On the origin of the isocyano function in marine sponges

Hagadone, Mark R.; Scheuer, Paul J.; Holm, Arne

doi:10.1021/ja00320a044

Cited by 69 publications

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“…Most isonitriles show a wide antibiotic activity spectrum and have potential as possible agents of practical use, e.g., a series of isocyanoterpenes isolated from marine sponges exhibit antimalarial activity (36,37) and an antifouling effect similar to those of copper sulfate (38). Interest in the biosynthesis of these metabolites, particularly in the origin of the isocyano group, has led to some experimental studies on them (20)(21)(22)(23)(24). However, the metabolism of isonitriles had been completely unknown at the protein and gene levels before we discovered an isonitrile-degrading enzyme, which was designated isonitrile hydratase (25).…”

Section: Discussionmentioning

confidence: 99%

“…This isonitrile exhibits a wide antibiotic activity spectrum (19). Although parts of the metabolic intermediates of some isonitriles have been elucidated through incorporation experiments (20)(21)(22)(23)(24), their synthetic and degradative pathways remained entirely undetermined. Furthermore, to our knowledge none of the enzymes involved in isonitrile metabolism, except for the enzyme we describe below, has yet been identified.…”

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confidence: 99%

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Amine-synthesizing enzyme N-substituted formamide deformylase: Screening, purification, characterization, and gene cloning

Fukatsu

Hashimoto²,

Goda³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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N-substituted formamide was produced through the hydration of an isonitrile by isonitrile hydratase in the isonitrile metabolism. The former compound was further degraded by a microorganism, strain F164, which was isolated from soil through an acclimatization culture. The N-substituted formamide-degrading microorganism was identified as Arthrobacter pascens. The microbial degradation was found to proceed through an enzymatic reaction, the N-substituted formamide being hydrolyzed to yield the corresponding amine and formate. The enzyme, designated as Nsubstituted formamide deformylase (NfdA), was purified and characterized. The native enzyme had a molecular mass of Ϸ61 kDa and consisted of two identical subunits. It stoichiometrically catalyzed the hydrolysis of N-benzylformamide (an N-substituted formamide) to benzylamine and formate. Of all of the N-substituted formamides tested, N-benzylformamide was the most suitable substrate for the enzyme. However, no amides were accepted as substrates. The gene (nfdA) encoding this enzyme was also cloned. The deduced amino acid sequence of nfdA exhibited the highest overall sequence identity (28%) with those of regulatory proteins among known proteins. Only the N-terminal region (residues 58 -72) of NfdA also showed significant sequence identity (27-73%) to that of each member of the amidohydrolase superfamily, although there was no similarity in the overall sequence except in the above limited region. N itriles are very toxic and generally unbiodegradable organic compounds containing a CϵN moiety. We have studied nitrile metabolism (1-3) and clarified the structures and functions of enzymes [i.e., nitrilase (4-7), nitrile hydratase (8-11), and amidase (12-14)] involved in metabolism and their genes and regulation mechanisms.On the other hand, information is quite limited on the metabolism of an isonitrile (more generally called an isocyanide) containing an isocyano group (ϪNϵC), which is an isomer of a nitrile. Isonitriles as well as nitriles are generally highly toxic and produced in nature by various organisms, including bacteria, fungi, marine sponges, etc. (15-17). An isocyanide metabolite, xanthocillin, was first isolated from Penicillium notatum (18). This isonitrile exhibits a wide antibiotic activity spectrum (19). Although parts of the metabolic intermediates of some isonitriles have been elucidated through incorporation experiments (20-24), their synthetic and degradative pathways remained entirely undetermined. Furthermore, to our knowledge none of the enzymes involved in isonitrile metabolism, except for the enzyme we describe below, has yet been identified.Recently, we isolated a microorganism, Pseudomonas putida strain N19-2, that is able to degrade isonitriles from soil and discovered an isonitrile-metabolizing enzyme, designated as isonitrile hydratase (EC 4.2.1.103), in this strain (25,26). This enzyme catalyzes the hydration of an isonitrile [R-NϵC] to the corresponding N-substituted formamide [R-NH-CH(ϭO)], and confers the ability of isonitrile-degrada...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Amine-synthesizing enzyme N-substituted formamide deformylase: Screening, purification, characterization, and gene cloning

Fukatsu

Hashimoto²,

Goda³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…A Hymeniacidon species (marine sponge) producing an isocyano-compound, 2-isocyanopupukeanane, was found to transform it into the corresponding formamide (10), which suggests the existence of isonitrile hydratase in the species. Because hydration is one of the simplest reactions that could occur in isonitrile metabolism, it is possible that isonitrile hydratase is not rarely present in isonitrile-producing organisms.…”

