Genome Sequence of the Bacterium Streptomyces davawensis JCM 4913 and Heterologous Production of the Unique Antibiotic Roseoflavin

Jankowitsch, Frank; Schwarz, Julia; Rückert, Christian; Gust, Bertolt; Szczepanowski, Rafael; Blom, Jochen; Pelzer, Stefan; Kalinowski, Jörn; Mack, Matthias

doi:10.1128/jb.01592-12

Cited by 47 publications

(69 citation statements)

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“…1,2 It is the only biosynthesized flavin analog with antibiotic activity and binds to the flavin mononucleotide (FMN) riboswitch, thus repressing riboflavin biosynthesis. 3,4 Roseoflavin has been used in the screening of mutants for maximum riboflavin production because bacteria overproducing riboflavin are resistant to roseoflavin toxicity.…”

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A Remarkable Oxidative Cascade That Replaces the Riboflavin C8 Methyl with an Amino Group during Roseoflavin Biosynthesis

et al. 2016

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Roseoflavin is a naturally occurring riboflavin analogue with antibiotic properties. It is biosynthesized from riboflavin in a reaction involving replacement of the C8 methyl with a dimethylamino group. Herein we report the identification of a flavin-dependent enzyme that converts flavin mononucleotide (FMN) and glutamate to 8-amino-FMN via the intermediacy of 8-formyl-FMN. A mechanistic proposal for this remarkable transformation is proposed.

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A Remarkable Oxidative Cascade That Replaces the Riboflavin C8 Methyl with an Amino Group during Roseoflavin Biosynthesis

et al. 2016

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“…he Gram-positive bacterium S. davawensis JCM 4913 (1,2) synthesizes the antibiotic roseoflavin, a structural riboflavin (vitamin B 2 ) analog (2,3). For Bacillus subtilis, S. davawensis, and Corynebacterium glutamicum, it was shown that roseoflavin is taken up via riboflavin transporters (4)(5)(6)(7)(8).…”

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Flavoproteins Are Potential Targets for the Antibiotic Roseoflavin in Escherichia coli

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Hashimoto

Hobl

et al. 2013

Journal of Bacteriology

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The riboflavin analog roseoflavin is an antibiotic produced by Streptomyces davawensis. Riboflavin transporters are responsible for roseoflavin uptake by target cells. Roseoflavin is converted to the flavin mononucleotide (FMN) analog roseoflavin mononucleotide (RoFMN) by flavokinase and to the flavin adenine dinucleotide (FAD) analog roseoflavin adenine dinucleotide (RoFAD) by FAD synthetase. In order to study the effect of RoFMN and RoFAD in the cytoplasm of target cells, Escherichia coli was used as a model. E. coli is predicted to contain 38 different FMN-or FAD-dependent proteins (flavoproteins). These proteins were overproduced in recombinant E. coli strains grown in the presence of sublethal amounts of roseoflavin. The flavoproteins were purified and analyzed with regard to their cofactor contents. It was found that 37 out of 38 flavoproteins contained either RoFMN or RoFAD. These cofactors have different physicochemical properties than FMN and FAD and were reported to reduce or completely abolish flavoprotein function. The Gram-positive bacterium S. davawensis JCM 4913 (1, 2) synthesizes the antibiotic roseoflavin, a structural riboflavin (vitamin B 2 ) analog (2, 3). For Bacillus subtilis, S. davawensis, and Corynebacterium glutamicum, it was shown that roseoflavin is taken up via riboflavin transporters (4-8). Moreover, it was found that roseoflavin is converted to the flavin cofactor analogs roseoflavin mononucleotide (RoFMN) and roseoflavin adenine dinucleotide (RoFAD) by flavokinases (EC 2.7.1.26) and FAD synthetases (EC 2.7.7.2) in vitro (9, 10) (Fig. 1A).RoFMN was reported to reduce expression of genes involved in riboflavin biosynthesis and/or transport in B. subtilis, Streptomyces coelicolor, and the human pathogen Listeria monocytogenes (10-13). These genes are all controlled by FMN riboswitches (14), regulatory elements which are negatively affected by RoFMN. This reduction of gene expression at least in part explains why roseoflavin acts as an antibiotic. For example, reduced expression of the FMN riboswitch-controlled riboflavin-biosynthetic genes ribEMAH in S. coelicolor (caused by RoFMN) led to a significantly decreased level of riboflavin synthase (RibE) activity (10) and consequently to a reduced supply of riboflavin. In another study, the addition of roseoflavin to riboflavin-auxotrophic L. monocytogenes led to reduced expression of the FMN riboswitch-controlled riboflavin transporter gene lmo1945 and to a reduced supply of riboflavin as well (11). In this study, an L. monocytogenes strain was described that contained a mutant FMN riboswitch which was not blocked by RoFMN. This strain constitutively transcribed lmo1945 and showed a significant decrease in roseoflavin sensitivity; however, it was still roseoflavin sensitive. We therefore concluded that additional targets for roseoflavin must be present in L. monocytogenes and very likely in other bacteria as well.Approximately 1 to 3% of all bacterial proteins depend on the riboflavin-derived cofactors FMN or FAD (15) and thus are plausi...

