides1. Annu Rev Microbiol. Combinatorial biosynthesis of reduced polyketides. Nat Rev Microbiol. Kopp F, Marahiel MA.

Where chemistry meets biology: the chemoenzymatic synthesis of nonribosomal peptides and polyketides. Curr Opin Biotechnol. Walsh CT. The chemical versatility of natural-product assembly lines. Acc Chem Res. Shen B. Curr Opin Chem Biol. Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: Logic, machinery, and mechanisms.

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Chem Rev. Type III polyketide synthases in natural product biosynthesis. Du L, Shen B. Identification and characterization of a type II peptidyl carrier protein from the bleomycin producer Streptomyces verticillus ATCC Chem Biol.

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