Studies on the biosynthesis of the antibiotic streptozotocin (streptozocin) by Streptomyces achromogenes var. streptozoticus. Feeding experiments with carbon-14 and tritium labelled precursors.

Singaram, Saraswathi; Lawrence, Rebecca S.; Hornemann, Ulfert

doi:10.7164/antibiotics.32.379

Cited by 19 publications

(18 citation statements)

References 11 publications

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“…c) experiments were performed. b, Exposing SZN to UV-light generated a one-carbon and one-nitrogen labeled cyclic urea previously reported to be a denitrosated SZN product, indicating that the distal nitroso nitrogen is labeled 9 . c, MS/MS fragmentation of SZN revealed a one-carbon labeled cyclic carbamate fragment, indicating that both the N-nitroso nitrogens are labeled.…”

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

confidence: 96%

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An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

Rohac

Mitchell

et al. 2019

Nature

121

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

confidence: 96%

“…streptozoticus NRRL 2697 revealed the origins of the sugar scaffold (D-glucosamine), the ureido linkage (Larginine or L-citrulline), and the N-methyl group (L-methionine) (Extended Data Fig. 1a) 9 . Though N-nitroso group biosynthesis was not investigated, the distal nitroso nitrogen atom was hypothesized to come from nitrite.…”

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confidence: 99%

An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

Rohac

Mitchell

et al. 2019

Nature

121

257

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“…The biosynthesis of streptozotocin is hypothesized to utilize nitrous acid or a biochemical equivalent to nitrosate the corresponding urea (Scheme 50). 1 Feeding studies with radioactively labeled compounds have indicated that glucosamine, L-methionine, and either L-citrulline or L-arginine are precursors to this metabolite. Future studies will be required to address the similarities and differences of N- nitrosation mechanism in primary and secondary metabolism.…”

Section: N–n Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.

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“…Microbes produce antimicrobial agents that can cause DNA damage through a variety of mechanisms, including DNA methylation by methyl halides (64), induction of single-or doublestrand breaks by bleomycin (65), inhibition of topoisomerase IV and DNA gyrase by quinolone derivatives (66), and induction of reactive oxygen species that can damage DNA by numerous antibiotics (67) and antifungals (68). Production of MNIBA by Muscodor isolates is most analogous to production of streptozotocin, a D-glucopyranose derivative of MNU, by Streptomyces achromogenes (69). Streptozotocin is a known methylating agent that is utilized as an anticancer drug that primarily targets pancreatic tumors (70).…”

Section: Discussionmentioning

confidence: 99%

Mycofumigation through production of the volatile DNA-methylating agent N-methyl-N-nitrosoisobutyramide by fungi in the genus Muscodor

Hutchings

Alpha-Cobb

Hiller

et al. 2017

Journal of Biological Chemistry

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Antagonistic microorganisms produce antimicrobials to inhibit the growth of competitors. Although water-soluble antimicrobials are limited to proximal interactions via aqueous diffusion, volatile antimicrobials are able to act at a distance and diffuse through heterogeneous environments. Here, we identify the mechanism of action of , an endophytic fungus known for its volatile antimicrobial activity toward a wide range of human and plant pathogens and its potential use in mycofumigation. Proposed uses of the species include protecting crops, produce, and building materials from undesired fungal or bacterial growth. By analyzing a collection of isolates with varying toxicity, we demonstrate that the volatile mycotoxin,-methyl--nitrosoisobutyramide, is the dominant factor in toxicity and acts primarily through DNA methylation. Additionally, isolates exhibit higher resistance to DNA methylation compared with other fungi. This work contributes to the evaluation of isolates as potential mycofumigants, provides insight into chemical strategies that organisms use to manipulate their environment, and provokes questions regarding the mechanisms of resistance used to tolerate constitutive, long-term exposure to DNA methylation.

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Studies on the biosynthesis of the antibiotic streptozotocin (streptozocin) by Streptomyces achromogenes var. streptozoticus. Feeding experiments with carbon-14 and tritium labelled precursors.

Abstract: Feeding experiments and chemical degradations have shown that D-[l-1'C,2-'H]-and-THE JOURNAL OF ANTIBIOTICS APR.

Cited by 19 publications

References 11 publications

An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Mycofumigation through production of the volatile DNA-methylating agent N-methyl-N-nitrosoisobutyramide by fungi in the genus Muscodor

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