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1.
Appl Environ Microbiol ; 75(7): 1938-49, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19201970

RESUMO

The pathways responsible for cell wall polysaccharide biosynthesis are vital in eukaryotic microorganisms. The corresponding synthases are potential targets of inhibitors such as fungicides. Despite their fundamental and economical importance, most polysaccharide synthases are not well characterized, and their molecular mechanisms are poorly understood. With the example of Saprolegnia monoica as a model organism, we show that chitin and (1-->3)-beta-d-glucan synthases are located in detergent-resistant membrane microdomains (DRMs) in oomycetes, a phylum that comprises some of the most devastating microorganisms in the agriculture and aquaculture industries. Interestingly, no cellulose synthase activity was detected in the DRMs. The purified DRMs exhibited similar biochemical features as lipid rafts from animal, plant, and yeast cells, although they contained some species-specific lipids. This report sheds light on the lipid environment of the (1-->3)-beta-d-glucan and chitin synthases, as well as on the sterol biosynthetic pathways in oomycetes. The results presented here are consistent with a function of lipid rafts in cell polarization and as platforms for sorting specific sets of proteins targeted to the plasma membrane, such as carbohydrate synthases. The involvement of DRMs in the biosynthesis of major cell wall polysaccharides in eukaryotic microorganisms suggests a function of lipid rafts in hyphal morphogenesis and tip growth.


Assuntos
Proteínas de Algas/análise , Quitina Sintase/análise , Glucosiltransferases/análise , Microdomínios da Membrana/química , Saprolegnia/química , Saprolegnia/enzimologia
2.
J Lipid Res ; 48(4): 816-25, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17220481

RESUMO

Hydroxy-alkenals, such as 4-hydroxy-2(E)-nonenal (4-HNE; from n-6 fatty acids), are degradation products of fatty acid hydroperoxides, including those generated by free radical attack of membrane polyunsaturated fatty acyl moieties. The cytotoxic effects of hydroxy-alkenals are well known and are mainly attributable to their interaction with different molecules to form covalent adducts. Indeed, ethanolamine phospholipids (PEs) can be covalently modified in a cellular system by hydroxy-alkenals, such as 4-HNE, 4-hydroxy-2(E)-hexenal (4-HHE; from n-3 fatty acids), and 4-hydroxy-dodecadienal (4-HDDE; from the 12-lipoxygenase product of arachidonic acid), to form mainly Michael adducts. In this study, we describe the formation of PE Michael adducts in human blood platelets in response to oxidative stress and in retinas of streptozotocin-induced diabetic rats. We have successfully characterized and evaluated, for the first time, PEs coupled with 4-HHE, 4-HNE, and 4-HDDE by gas chromatography-mass spectrometry measurement of their ethanolamine moieties. We also report that aggregation of isolated human blood platelets enriched with PE-4-hydroxy-alkenal Michael adducts was altered. These data suggest that these adducts could be used as specific markers of membrane disorders occurring in pathophysiological states with associated oxidative stress and might affect cell function.


Assuntos
Aldeídos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Fosfatidiletanolaminas/metabolismo , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Cromatografia Gasosa , Diabetes Mellitus Experimental/induzido quimicamente , Humanos , Peróxido de Hidrogênio , Espectrometria de Massas , Estresse Oxidativo , Ratos , Retina/metabolismo , Retina/patologia , Estreptozocina
3.
Bioorg Med Chem Lett ; 17(5): 1428-31, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17169556

RESUMO

Ac2-DPD, the bis-(O)-acetylated derivative of 4,5-dihydroxy-2,3-pentanedione (DPD), was prepared both as a racemic mixture and in the optically active form found in naturally occurring DPD. It was shown to exhibit the same ability as DPD to induce bioluminescence in Vibrio harveyi and beta-galactosidase activity in Salmonella enterica Typhimurium, both gram-negative bacteria. Likewise, it was also shown to inhibit biofilm formation in gram-positive Bacillus cereus. The most likely hypothesis is that Ac2-DPD activity is due to the release of DPD by in situ hydrolysis of the ester groups. Importantly, by contrast with DPD, Ac2-DPD proved to be a stable compound which can be purified and stored.


Assuntos
Homosserina/análogos & derivados , Lactonas , Pentanos/química , Acetilação , Estabilidade de Medicamentos , Hidrólise , Percepção de Quorum/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 14(14): 4781-91, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16574415

RESUMO

A series of 15 racemic alkyl- and aryl-N-substituted ureas, derived from homoserine lactone, were synthesized and tested for their ability to competitively inhibit the action of 3-oxohexanoyl-l-homoserine lactone, the natural inducer of bioluminescence in the bacterium Vibrio fischeri. N-alkyl ureas with an alkyl chain of at least 4 carbon atoms, as well as certain ureas bearing a phenyl group at the extremity of the alkyl chain, were found to be significant antagonists. In the case of N-butyl urea, it has been shown that the antagonist activity was related to the inhibition of the dimerisation of the N-terminal domain of ExpR, a protein of the receptor LuxR family. Molecular modelling suggested that this would result from the formation of an additional hydrogen bond in the protein acylhomoserine lactone binding cavity.


