The biosynthesis of the antibiotic pyrrolnitrin by Pseudomonas aureofaciens.

Chang, Ching‐Jer; Floss, Heinz G.; Hook, Derek J.; Mabe, J. A.; Manni, Peter E.; Martin, Lydie; Schröder, Karsten; Shieh, Tiee Leou

doi:10.7164/antibiotics.34.555

Cited by 48 publications

(26 citation statements)

References 25 publications

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“…The nOe between each pair of protons along the circumference of the structure, i.e., H-1 ↔ H-2 ↔ 2′-NH 2 ↔ H-3′ ↔ H-4′ ↔ H-5′ ↔ H-6′ ↔ H-4 ↔ H-5 ↔ H-1, strongly supported the proposed structure. The structure of 3 has been proposed as one of theoretical biosynthetic intermediates of the antibiotic pyrronitrin ( 5 ) [5–7], previously reported from several pseudomonads and related bacteria [5,8–10]. This hypothesis was challenged in a recent report by Kirner et al [11], who suggested that 3 was in fact either a side product or biosynthetic dead-end of 5 .…”

Section: Resultsmentioning

confidence: 99%

Acetylcholinesterase-Inhibiting Activity of Pyrrole Derivatives from a Novel Marine Gliding Bacterium, Rapidithrix thailandica

et al. 2008

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Acetylcholinesterase-inhibiting activity of marinoquinoline A (1), a new pyrroloquinoline from a novel species of a marine gliding bacterium Rapidithrix thailandica, was assessed (IC 50 4.9 μM). Two related pyrrole derivatives, 3-(2'-aminophenyl)-pyrrole (3) and 2,2-dimethyl-pyrrolo-1,2-dihydroquinoline (4), were also isolated from two other strains of R. thailandica. The isolation of 3 from a natural source is reported here for the first time. Compound 4 was proposed to be an isolation artifact derived from 3.The two isolated compounds were virtually inactive in the acetylcholinesterase-inhibitory assay (enzyme inhibition < 30% at 0.1 g L -1 ).

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Section: Resultsmentioning

confidence: 99%

Acetylcholinesterase-Inhibiting Activity of Pyrrole Derivatives from a Novel Marine Gliding Bacterium, Rapidithrix thailandica

et al. 2008

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“…Supplementing growth media with isotopically labeled L-or D-tryptophan produces the isotopic pyrrolnitrin in vivo (28). L-Tryptophan was regarded as the more likely or dominant substrate (28).…”

Section: Discussionmentioning

confidence: 99%

“…L-Tryptophan was regarded as the more likely or dominant substrate (28). Cells lacking PrnB only accumulate 7-Cl-L-tryptophan in measurable amounts in vivo (4).…”

Section: Discussionmentioning

confidence: 99%

The Ternary Complex of PrnB (the Second Enzyme in the Pyrrolnitrin Biosynthesis Pathway), Tryptophan, and Cyanide Yields New Mechanistic Insights into the Indolamine Dioxygenase Superfamily

Zhu

Pée

Naismith

2010

Journal of Biological Chemistry

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Pyrrolnitrin (3-chloro-4-(2-nitro-3-chlorophenyl)pyrrole) is a broad-spectrum antifungal compound isolated from Pseudomonas pyrrocinia. Four enzymes (PrnA, PrnB, PrnC, and PrnD) are required for pyrrolnitrin biosynthesis from tryptophan. PrnB rearranges the indole ring of 7-Cl-L-tryptophan and eliminates the carboxylate group. PrnB shows robust activity in vivo, but in vitro activity for PrnB under defined conditions remains undetected. The structure of PrnB establishes that the enzyme belongs to the heme b-dependent indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) family. We report the cyanide complex of PrnB and two ternary complexes with both L-tryptophan or 7-Cl-L-tryptophan and cyanide. The latter two complexes are essentially identical and mimic the likely catalytic ternary complex that occurs during turnover. In the cyanide ternary complexes, a loop previously disordered becomes ordered, contributing to the binding of substrates. The conformations of the bound tryptophan substrates are changed from that seen previously in the binary complexes. In L-tryptophan ternary complex, the indole ring now adopts the same orientation as seen in the PrnB binary complexes with other tryptophan substrates. The amide and carboxylate group of the substrate are orientated in a new conformation. Tyr 321 and Ser 332 play a key role in binding these groups. The structures suggest that catalysis requires an L-configured substrate. Isothermal titration calorimetry data suggest D-tryptophan does not bind after cyanide (or oxygen) coordinates with the distal (or sixth) site of heme. This is the first ternary complex with a tryptophan substrate of a member of the tryptophan dioxygenase superfamily and has mechanistic implications.Pyrrolnitrin is a broad-spectrum potent antifungal compound (1) first isolated from Pseudomonas pyromania (2) and the active component of PYRO-ACE (treatment for fungal infections of skin). The gene cluster responsible for pyrrolnitrin biosynthesis was identified in Pseudomonas fluorescens (BL915) (3, 4) and subsequently in Pseudomonas pyrrocinia, Burkholderia cepacia LT4-12-W, Myxococcus fulvus Mx f147, and other pyrrolnitrin producing bacteria (5). Four conserved enzymes are involved in pyrrolnitrin biosynthesis and named PrnA, PrnB, PrnC, and PrnD, reflecting their order in catalysis. Introduction of the entire cluster to Escherichia coli results in the production of pyrrolnitrin, thereby demonstrating that the four genes are sufficient and essential for pyrrolnitrin biosynthesis in vivo (3). Genetic manipulation in P. fluorescens BL915 has identified the intermediate products from each enzyme in the pyrrolnitrin pathway, leading to the current model for the biosynthetic pathway (4). The first enzyme, PrnA (tryptophan 7-halogenase), incorporates the chlorine into the substrate tryptophan (6). Structural and biochemical analyses of both tryptophan 7 and 5-halogenase (7-10) have established a novel chemical mechanism of hypohalous acid formation at the flavin cofactor, followed by ...

