Novel .alpha.,.beta.-unsaturated azoxy-containing antibiotic

McGahren, William J.; Kunstmann, M. P.

doi:10.1021/ja01038a081

Cited by 45 publications

(30 citation statements)

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“…Naturally occurring azoxyalkene compounds constitute a fascinating group of secondary metabolites with vast structural diversity, for example, elaiomycin, LL‐BH872α, valanimycin, jietacin, maniwamycins, and elaiomycins D and E (Scheme S2) . Elaiomycin and valanimycin are well‐studied azoxy‐bearing natural products.…”

Section: Resultsmentioning

confidence: 99%

Isolation and Biosynthesis of an Azoxyalkene Compound Produced by a Multiple Gene Disruptant of Streptomyces rochei

et al. 2015

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Streptomyces rochei 7434AN4 predominantly produces lankacidin and lankamycin under normal culture conditions, thus suggesting that other biosynthetic gene clusters for secondary metabolites are silent. To identify the silent metabolites of 7434AN4, we constructed mutant KA57 with multiple disruptions of the transcriptional repressor srrB and the biosynthesis genes for both antibiotics. KA57 accumulated a compound (KA57A) with a strong UV absorption at 235 nm, not detected in the parent strain or other mutants. Various spectroscopic analyses revealed that KA57A is an azoxyalkene compound with the molecular formula C10 H20 N2 O3 and with the R configuration at C-2. Biosynthesis of KA57A was also studied by feeding with labeled acetates, amino acids, and 1-hexylamine. The hexenyl moiety (C1'-C6') was derived from fatty acid, whereas the 3-aminobutan-1,2-diol moiety (C1-C4) was derived from C-2 of acetate (C1) and serine (C2-C4). Incorporation of [1,1-(2) H2 ]-1-hexylamine indicated that C1'-C2' dehydrogenation occurs as the final step of biosynthesis.

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Section: Resultsmentioning

confidence: 99%

Isolation and Biosynthesis of an Azoxyalkene Compound Produced by a Multiple Gene Disruptant of Streptomyces rochei

et al. 2015

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“…Cycad plants accumulate the carcinogenic and cytotoxic azoxy compounds macrozamin and cycasin in their nuts [46]. Similar azoxy compounds are produced by several actinomycetes [47,48] and fungi [49]. Arabidopsis P1‐ZCr might protect cells when azoxy compounds are produced endogenously under stressed conditions or introduced exogenously by infection.…”

Section: Resultsmentioning

confidence: 99%

A novel NADPH:diamide oxidoreductase activity in Arabidopsis thaliana P1 ζ‐crystallin

Mano

Babiychuk

Belles‐Boix

et al. 2000

European Journal of Biochemistry

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The z-crystallin (ZCr) gene P1 of Arabidopsis thaliana, known to confer tolerance toward the oxidizing drug 1,1 H -azobis(N,N-dimethylformamide) (diamide) to yeast [Babiychuk, E., Kushnir, S., Belles-Boix, E., Van Montagu, M. & Inze Â, D. (1995) J. Biol. Chem. 270, 26224], was expressed in Escherichia coli to characterize biochemical properties of the P1-z-crystallin (P1-ZCr). Recombinant P1-ZCr, a noncovalent dimer, showed NADPH:quinone oxidoreductase activity with specificity to quinones similar to that of guinea-pig ZCr. P1-ZCr also catalyzed the divalent reduction of diamide to 1,2-bis(N,N-dimethylcarbamoyl)hydrazine, with a k cat comparable with that for quinones. Two other azodicarbonyl compounds also served as substrates of P1-ZCr. Guinea-pig ZCr, however, did not catalyze the azodicarbonyl reduction. Hence, plant ZCr is distinct from mammalian ZCr, and can be referred to as NADPH:azodicarbonyl/quinone reductase. The quinone-reducing reaction was accompanied by radical chain reactions to produce superoxide radicals, while the azodicarbonylreducing reaction was not. Specificity to NADPH, as judged by k cat /K m , was . 1000-fold higher than that to NADH both for quinones and diamide. N-Ethylmaleimide and p-chloromercuribenzoic acid inhibited both quinone-reducing and diamide-reducing activities. Both NADPH and NADP 1 suppressed the inhibition, but NADH did not, suggesting that sulfhydryl groups reside in the binding site for the phosphate group on the adenosine moiety of NADPH. The diamide-reducing activity of P1-ZCr accounts for the tolerance of P1-overexpressing yeast to diamide. Other possible physiological functions of P1-ZCr in plants are discussed.