Section: Fig 4 CD Spectra Of the Wild-type And Mutant Isonitrile Hymentioning

confidence: 99%

Isonitrile Hydratase from Pseudomonas putidaN19–2

Goda

Hashimoto

Takase

et al. 2002

Journal of Biological Chemistry

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Isonitrile hydratase is a novel enzyme in Pseudomonas putida N19 -2 that catalyzes the conversion of isonitriles to N-substituted formamides. Based on N-terminal and internal amino acid sequences, a 535-bp DNA fragment corresponding to a portion of the isonitrile hydratase gene was amplified, which was used as a probe to clone a 6.4-kb DNA fragment containing the whole gene. Sequence analysis of the 6.4-kb fragment revealed that the isonitrile hydratase gene (inhA) was 684 nucleotides long and encoded a protein with a molecular mass of 24,211 Da. Overexpression of inhA in Escherichia coli gave a large amount of soluble isonitrile hydratase exhibiting the same molecular and catalytic properties as the native enzyme from the Pseudomonas strain. The predicted amino acid sequence of inhA showed low similarity to that of an intracellular protease in Pyrococcus horikoshii (PH1704), and an active cysteine residue in the protease was conserved in the isonitrile hydratase at the corresponding position (Cys-101). A mutant enzyme containing Ala instead of Cys-101 did not exhibit isonitrile hydratase activity at all, demonstrating the essential role of this residue in the catalytic function.

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“…Among these, novel sesqui-and di-terpenoid isocyanides, isothiocyanates, and formamides represent a group of closely related compounds, none of which is yet known to be produced by any other marine organism (1). Undoubtedly, the mediterranean Axinella cannabina is the most prolific source of these unusual metabolites since its chemical investigation resulted in the isolation of isocyanides always accompanied by the corresponding isothiocyanates and formamides (2), most likely biogenetically deriving from them (3,4).…”

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New nitrogenous sesquiterpenes based on alloaromadendrane and epi-eudesmane skeletons from the marine sponge Axinellacannabina

Ciminiello¹,

Fattorusso²,

Magno³

et al. 1987

Can. J. Chem.

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PATRIZIA CIMINIELLO, ERNESTO FATTORUSSO, SILVANA MAGNO, and LUCIANO MAYOL. Can. J. Chem. 65, 518 (1987). Six new nitrogenous sesquiterpenes (1-6), which form two new isocyanide-isothiocyanate-formamide series, have been isolated from the marine sponge Axinella cannabina. The structure elucidation of these compounds is based upon spectral data, including 2D-nmr, and chemical interconversions. The complete assignment of all proton and carbon resonances in nrnr spectra of axisonitrile-2 (7), an isonitrile previously isolated from the same source, is also reported, along with its complete relative stereochemistry.PATRIZIA CIMINIELLO, ERNESTO FATTORUSSO, SILVANA MAGNO et LIJCIANO MAYOL. Can. J. Chem. 65, 518 (1987). De I'Cponge marine Axinella cannabina ont CtC isolCs six nouveaux sesquiterpknes azotCs (1-6) qui constituent deux nouvelles sCries de trois composCs voisins : isonitrile, isothiocyanate et formamide. Se basant sur leurs intercorrClations chimiques et faisant appel A la rmn, y compris la rmn ' H -2~, on a determink les structures. On a aussi donne I'attribution complkte des rksonances de tous les protons et de tous les carbones, dans la rmn du composC axisonitrile-2, un isonitrile deji is016 de la m2me eponge, avec sa complkte configuration relative.Numerous bioactive natural products carrying rare functionalities have been isolated from marine sponges. Among these, novel sesqui-and di-terpenoid isocyanides, isothiocyanates, and formamides represent a group of closely related compounds, none of which is yet known to be produced by any other marine organism (1). Undoubtedly, the mediterranean Axinella cannabina is the most prolific source of these unusual metabolites since its chemical investigation resulted in the isolation of isocyanides always accompanied by the corresponding isothiocyanates and formamides (2), most likely biogenetically deriving from them (3, 4).In this paper we amplify on our earlier work by reporting the presence in this organism of two further isocyanideisothiocyanate-formamide series based on the epi-eudesmane (1-3) and alloaromadendrane (4-6) carbon skeletons. Compound 4 is epimeric at C-1 to the co-occurring axisonitrile-2 whose structure had been previously established devoid of the chirality of the 10-carbon atom (5), which is here described.Isolation of sesquiterpenes 1-6 from the CHC13 soluble material of the methanolic extract of the animals was carried out by chromatography on Si02 columns followed by reversed phase high performance liquid chromatographies.Spectral (nrnr and ms) examination of the pure constituents thus obtained made it apparent that each of the two terpenoid series was based on a single carbon skeleton and that the members of each series differed only in the nature of the functional groups. This was confirmed by conversion of the isocyanides into the formamides, by treatment with aqueous ACOH, and into the isothiocyanates, by heating with sulphur.epi -Eudesmane compounds (1 -3)Compound 1 (1 1-isocyano-7 pH-eudesm-5-ene), an oil, showed [a], -85.7 and was a...

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On the origin of the isocyano function in marine sponges

Cited by 69 publications

References 0 publications

Amine-synthesizing enzyme N-substituted formamide deformylase: Screening, purification, characterization, and gene cloning

Amine-synthesizing enzyme N-substituted formamide deformylase: Screening, purification, characterization, and gene cloning

Isonitrile Hydratase from Pseudomonas putidaN19–2

New nitrogenous sesquiterpenes based on alloaromadendrane and epi-eudesmane skeletons from the marine sponge Axinellacannabina

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