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“…In fact, it is not only incorporated into polypeptide chains but: (1) it is used for the biosynthesis of NAD in both Eukaryotes (Rongvaux et al 2003) and Prokaryotes (Kurnasov et al 2003); (2) in humans, it is the precursor of some neurotransmitters (Richard et al 2009;Colabroy and Begley 2005); (3) in bacteria, it is incorporated in antibiotics as pyrrolnitrin and pacidamycin (Chang et al 1981;Grüschow et al 2009). In mammals (Gholson et al 1959) and microorganisms (Bouknight and Sadoff 1975;Suemori et al 1995), tryptophan can be also fully catabolized to CO 2 , NH 3 , and H 2 O.…”

Section: Discussionmentioning

confidence: 98%

Tryptophan catabolism via kynurenine production in Streptomyces coelicolor: identification of three genes coding for the enzymes of tryptophan to anthranilate pathway

Zummo

Marineo

Pace

et al. 2012

Appl Microbiol Biotechnol

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Most enzymes involved in tryptophan catabolism via kynurenine formation are highly conserved in Prokaryotes and Eukaryotes. In humans, alterations of this pathway have been related to different pathologies mainly involving the central nervous system. In Bacteria, tryptophan and some of its derivates are important antibiotic precursors. Tryptophan degradation via kynurenine formation involves two different pathways: the eukaryotic kynurenine pathway, also recently found in some bacteria, and the tryptophan-to-anthranilate pathway, which is widespread in microorganisms. The latter produces anthranilate using three enzymes also involved in the kynurenine pathway: tryptophan 2,3-dioxygenase (TDO), kynureninase (KYN), and kynurenine formamidase (KFA). In Streptomyces coelicolor, where it had not been demonstrated which genes code for these enzymes, tryptophan seems to be important for the calcium- dependent antibiotic (CDA) production. In this study, we describe three adjacent genes of S. coelicolor (SCO3644, SCO3645, and SCO3646), demonstrating their involvement in the tryptophan-to-anthranilate pathway: SCO3644 codes for a KFA, SCO3645 for a KYN and SCO3646 for a TDO. Therefore, these genes can be considered as homologous respectively to kynB, kynU, and kynA of other microorganisms and belong to a constitutive catabolic pathway in S. coelicolor, which expression increases during the stationary phase of a culture grown in the presence of tryptophan. Moreover, the S. coelicolor ΔkynU strain, in which SCO3645 gene is deleted, produces higher amounts of CDA compared to the wild-type strain. Overall, these results describe a pathway, which is used by S. coelicolor to catabolize tryptophan and that could be inactivated to increase antibiotic production.

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The biosynthesis of the antibiotic pyrrolnitrin by Pseudomonas aureofaciens.

Cited by 48 publications

References 25 publications

Acetylcholinesterase-Inhibiting Activity of Pyrrole Derivatives from a Novel Marine Gliding Bacterium, Rapidithrix thailandica

Acetylcholinesterase-Inhibiting Activity of Pyrrole Derivatives from a Novel Marine Gliding Bacterium, Rapidithrix thailandica

The Ternary Complex of PrnB (the Second Enzyme in the Pyrrolnitrin Biosynthesis Pathway), Tryptophan, and Cyanide Yields New Mechanistic Insights into the Indolamine Dioxygenase Superfamily

Tryptophan catabolism via kynurenine production in Streptomyces coelicolor: identification of three genes coding for the enzymes of tryptophan to anthranilate pathway

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