Formation of the Pyridazine Natural Product Azamerone by Biosynthetic Rearrangement of an Aryl Diazoketone

Winter, Jaclyn M.; Jansma, Ariane; Handel, Tracy M.; Moore, Bradley S.

doi:10.1002/ange.200805140

Cited by 15 publications

(3 citation statements)

References 17 publications

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“…3c). This outcome contrasts sharply with the results of previous 15 N-nitrite feeding experiments performed with the producers of the diazo-containing secondary metabolite SF2415A3, in which only the distal diazo nitrogen atom was labeled ( Supplementary Fig 1c) 3 . In this study, both 15 N-nitrite and 15 N-nitrate selectively enriched the distal diazo nitrogen atom.…”

Section: Feeding Studies In a Kinamycin Producercontrasting

confidence: 99%

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Glutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin

Wang

et al. 2018

Preprint

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Fosfazinomycin and kinamycin are natural products that contain nitrogennitrogen (N-N) bonds but that are otherwise structurally unrelated. Despite their considerable structural differences, their biosynthetic gene clusters share a set of genes predicted to facilitate N-N bond formation. In this study, we show that for both compounds, one of the nitrogen atoms in the N-N bond originates from nitrous acid. Furthermore, we show that for both compounds, an acetylhydrazine biosynthetic synthon is generated first and then funneled via a glutamyl carrier into the respective biosynthetic pathways. Therefore, unlike other pathways to N-N bond-containing natural products wherein the N-N bond is formed directly on a biosynthetic intermediate, during the biosyntheses of fosfazinomycin, kinamycin, and related compounds, the N-N bond is made in an independent pathway that forms a branch of a convergent route to structurally complex natural products.More than 200 natural products containing nitrogen-nitrogen (N-N) bonds have been identified with various bioactivities (Fig. 1a) 1 . For instance, streptozotocin, a nitrosamine-containing compound, exhibits cytotoxic activity and is currently deployed clinically 2 , and valanimycin, featuring an azoxy group, displays both antimicrobial and cytotoxic activities 1 . Other examples are azamerone containing a pyridazine, kutzneride with a piperazic acid 2, 3 , the fosfazinomycins having a phosphonohydrazide 4 , and a group of molecules including cremeomycin, the lomaiviticins and the kinamycins containing diazo groups 1 .

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Section: Feeding Studies In a Kinamycin Producercontrasting

confidence: 99%

“…In our prior work concerning the biosynthesis of fosfazinomycin, we reconstituted in vitro the activities of FzmQ and FzmR. FzmQ performs the acetylation of hydrazinosuccinic acid (3) to yield N-acetylhydrazinosuccinic acid (4, Fig. 1b), and FzmR catalyzes an elimination reaction of 4 to afford fumaric acid and acetylhydrazine 8 .…”

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confidence: 99%

Glutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin

Wang

et al. 2018

Preprint

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“…strong labeling (>75%) observed in studies of pathways that use nitrite for diazo biosynthesis 36,37 . c) experiments were performed.…”

Section: Addition Of Superoxide Dismutase and Catalase To Sznf Reaction Mixtures-mentioning

confidence: 99%

An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

Rohac

Mitchell

et al. 2019

Nature

125

257

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N-nitroso-containing small molecules, such as the bacterial natural product streptozotocin, are prominent carcinogens 1,2 and important cancer chemotherapeutics 3,4 . Despite this functional group's significant impact on human health, dedicated enzymes involved in N-nitroso assembly have not been identified. Here, we describe a metalloenzyme from streptozotocin biosynthesis (SznF) that catalyzes an oxidative rearrangement of the guanidine group of N ω -methyl-L-arginine to generate an N-nitrosourea product. Structural characterization and mutagenesis of SznF uncovered two separate active sites that promote distinct steps in this transformation using different iron-containing metallocofactors. The discovery of this biosynthetic reaction, which has little precedent in enzymology or organic synthesis, expands the catalytic capabilities of non-heme iron-dependent enzymes to include N-N bond formation. We find biosynthetic gene clusters encoding SznF homologs are widely distributed among bacteria, including environmental organisms, plant symbionts, and human pathogens, suggesting an unexpectedly diverse and uncharacterized microbial reservoir of bioactive N-nitroso metabolites. Streptozotocin (SZN) (Zanosar®) is an N-nitrosourea natural product and approved cancer chemotherapeutic (Fig. 1a) 3,5 . SZN is also used to induce type I diabetes in animal models due to its toxicity towards pancreatic beta cells (> 28,500 PubMed references) 6 . Like other N-nitrosoureas, SZN exerts its activity in vivo by generating electrophilic DNA alkylating Reprints and permissions information is available at www.nature.com/reprints.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://

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