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Natural products genomics.

Siezen RJ, Khayatt BI - Microb Biotechnol (2008)

View Article: PubMed Central - PubMed

Affiliation: Kluyver Centre for Genomics of Industrial Fermentation, TI Food and Nutrition, 6700AN Wageningen, the Netherlands. r.siezen@cmbi.ru.nl

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Secondary metabolites (or natural products) are often synthesized by multi‐modular, multi‐domain proteins called non‐ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS)... Polyketide synthase modules can contain four core domains (Fig.  2B): an acyltransferase (AT) domain that selects and activates the acyl‐CoA building blocks (such as acetyl‐CoA, malonyl‐CoA, methylmalonyl‐CoA and ethylmalonyl‐CoA), an acyl carrier (ACP) domain, a keto‐acylsynthase (KS) condensation domain and a releasing thio‐esterase (Te) domain... The modules may contain other modification domains such as ketoreductase (KR), dehydratase (DH) and enoylreductase (ER)... The NRPS‐PKS tool is web‐based software (http://www.nii.res.in/nrps‐pks.html) for analysing the large multi‐enzymatic, multi‐domain megasynthases... These databases provide an interface to correlate chemical structures of these natural products with the domains and modules in the corresponding PKS or NRPS... Numerous NRPS/PKS systems were found, and Table 2 lists the genomes with three or more systems; several are described in more detail below... They are mainly found in microorganisms with genomes larger than 4 Mb isolated from soil or aquatic environments... Bacillus spores are notoriously resistant to unfavourable conditions such as UV radiation, γ‐radiation, H2O2, desiccation, chemical disinfection or starvation... Bacillus pumilus SAFR‐032 spores and vegetative cells exhibit elevated resistance to UV radiation and H2O2 compared with other Bacillus species, and its genome sequence provides insight into numerous DNA repair and oxidative stress pathways... Herpetosiphon aurantiacus is a non‐phototrophic, strictly aerobic, gliding bacterium... Herpetosiphon spp. have been found in soil, freshwater and sewage treatment plants and grow in microbial mats... A phage‐display method was developed for high‐throughput mining of gene clusters encoding PKS and NRPS systems, which can be applied to genomes of unknown sequence and metagenomes, providing opportunities for exploiting the potentially rich source of natural products from unculturable microbes... The past decade has already seen numerous examples of genetic engineering, metabolic engineering, rational design, and directed evolution of NRPS and PKS systems to provide novel compounds based on known NRPS/PKS gene clusters for biosynthesis of natural products... The ever‐increasing pace of microbial genome sequencing is revealing a plethora of new NRPS/PKS gene clusters, mostly of unknown function... A major challenge for the next decade is to back this up with characterization of the chemical structures and biological activities of these secondary metabolites, so that we can chart Nature's unique repertoire of natural products and exploit them for the directed synthesis of novel molecules of biotechnological, agricultural and pharmaceutical utility.

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Examples of some chemical structures of (A) polyketides, (B) non‐ribosomal peptides and (C) mixed NRP‐PK compounds. Reprinted with permission from Watanabe and Oikawa (2007). Copyright Royal Society of Chemistry.
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f1: Examples of some chemical structures of (A) polyketides, (B) non‐ribosomal peptides and (C) mixed NRP‐PK compounds. Reprinted with permission from Watanabe and Oikawa (2007). Copyright Royal Society of Chemistry.

Mentions: Secondary metabolites (or natural products) are often synthesized by multi‐modular, multi‐domain proteins called non‐ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS). Various well‐known metabolites produced by microorganisms are listed in Table 1, and examples of structures are shown in Fig. 1. In particular, Streptomyces species are known for their ability to produce a wide variety of secondary metabolites such as antibiotics, herbicides, parasitocides, siderophores and pharmacologically active substances including antitumour agents and immunosuppressants. Genome sequencing of Streptomyces coelicolor (Bentley et al., 2002) and S. avermitilis (Omura et al., 2001) revealed over 20 gene clusters for biosynthesis of secondary metabolites, while only a few of their natural products were known prior to sequencing. High‐throughput genome sequencing of hundreds of other bacterial species and strains is now rapidly increasing the repertoire of identified gene clusters for biosynthesis of natural products (Donadio et al., 2007). Here we give a brief update of the current status of genome mining and bioinformatic tools to identify novel NRPS and PKS systems.


Natural products genomics.