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“…[1] Drei natürliche Vitaminanaloga wurden bisher beschrieben, das Vitamin-B 1 -Analogon Bacimethrin, [2] das Vitamin-B 6 -Analogon Ginkgotoxin [3] und das Vitamin-B 2 (Riboflavin)-Analogon Roseoflavin (RoF). [5] Die bei Mikroorganismen weit verbreiteten Riboflavintransporter vermitteln dabei die effiziente Aufnahme von RoF durch die Zielzellen, [6] da sie offenbar neben Riboflavin auch RoF als Aufnahmesubstrat akzeptieren. [5] Die bei Mikroorganismen weit verbreiteten Riboflavintransporter vermitteln dabei die effiziente Aufnahme von RoF durch die Zielzellen, [6] da sie offenbar neben Riboflavin auch RoF als Aufnahmesubstrat akzeptieren.…”

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“…[11] In früheren Arbeiten zur Biosynthese von RoF wurde vorgeschlagen, dass es aus Riboflavin über 8-Demethyl-8aminoriboflavin (AF) und 8-Demethyl-8-methylaminoriboflavin (MAF) gebildet wird. [5] Ein wichtiger Schritt hin zur Identifizierung der unbekannten AF-Biosynthesegene war das Ergebnis des folgenden Genexpressionsexperiments. [13] Dieses Enzym bildet RoF aus AF (über MAF;A bbildung 1, Umwandlung von 6 in 8).…”

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“…[12] Die Zwischenprodukte AF und MAF wurden durch die Entdeckung des ersten Enzyms der RoF-Biosynthese,d er S-Adenosylmethionin(SAM)-abhängigen Dimethyltransferase RosA, bestätigt. Ein Cosmid (pESAC13-SD106kbp), [5] das ein bestimmtes 106 kbp großes,s ubgenomisches DNA-Fragment mit 95 putativen Genen aus S. davawensis enthielt (Abbildung 2), wurde in das Chromosom des Expressionswirts S. coelicolor integriert. Das zugehçrige Gen rosA liegt in einer Gengruppe aus neun Genen (Cluster 7, Abbildung 2).…”

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Identifizierung des Schlüsselenzyms der Roseoflavinbiosynthese

et al. 2016

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Die Bakterienarten Streptomyces davawensis und Streptomyces cinnabarinus produzieren Roseoflavin, das einzige bekannte natürliche Analogon von Riboflavin (Vitamin B 2 )m it antibiotischer Wirkung.R oseoflavin kann als natürlicher Antimetabolit bezeichnet werden und soll aus Riboflavin über das Schlüsselintermediat 8-Demethyl-8-aminoriboflavin (AF) synthetisiert werden. Der ortsspezifische Austausch einer Methylgruppe des Dimethylbenzolrings von Riboflavin gegen eine Aminogruppe (der zu AF führt) ist mechanistisch schwierig. Der Biosyntheseweg von Riboflavin zu AF war unklar,u nd das/die zugehçrige/n Enzym/e war/en unbekannt. Systematische Gendeletions-und -expressionsexperimente sowie biochemischeAnalysen zeigten jetzt, dass das vom Gen BN159_7989 aus S. davawensis kodierte Enzym mehrere chemischer Reaktionen katalysieren kann:A usgehend von Riboflavin-5'-phosphat bildet BN159_7989 8-Demethyl-8-aminoriboflavin-5'-phosphat.

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Genome Sequence of the Bacterium Streptomyces davawensis JCM 4913 and Heterologous Production of the Unique Antibiotic Roseoflavin

Cited by 47 publications

References 61 publications

A Remarkable Oxidative Cascade That Replaces the Riboflavin C8 Methyl with an Amino Group during Roseoflavin Biosynthesis

A Remarkable Oxidative Cascade That Replaces the Riboflavin C8 Methyl with an Amino Group during Roseoflavin Biosynthesis

Flavoproteins Are Potential Targets for the Antibiotic Roseoflavin in Escherichia coli

Identifizierung des Schlüsselenzyms der Roseoflavinbiosynthese

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