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“…Besides elaiomycin, only a few antibiotics containing an azoxy chromophore have been described; these include: antibiotic LL-BH872a, 9 maniwamycins A and B 10 and azoxybacilin 11 (all show strong antifungal activity); valanimycin, which shows antitumor and antibacterial activity; 12 and jietacins A and B, which exhibit a pronounced nematocidal and weak antifungal activity. 13 In contrast to azoxy-containing compounds, naturally occurring hydrazines and hydrazides are rarely described.…”

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Elaiomycins B and C, novel alkylhydrazides produced by Streptomyces sp. BK 190

et al. 2011

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Dereplicated novel actinomycetes from neglected habitats provide high quality biological material for screening programs designed to detect novel bioactive secondary metabolites. 2 Such organisms include neutrotolerant acidophilic streptomycetes which grow from pH 4.5 to 7.5, with an optimum between pH 5.0 and 5.5. 3 Members of this group were isolated from a hay meadow soil taken from Cockle Park Experimental Farm in Northumberland, UK. The isolates were grown as submerged cultures in complex media, and extracts from the culture filtrates and mycelia included in our HPLC-diode array screening program to detect novel secondary metabolites by means of an in-house HPLC-UV-Vis database, which contains approximately 950 natural products, mainly antibiotics. 4 Strain BK 190 was of interest because of the presence of three prominent peaks in the HPLC profile of a culture filtrate extract. The strain was assigned to the genus Streptomyces by its morphological and chemotaxonomic properties. 5 Strain BK 190 formed an extensively branched substrate mycelium, a grey aerial spore mass and aerial hyphae, which differentiated into spiral chains of smooth-surfaced spores on oatmeal agar, contained LL-diaminopimelic acid, galactose, glucose and xylose as major sugars, N-acetylated muramic acid, predominant amounts of hexa-and octa-hydrogenated menaquinones with nine isoprene units, and produced iso-and anteiso-branched fatty acids with C 15:0 and iso-C 16:0 as major components. The temperature and pH ranges for growth were 10-35 1C and pH 4.0-8.0, respectively. Phylogenetic analyses showed that the organism was most closely related to the type strain of Streptomyces sanglieri; the two organisms shared a 16S rRNA similarity of 99.9%, a value that corresponds to a single nucleotide difference at 1434 locations.The metabolite with retention time of 12.3 min in our standardized reversed-phase gradient elution profile was identified by HPLC-diode array and HPLC-ESI-MS analysis to be elaiomycin (1), an azoxy antibiotic that was first isolated from Streptomyces hepaticus and found to strongly inhibit the growth of Mycobacterium tuberculosis. 6 Two further prominent peaks, elaiomycin B (2) with a retention time of 16.4 min, and elaiomycin C (3) with a retention time of 17.2 min showed characteristic UV-vis spectra that differed from those of all of the reference compounds stored in the database. A significant production of 1-3 was observed in oatmeal medium in the 100 ml shake flask scale, which was reproducible in a scale up to a 20-liter fermentor. Strain BK 190 reached a maximal biomass of 12 volume (%) at a cultivation time of 96 h and this correlated with the highest production of elaiomycins, which reached yields of 24 mg l À1 elaiomycin (1), 15 mg l À1 elaiomycin B (2) and 9.5 mg l À1 elaiomycin C (3) in the culture filtrate, and 15 mg l À1 of 2 and 12 mg l À1 of 3 in the mycelium, respectively. Compounds 1-3 were isolated from the culture filtrate by separation on an Amberlite XAD-16 column (Rohm and Haas Deutschland, Frankfurt...

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Novel .alpha.,.beta.-unsaturated azoxy-containing antibiotic

Cited by 45 publications

References 0 publications

Isolation and Biosynthesis of an Azoxyalkene Compound Produced by a Multiple Gene Disruptant of Streptomyces rochei

Isolation and Biosynthesis of an Azoxyalkene Compound Produced by a Multiple Gene Disruptant of Streptomyces rochei

A novel NADPH:diamide oxidoreductase activity in Arabidopsis thaliana P1 ζ‐crystallin

Elaiomycins B and C, novel alkylhydrazides produced by Streptomyces sp. BK 190

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