Siezen RJ, Khayatt BI - Microb Biotechnol (2008)

Examples of some chemical structures of (A) polyketides, (B) non‐ribosomal peptides and (C) mixed NRP‐PK compounds. Reprinted with permission from Watanabe and Oikawa (2007). Copyright Royal Society of Chemistry.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815393&req=5

f1: Examples of some chemical structures of (A) polyketides, (B) non‐ribosomal peptides and (C) mixed NRP‐PK compounds. Reprinted with permission from Watanabe and Oikawa (2007). Copyright Royal Society of Chemistry.
Mentions: Secondary metabolites (or natural products) are often synthesized by multi‐modular, multi‐domain proteins called non‐ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS). Various well‐known metabolites produced by microorganisms are listed in Table 1, and examples of structures are shown in Fig. 1. In particular, Streptomyces species are known for their ability to produce a wide variety of secondary metabolites such as antibiotics, herbicides, parasitocides, siderophores and pharmacologically active substances including antitumour agents and immunosuppressants. Genome sequencing of Streptomyces coelicolor (Bentley et al., 2002) and S. avermitilis (Omura et al., 2001) revealed over 20 gene clusters for biosynthesis of secondary metabolites, while only a few of their natural products were known prior to sequencing. High‐throughput genome sequencing of hundreds of other bacterial species and strains is now rapidly increasing the repertoire of identified gene clusters for biosynthesis of natural products (Donadio et al., 2007). Here we give a brief update of the current status of genome mining and bioinformatic tools to identify novel NRPS and PKS systems.

View Article: PubMed Central - PubMed

Affiliation: Kluyver Centre for Genomics of Industrial Fermentation, TI Food and Nutrition, 6700AN Wageningen, the Netherlands. r.siezen@cmbi.ru.nl

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Secondary metabolites (or natural products) are often synthesized by multi‐modular, multi‐domain proteins called non‐ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS)... Polyketide synthase modules can contain four core domains (Fig.  2B): an acyltransferase (AT) domain that selects and activates the acyl‐CoA building blocks (such as acetyl‐CoA, malonyl‐CoA, methylmalonyl‐CoA and ethylmalonyl‐CoA), an acyl carrier (ACP) domain, a keto‐acylsynthase (KS) condensation domain and a releasing thio‐esterase (Te) domain... The modules may contain other modification domains such as ketoreductase (KR), dehydratase (DH) and enoylreductase (ER)... The NRPS‐PKS tool is web‐based software (http://www.nii.res.in/nrps‐pks.html) for analysing the large multi‐enzymatic, multi‐domain megasynthases... These databases provide an interface to correlate chemical structures of these natural products with the domains and modules in the corresponding PKS or NRPS... Numerous NRPS/PKS systems were found, and Table 2 lists the genomes with three or more systems; several are described in more detail below... They are mainly found in microorganisms with genomes larger than 4 Mb isolated from soil or aquatic environments... Bacillus spores are notoriously resistant to unfavourable conditions such as UV radiation, γ‐radiation, H2O2, desiccation, chemical disinfection or starvation... Bacillus pumilus SAFR‐032 spores and vegetative cells exhibit elevated resistance to UV radiation and H2O2 compared with other Bacillus species, and its genome sequence provides insight into numerous DNA repair and oxidative stress pathways... Herpetosiphon aurantiacus is a non‐phototrophic, strictly aerobic, gliding bacterium... Herpetosiphon spp. have been found in soil, freshwater and sewage treatment plants and grow in microbial mats... A phage‐display method was developed for high‐throughput mining of gene clusters encoding PKS and NRPS systems, which can be applied to genomes of unknown sequence and metagenomes, providing opportunities for exploiting the potentially rich source of natural products from unculturable microbes... The past decade has already seen numerous examples of genetic engineering, metabolic engineering, rational design, and directed evolution of NRPS and PKS systems to provide novel compounds based on known NRPS/PKS gene clusters for biosynthesis of natural products... The ever‐increasing pace of microbial genome sequencing is revealing a plethora of new NRPS/PKS gene clusters, mostly of unknown function... A major challenge for the next decade is to back this up with characterization of the chemical structures and biological activities of these secondary metabolites, so that we can chart Nature's unique repertoire of natural products and exploit them for the directed synthesis of novel molecules of biotechnological, agricultural and pharmaceutical utility.

Show MeSH