Insights into an Unusual Nonribosomal Peptide Synthetase Biosynthesis

Binz, Tina M.; Maffioli, Sonia; Sosio, Margherita; Donadio, Stefano; Müller, Rolf

doi:10.1074/jbc.m110.146803

Cited by 38 publications

(39 citation statements)

References 53 publications

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“…Außer der Verbindung mit beschriebener Struktur (1) [5] wurde auch die die Zielverbindung (25)m it revidierter Struktur synthetisiert. Außer der Verbindung mit beschriebener Struktur (1) [5] wurde auch die die Zielverbindung (25)m it revidierter Struktur synthetisiert.…”

Section: Angewandte Chemieunclassified

Totalsynthese und Strukturkorrektur des antibiotisch wirksamen Tetrapeptids GE81112A

et al. 2018

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Die erste Totalsynthese des antibiotischw irksamen Naturstoffs GE81112A, eines hoch funktionalisierten Tetrapeptids,w urdea bgeschlossen. Der Vergleichd er NMR-Daten und der biologischen Aktivitätd er synthetischen Verbindung mit den Daten fürd en Naturstoff führte zur Korrektur der publizierten absoluten Konfiguration eines stereogenen Zentrums der 3-Hydroxypipecolinsäure-Einheit und zur Synthese des biologischa ktiven GE81112A mit der korrekten Konfiguration.

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Section: Angewandte Chemieunclassified

Totalsynthese und Strukturkorrektur des antibiotisch wirksamen Tetrapeptids GE81112A

et al. 2018

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“…It is involved in the biosynthesis of the tetrapeptide antibiotic GE81112 in Streptomyces sp. L‐49973, which contains hydroxypipecolic acid as a starter unit . The function of GetF encoded in the GE81112 biosynthetic gene cluster was originally identified through significant sequence similarity to that of bacterial cis ‐PHs .…”

Section: Introductionmentioning

confidence: 99%

“…L‐49973, which contains hydroxypipecolic acid as a starter unit . The function of GetF encoded in the GE81112 biosynthetic gene cluster was originally identified through significant sequence similarity to that of bacterial cis ‐PHs . The stereochemistry at position C‐2 of the hydroxypipecolic acid residue in GE81112 has been determined as l indirectly through the affinity of l ‐ and d ‐pipecolic acid to the corresponding A domain of the non‐ribosomal peptide synthetase.…”

Section: Introductionmentioning

confidence: 99%

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Pipecolic Acid Hydroxylases: A Monophyletic Clade among cis‐Selective Bacterial Proline Hydroxylases that Discriminates l‐Proline

Mattay

Hüttel

2017

ChemBioChem

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Proline hydroxylases are iron(II)/2-oxoglutarate-dependent enzymes that hydroxylate l-proline and derivatives, such as lpipecolic acid, which is the six-membered-ring homologue of l-proline. It has been established that there is a distinct group of conserved bacterial enzymes that hydroxylate l-pipecolic acid and trans-3- and trans-4-methyl-l-proline, but virtually no l-proline. This allows the organism to produce hydroxyproline congeners without hydroxylation of the physiologically omnipresent l-proline. In vitro conversions showed that the substrate spectrum of the pipecolic acid hydroxylases GetF (from a Streptomyces sp.; producer of the tetrapeptide antibiotic GE81112) and PiFa (from Frankia alni) overlaps that of proline hydroxylases, except for the nonacceptance of l-proline and smaller homologues. Distinct and conserved residues were determined for both types of enzymes. However, site-directed mutagenesis in GetF did not yield variants that accepted l-proline; this suggested a complex interaction of several residues around the active site, which resulted in delicate changes in substrate specificity. This is supported by substrate docking in a homology model of GetF, which revealed an altered orientation for l-proline relative to that of preferred substrates.

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“…GetF was recently characterized as an l ‐pipecolic acid hydroxylase responsible for the production of the 3‐hydroxy‐ l ‐pipecolic acid monomer ( 2 ) . GetI was initially proposed to catalyze the β‐hydroxylation of 2‐chloro‐ l ‐histidine, either as the free or peptidyl carrier protein (PCP)‐bound amino acid ( 3 ) . Given the potential utility of GetI in the production of novel noncanonical amino acids, we became interested in its functional characterization and exploration of its biocatalytic utility…”

Section: Figurementioning

confidence: 99%

Characterization of a Citrulline 4‐Hydroxylase from Nonribosomal Peptide GE81112 Biosynthesis and Engineering of Its Substrate Specificity for the Chemoenzymatic Synthesis of Enduracididine

2019

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The GE81112 tetrapeptides are a small family of unusual nonribosomal peptide congeners with potent inhibitory activity against prokaryotic translation initiation. With the exception of the 3‐hydroxy‐l‐pipecolic acid unit, little is known about the biosynthetic origins of the non‐proteinogenic amino acid monomers of the natural product family. Here, we elucidate the biogenesis of the 4‐hydroxy‐l‐citrulline unit and establish the role of an iron‐ and α‐ketoglutarate‐dependent enzyme (Fe/αKG) in the pathway. Homology modelling and sequence alignment analysis further facilitate the rational engineering of this enzyme to become a specific 4‐arginine hydroxylase. We subsequently demonstrate the utility of this engineered enzyme in the synthesis of a dipeptide fragment of the antibiotic enduracidin. This work highlights the value of applying a bioinformatics‐guided approach in the discovery of novel enzymes and engineering of new catalytic activity into existing ones.

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Insights into an Unusual Nonribosomal Peptide Synthetase Biosynthesis

Cited by 38 publications

References 53 publications

Totalsynthese und Strukturkorrektur des antibiotisch wirksamen Tetrapeptids GE81112A

Totalsynthese und Strukturkorrektur des antibiotisch wirksamen Tetrapeptids GE81112A

Pipecolic Acid Hydroxylases: A Monophyletic Clade among cis‐Selective Bacterial Proline Hydroxylases that Discriminates l‐Proline

Characterization of a Citrulline 4‐Hydroxylase from Nonribosomal Peptide GE81112 Biosynthesis and Engineering of Its Substrate Specificity for the Chemoenzymatic Synthesis of Enduracididine

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