RESUMO
Nonthmicin (1), a new polyether polyketide bearing a chlorinated tetronic acid, was isolated from the culture extract of a soil-derived Actinomadura strain. The structure of 1 was elucidated by interpretation of NMR and MS spectroscopic data, and the absolute configuration of 1 was proposed on the basis of the crystal structure of its dechloro congener ecteinamycin (2) also isolated from the same strain. Tetronic acids modified by halogenation have never been reported from natural products. Compounds 1 and 2 were found to have neuroprotective activity and antimetastatic properties at submicromolar concentrations in addition to antibacterial activity.
Assuntos
Actinomycetales/química , Antibacterianos/química , Antineoplásicos/química , Fármacos Neuroprotetores/química , Policetídeos/química , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Autofagia , Sobrevivência Celular/efeitos dos fármacos , Éteres/química , Furanos/química , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Invasividade Neoplásica , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Células PC12 , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Ratos , EstereoisomerismoRESUMO
Maklamicin is a spirotetronate-class antibiotic produced by Micromonospora sp. NBRC 110955, and a polyketide assembly line and a glycerate utilization system are involved in its biosynthesis. One tailoring step in the biosynthesis is predicted to be post-polyketide synthase (PKS) modification, which seems to be catalysed by putative cytochrome P450 monooxygenases, MakC2 and/or MakC3. In this study, we characterized makC2 and makC3 in the biosynthesis of maklamicin and identified a new maklamicin analogue from a makC2 disruptant. Gene deletion of makC2 resulted in the complete loss of maklamicin production with concomitant accumulation of a new compound (29-deoxymaklamicin), while gene deletion of makC3 did not affect the maklamicin production, indicating that 29-deoxymaklamicin is an intermediate in the biosynthetic pathway of maklamicin and should serve as the substrate of MakC2. 29-Deoxymaklamicin showed strong-to-modest anti-microbial activity against gram-positive bacteria. The fact that Streptomyces avermitilis heterologously expressing makC2 successfully converted 29-deoxymaklamicin into maklamicin confirmed that MakC2 is the final-step hydroxylase in the formation of mature maklamicin.
Assuntos
Antibacterianos/biossíntese , Macrolídeos/metabolismo , Micromonospora/genética , Micromonospora/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Vias Biossintéticas/genética , Sistema Enzimático do Citocromo P-450/deficiência , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Hidroxilação , Macrolídeos/química , Macrolídeos/farmacologia , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Streptomyces/genética , Streptomyces/metabolismoRESUMO
Three new cyclic pentadepsipeptides, hikiamides A-C (1-3), were isolated from the culture extract of Fusarium sp. TAMA 456. The structures were determined by spectroscopic analysis using NMR and MS, and the absolute configurations were established by using Marfey's method and chiral HPLC analysis. Hikiamides induced the differentiation of murine ST-13 preadipocytes into mature adipocytes at 2 µM and adiponectin mRNA expression (5- to 13-fold higher than control). They also induced PPAR-γ-dependent gene expression at a concentration from 0.63 to 10 µM in a gene reporter assay.
Assuntos
Depsipeptídeos/isolamento & purificação , Fusarium/química , Adipócitos/efeitos dos fármacos , Animais , Sequência de Bases , Cromatografia Líquida de Alta Pressão , Depsipeptídeos/química , Luciferases/metabolismo , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , PPAR gama/metabolismo , Reação em Cadeia da PolimeraseAssuntos
Adipogenia/efeitos dos fármacos , Descoberta de Drogas , Hypocreales/metabolismo , Hipoglicemiantes/isolamento & purificação , PPAR gama/agonistas , Pirrolidinonas/isolamento & purificação , Ácido Tenuazônico/análogos & derivados , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Fármacos Antiobesidade/farmacologia , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/isolamento & purificação , Fármacos Gastrointestinais/farmacologia , Genes Reporter/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Micrococcus luteus/efeitos dos fármacos , Micrococcus luteus/crescimento & desenvolvimento , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , PPAR gama/genética , PPAR gama/metabolismo , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Ácido Tenuazônico/química , Ácido Tenuazônico/isolamento & purificação , Ácido Tenuazônico/farmacologiaRESUMO
A new pyrrolidine alkaloid, preussin B (1), was isolated from the culture extract of the fungus Simplicillium lanosoniveum TAMA 173 along with the known congener preussin (2). The structure and absolute configuration of 1 were determined by spectroscopic analysis and spectral comparison with 2. Feeding experiments with 13C-labeled precursors revealed that the pyrrolidine ring of 1 was assembled from acetate and l-phenylalanine by a PKS-NRPS hybrid biosynthetic pathway.
Assuntos
Anisomicina/análogos & derivados , Hypocreales/química , Alcaloides/biossíntese , Alcaloides/metabolismo , Anisomicina/química , Anisomicina/isolamento & purificação , Estrutura Molecular , Complexos Multienzimáticos/biossíntese , Complexos Multienzimáticos/metabolismo , Peptídeo Sintases/biossíntese , Peptídeo Sintases/química , Peptídeo Sintases/metabolismo , Fenilalanina/biossíntese , Fenilalanina/metabolismo , Estereoisomerismo , Streptomyces/metabolismoRESUMO
Marianins A (1) and B (2), two new prenylated phenylpropanoids, were isolated from the culture extract of the fungus Mariannaea camptospora. Structures of marianins were elucidated by interpretation of NMR and other spectroscopic data. 1 is a 5-methylcoumarin bearing two prenyloxy groups, while 2 is an orcinol derivative substituted with a 3,3-dimethyl-4-pentenoyl chain. 2 is possibly derived from 1 through a Claisen rearrangement of the prenyl group, followed by lactone hydrolysis and decarboxylation. These compounds showed weak antibacterial activity against Micrococcus luteus.