Assuntos
Aliivibrio fischeri/efeitos dos fármacos , Aliivibrio fischeri/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Transativadores/antagonistas & inibidores , Ureia/análogos & derivados , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Aliivibrio fischeri/genética , Sequência de Bases , Sítios de Ligação , DNA Bacteriano/genética , Dimerização , Luminescência , Modelos Moleculares , Estrutura Terciária de Proteína , Proteínas Repressoras/química , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transativadores/química , Transativadores/genética , Transativadores/metabolismo , Ureia/síntese química , Ureia/química , Ureia/farmacologia
5.
Bioorg Med Chem Lett ; 14(20): 5145-9, 2004 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-15380216

RESUMO

A series of 11 new analogues of N-acylhomoserine lactones in which the carboxamide bond was replaced by a sulfonamide one, has been synthesised. These compounds were evaluated for their ability to competitively inhibit the action of 3-oxohexanoyl-L-homoserine lactone, the natural ligand of the quorum sensing transcriptional regulator LuxR, which in turn activates expression of bioluminescence in the model bacterium Vibrio fischeri. Several compounds were found to display antagonist activity. Molecular modeling suggests that the latter prevent a cascade of structural rearrangements necessary for the formation of the active LuxR dimer.


Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/síntese química , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Homosserina/análogos & derivados , Homosserina/síntese química , Lactonas/síntese química , Sulfonamidas/síntese química , 4-Butirolactona/antagonistas & inibidores , 4-Butirolactona/química , Aliivibrio fischeri/efeitos dos fármacos , Sequência de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , Dimerização , Homosserina/química , Homosserina/farmacologia , Lactonas/química , Lactonas/farmacologia , Medições Luminescentes , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Transativadores/antagonistas & inibidores , Transativadores/química , Transativadores/metabolismo
6.
J Lipid Res ; 44(5): 917-26, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12588949

RESUMO

Lipid oxidation is implicated in a wide range of pathophysiogical disorders, and leads to reactive compounds such as fatty aldehydes, of which the most well known is 4-hydroxy-2E-nonenal (4-HNE) issued from 15-hydroperoxyeicosatetraenoic acid (15-HpETE), an arachidonic acid (AA) product. In addition to 15-HpETE, 12(S)-HpETE is synthesized by 12-lipoxygenation of platelet AA. We first show that 12-HpETE can be degraded in vitro into 4-hydroxydodeca-(2E,6Z)-dienal (4-HDDE), a specific aldehyde homologous to 4-HNE. Moreover, 4-HDDE can be detected in human plasma. Second, we compare the ability of 4-HNE, 4-HDDE, and 4-hydroxy-2E-hexenal (4-HHE) from n-3 fatty acids to covalently modify different ethanolamine phospholipids (PEs) chosen for their biological relevance, namely AA- (20: 4n-6) or docosahexaenoic acid- (22:6n-3) containing diacyl-glycerophosphoethanolamine (diacyl-GPE) and alkenylacyl-glycerophosphoethanolamine (alkenylacyl-GPE) molecular species. The most hydrophobic aldehyde used, 4-HDDE, generates more adducts with the PE subclasses than does 4-HNE, which itself appears more reactive than 4-HHE. Moreover, the aldehydes show higher reactivity toward alkenylacyl-GPE compared with diacyl-GPE, because the docosahexaenoyl-containing species are more reactive than those containing arachidonoyl. We conclude that the different PE species are differently targeted by fatty aldehydes: the higher their hydrophobicity, the higher the amount of adducts made. In addition to their antioxidant potential, alkenylacyl-GPEs may efficiently scavenge fatty aldehydes.


Assuntos
Aldeídos/química , Fosfatidiletanolaminas/química , Aldeídos/síntese química , Aldeídos/metabolismo , Animais , Sítios de Ligação , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Ácido Eicosapentaenoico/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Ratos , Fatores de Tempo
7.
Bioorg Med Chem Lett ; 12(8): 1153-7, 2002 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-11934577

RESUMO

A series of 22 novel synthetic N-acyl-homoserine lactone analogues has been evaluated for both their inducing activity and their ability to competitively inhibit the action of 3-oxo-hexanoyl-L-homoserine lactone, the natural inducer of bioluminescence in the bacterium Vibrio fischeri. In the newly synthesized analogues, the extremity of the acyl chain was modified by introducing ramified alkyl, cycloalkyl or aryl substituents at the C-4 position. Most of the analogues bearing either acyclic or cyclic alkyl substituents showed inducing activity. In contrast, the phenyl substituted analogues displayed significant antagonist activity. We hypothesized that the antagonist activity of the phenyl compounds may result from the interaction between the aryl group and aromatic amino acids of the LuxR receptor, preventing it from adopting the active dimeric form.


Assuntos
4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , 4-Butirolactona/síntese química , Proteínas de Bactérias/genética , Proteínas Repressoras/genética , Transativadores/genética , Vibrio/genética , Vibrio/fisiologia
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