Crystal structure of the nitrosuccinate lyase CreD in complex with fumarate provides insights into the catalytic mechanism for nitrous acid elimination

Katsuyama, Yoshihiko; Sato, Yukari; Sugai, Yoshinori; Higashiyama, Yousuke; Senda, Masuo; Senda, Toshiya; Ohnishi, Yasuo

doi:10.1111/febs.14429

Cited by 15 publications

(15 citation statements)

References 44 publications

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“…To follow the fate of acetylhydrazine, we also reconstituted the activities of FzmN and FzmO, revealing that acetylhydrazine is first condensed onto the side chain carboxyl group of glutamic acid to form glutamylacetylhydrazine (5) before deacetylation to yield glutamylhydrazine (6). Glutamic acid is present in relatively high concentrations in the cytoplasm of most bacteria, and perhaps for that reason, glutamic acid has previously been demonstrated to be a common carrier molecule to effect many different types of transformations 18 In the fosfazinomycin biosynthetic pathway, we previously reported that argininylhydrazine is the substrate for the N-methyltransferase FzmH 15 .…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…For instance, during the biosynthesis of cremeomycin, a flavin-dependent monooxygenase, CreE, oxidizes aspartic acid to nitrosuccinic acid (1, Fig. 1b), and a lyase, CreD, subsequently liberates nitrous acid 6 .…”

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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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“…Furthermore, preliminary experiments explored the origin of the terminal N atom of the diazeniumdiolate group and chromatographic evidence suggested that it originated from nitrite. Recently, several reports have indicated similar biosynthetic pathways for the diazeniumdiolate alanosine, the diazo compounds cremeomycin and kanamycin, the pyridazine azamerone, the N ‐hydroxytriazenes triacsins and the hydrazide fosfazinomycin …”

Section: Methodsmentioning

confidence: 99%

Biosynthesis and Structure–Activity Relationship Investigations of the Diazeniumdiolate Antifungal Agent Fragin

et al. 2020

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Only a few natural products incorporating a diazeniumdiolate moiety have been isolated, and these compounds usually display a broad range of biological activities. Only recently has the first diazeniumdiolate natural product biosynthetic gene cluster been identified in Burkholderia cenocepacia H111, which produces the fungicide (−)‐fragin and the signal molecule rac‐valdiazen. In this study, l‐valine was identified as the initial substrate of (−)‐fragin biosynthesis with the aid of feeding experiments using isotopically labelled amino acid. The formation of the diazeniumdiolate was chemically studied with several proposed intermediates. Our results indicate that the functional group is formed during an early stage of the biosynthesis. Furthermore, an oxime compound was identified as a degradation product of (−)‐fragin and was also observed in the crude extract of the wild‐type strain. Moreover, a structure–activity relationship analysis revealed that each moiety of (−)‐fragin is essential for its biological activity.

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“…An alternative mechanism for N−N bond formation features the reaction between an amine and nitrous acid that is generated through the sequential function of a flavin‐dependent enzyme (CreE) and a lyase (CreD) on aspartate (Figure S1) . The diazo moiety found in cremeomycin, for example, is generated through the reaction between an arylamine and nitrous acid promoted by an acyl‐CoA ligase homologue (CreM, Figure S1) .…”

Section: Figurementioning

confidence: 99%

Identifying the Biosynthetic Gene Cluster for Triacsins with an N‐Hydroxytriazene Moiety

et al. 2019

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Triacsins are a family of natural products having in common an N‐hydroxytriazene moiety not found in any other known secondary metabolites. Though many studies have examined the biological activity of triacsins in lipid metabolism, their biosynthesis has remained unknown. Here we report the identification of the triacsin biosynthetic gene cluster in Streptomyces aureofaciens ATCC 31442. Bioinformatic analysis of the gene cluster led to the discovery of the tacrolimus producer Streptomyces tsukubaensis NRRL 18488 as a new triacsin producer. In addition to targeted gene disruption to identify necessary genes for triacsin production, stable isotope feeding was performed in vivo to advance the understanding of N‐hydroxytriazene biosynthesis.

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Crystal structure of the nitrosuccinate lyase CreD in complex with fumarate provides insights into the catalytic mechanism for nitrous acid elimination

Abstract: Nitrosuccinate lyase CreD, EC4.3.

Cited by 15 publications

References 44 publications

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

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

Biosynthesis and Structure–Activity Relationship Investigations of the Diazeniumdiolate Antifungal Agent Fragin

Identifying the Biosynthetic Gene Cluster for Triacsins with an N‐Hydroxytriazene Moiety

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