The kirromycin gene cluster of Streptomyces collinus Tü 365 codes for an aspartate-α-decarboxylase, KirD, which is involved in the biosynthesis of the precursor β-alanine

Laiple, Kristina J; Härtner, Thomas; Fiedler, Hans‐Peter; Wohlleben, Wolfgang; Weber, Tilmann

doi:10.1038/ja.2009.67

Cited by 15 publications

(10 citation statements)

References 19 publications

(14 reference statements)

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“…7). 57 This example suggests that homologous genes for ADCs are required for secondary metabolism, although b-alanine and b-aminoisobutyrate would generally occur from primary metabolism.…”

Section: Sugar-b-amino Acid Hybridsmentioning

confidence: 99%

Biosynthesis of natural products containing β-amino acids

2014

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Covering: up to January, 2014. We focus here on β-amino acids as components of complex natural products because the presence of β-amino acids produces structural diversity in natural products and provides characteristic architectures beyond those of ordinary α-L-amino acids, thus generating significant and unique biological functions in nature. In this review, we first survey the known bioactive β-amino acid-containing natural products including nonribosomal peptides, macrolactam polyketides, and nucleoside-β-amino acid hybrids. Next, the biosynthetic enzymes that form β-amino acids from α-amino acids and the de novo synthesis of β-amino acids are summarized. Then, the mechanisms of β-amino acid incorporation into natural products are reviewed. Because it is anticipated that the rational swapping of the β-amino acid moieties with various side chains and stereochemistries by biosynthetic engineering should lead to the creation of novel architectures and bioactive compounds, the accumulation of knowledge regarding β-amino acid-containing natural product biosynthetic machinery could have a significant impact in this field. In addition, genome mining of characteristic β-amino acid biosynthetic genes and unique β-amino acid incorporation machinery could lead to the discovery of new β-amino acid-containing natural products.

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“…7). 57 This example suggests that homologous genes for ADCs are required for secondary metabolism, although b-alanine and b-aminoisobutyrate would generally occur from primary metabolism.…”

Section: Sugar-b-amino Acid Hybridsmentioning

confidence: 99%

Biosynthesis of natural products containing β-amino acids

2014

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“…In previous studies, the kirromycin biosynthetic gene cluster was identified using a genetic screening approach (Weber et al , 2003). The antibiotic is synthesized via a combined cis‐/trans ‐AT type I polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) mechanism (Weber et al , 2008; Laiple et al , 2009). Both PKS and NRPS megaenzymes have a modular architecture where multiple partial reactions involved in the biosynthesis take place at specific enzymatic domains.…”

Section: Introductionmentioning

confidence: 99%

The phosphopantetheinyl transferase KirP activates the ACP and PCP domains of the kirromycin NRPS/PKS of Streptomyces collinus Tü 365

Pavlidou

Musiol

Kulik

et al. 2011

FEMS Microbiology Letters

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The main steps in the biosynthesis of complex secondary metabolites such as the antibiotic kirromycin are catalyzed by modular polyketide synthases (PKS) and/or nonribosomal peptide synthetases (NRPS). During antibiotic assembly, the biosynthetic intermediates are attached to carrier protein domains of these megaenzymes via a phosphopantetheinyl arm. This functional group of the carrier proteins is attached post-translationally by a phosphopantetheinyl transferase (PPTase). No experimental evidence exists about how such an activation of the carrier proteins of the kirromycin PKS/NRPS is accomplished. Here we report on the characterization of the PPTase KirP, which is encoded by a gene located in the kirromycin biosynthetic gene cluster. An inactivation of the kirP gene resulted in a 90% decrease in kirromycin production, indicating a substantial role for KirP in the biosynthesis of the antibiotic. In enzymatic assays, KirP was able to activate both acyl carrier protein and petidyl carrier domains of the kirromycin PKS/NRPS. In addition to coenzyme A (CoA), which is the natural substrate of KirP, the enzyme was able to transfer acyl-phosphopantetheinyl groups to the apo forms of the carrier proteins. Thus, KirP is very flexible in terms of both CoA substrate and carrier protein specificity. Our results indicate that KirP is the main PPTases that activates the carrier proteins in kirromycin biosynthesis.

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“…This facilitated the prediction that the catalytic domains of AurI to AurVI largely follow those of KirI to KirVI of the kirromycin gene cluster despite the rearrangements in the overall cluster architecture (Fig. 2 & 4; (7,9). In AurAI and AurAII, acetyl Co-A extension is via Claisen condensation reactions (8), however the PKSs are atypical in arrangement, with two additional dehydratase domains present.…”

Section: Proposed Biosynthesis Of Aurodox Follows That Of Kirromycinmentioning

confidence: 91%

“…Aurodox was discovered in 1973 (2), it is a linear polyketide compound which is highly similar to kirromycin (7) differing only in methylation of the pyridone moiety. Kirromycin biosynthesis has been characterised and the BGC encodes five large polyketide synthase (PKS) units which act to form the polyketide backbone, before tailoring enzymes decorate the molecule (7)(8)(9)(10). Given the similarity of the molecules, we hypothesised that the aurodox biosynthetic gene cluster (BGC) may be homologous to the hybrid PKS/Non-ribosomal peptide synthetase (NRPS) BGC of kirromycin, with the addition of an ORF responsible for pyridone-associated methylation (Fig.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of aurodox, a Type III secretion system inhibitor from Streptomyces goldiniensis

McHugh

Munnoch

Braes

et al. 2022

Preprint

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The global increase in antimicrobial-resistant infections means that there is a need to develop new antimicrobial molecules and strategies to combat the issue. Aurodox is a linear polyketide natural product that is produced by Streptomyces goldiniensis, yet little is known about aurodox biosynthesis or the nature of the biosynthetic gene cluster (BGC) that encodes its production. To gain a deeper understanding of aurodox biosynthesis by S. goldiniensis, the whole genome of the organism was sequenced, revealing the presence of an 87 kb hybrid Polyketide Synthase/Non-Ribosomal Peptide Synthetase (PKS/NRPS) BGC. The aurodox BGC shares significant homology with the kirromycin BGC from S. collinus Tϋ 365; however, the genetic organisation of the BGC differs significantly. The candidate aurodox gene cluster was cloned and expressed in a heterologous host to demonstrate that it was responsible for aurodox biosynthesis and disruption of the primary PKS gene (aurAI) abolished aurodox production. These data support a model whereby the initial core biosynthetic reactions involved in aurodox biosynthesis follow that of kirromycin. Cloning aurM* from S. goldiniensis and expressing this in the kirromycin producer S. collinus Tϋ 365 enabled methylation of the pyridone group, suggesting this is the last step in biosynthesis. This methylation step is also sufficient to confer the unique Type III Secretion System inhibitory properties to aurodox.

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The kirromycin gene cluster of Streptomyces collinus Tü 365 codes for an aspartate-α-decarboxylase, KirD, which is involved in the biosynthesis of the precursor β-alanine

Cited by 15 publications

References 19 publications

Biosynthesis of natural products containing β-amino acids

Biosynthesis of natural products containing β-amino acids

The phosphopantetheinyl transferase KirP activates the ACP and PCP domains of the kirromycin NRPS/PKS of Streptomyces collinus Tü 365

Biosynthesis of aurodox, a Type III secretion system inhibitor from Streptomyces goldiniensis

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