RESUMEN
Pyridinochelin, a novel tetradentate catecholate-type siderophore, has been designed on the basis of the active analog enterobactin and was then synthesized. Growth promotion tests indicate that this synthetic siderophore feeds various pathogenic bacteria most effectively with iron even though it lacks one catecholate group compared to enterobactin. The superposition of the mentioned siderophore structures suggests that the structure of the skeleton connecting the catecholate groups might be an important factor for the iron transport.
Asunto(s)
Bacterias/crecimiento & desarrollo , Catecoles , Sideróforos , Sideróforos/química , Bacterias/efectos de los fármacos , Simulación por Computador , Diseño de Fármacos , Modelos Moleculares , Conformación Molecular , Sideróforos/síntesis química , Sideróforos/farmacología , Programas InformáticosRESUMEN
The human T cell receptor CD4 is a type I integral membrane glycoprotein that is involved in T cell activation and also acts as the primary coreceptor for human immunodeficiency viruses (HIV). Here the structure of a synthetic 38 amino acid peptide corresponding to the complete cytoplasmic domain of CD4 (CD4CYTO) has been investigated under a variety of solution conditions using a combination of circular dichroism and homonuclear two-dimensional 1H nuclear magnetic resonance spectroscopy. In the presence of the membrane mimetic 2,2,2-trifluoroethanol (TFE), a conformational change of CD4CYTO from a random coil to an alpha-helical structure was observed. In keeping with this, CD4CYTO has the potential to associate with membranes as demonstrated by binding studies of in vitro phosphorylated CD4CYTO with microsomal membranes. Both chemical shift and nuclear Overhauser enhancement data in 50% 2,2, 2-trifluoroethanol solution provide direct experimental evidence for the predominance of a short amphiphatic alpha-helix that is approximately 4 turns in length and extends from positions Arg-402 to Lys-417. The present data provide, for the first time, compelling experimental evidence that only a fraction of CD4CYTO has a propensity for adopting secondary structure under conditions that are assumed to exist at or near to the membrane surface and that this alpha-helical structure is located in the membrane-proximal region of CD4CYTO. The N-terminal residues, that link the alpha-helix to the transmembrane anchor of CD4, and a substantial C-terminal portion (14-18 residues) of CD4CYTO are unstructured under the solution conditions investigated. Correlation of our structural data with recent studies on the biological activity of CD4CYTO indicates that the alpha-helix is of crucial importance for the interaction of CD4 with Nef and Vpu in the process of HIV-mediated CD4 down-regulation.
Asunto(s)
Antígenos CD4/química , Citoplasma/metabolismo , Secuencia de Aminoácidos , Antígenos CD4/aislamiento & purificación , Antígenos CD4/metabolismo , Dicroismo Circular , Citoplasma/química , Citoplasma/inmunología , Humanos , Membranas Intracelulares/metabolismo , Microsomas/metabolismo , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Péptidos/síntesis química , Péptidos/aislamiento & purificación , Péptidos/metabolismo , Estructura Secundaria de Proteína/efectos de los fármacos , Soluciones , Trifluoroetanol/farmacologíaRESUMEN
The effect of ten naturally occurring and two synthetic inhibitors of NADH:ubiquinone oxidoreductase (complex I) of bovine heart, Neurospora crassa and Escherichia coli and glucose:ubiquinone oxidoreductase (glucose dehydrogenase) of Gluconobacter oxidans was investigated. These inhibitors could be divided into two classes with regard to their specificity and mode of action. Class I inhibitors, including the naturally occurring piericidin A, annonin VI, phenalamid A2, aurachins A and B, thiangazole and the synthetic fenpyroximate, inhibit complex I from all three species in a partially competitive manner and glucose dehydrogenase in a competitive manner, both with regard to ubiquinone. Class II inhibitors including the naturally occurring rotenone, phenoxan, aureothin and the synthetic benzimidazole inhibit complex I from all species in an non-competitive manner, but have no effect on the glucose dehydrogenase. Myxalamid PI could not be classified as above because it inhibits only the mitochondrial complex I and in a competitive manner. All inhibitors affect the electron-transfer step from the high-potential iron-sulphur cluster to ubiquinone. Class I inhibitors appear to act directly at the ubiquinone-catalytic site which is related in complex I and glucose dehydrogenase.
Asunto(s)
Acetobacteraceae/enzimología , Inhibidores Enzimáticos/metabolismo , Escherichia coli/enzimología , Glucosa Deshidrogenasas/metabolismo , Mitocondrias Cardíacas/enzimología , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Neurospora crassa/enzimología , Ubiquinona/metabolismo , Animales , Sitios de Unión , Bovinos , Inhibidores Enzimáticos/farmacología , Glucosa 1-Deshidrogenasa , Glucosa Deshidrogenasas/antagonistas & inhibidores , Membranas Intracelulares/enzimología , Cinética , Estructura Molecular , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , NAD(P)H Deshidrogenasa (Quinona)/química , Relación Estructura-ActividadRESUMEN
Novel citrate-hydroxamate siderophores, named nannochelins A, B and C, were isolated from the culture broth of the myxobacterium Nannocystis exedens strain Na e485. The new substances showed weak growth-inhibitory activity against some bacteria and fungi.
Asunto(s)
Antifúngicos/aislamiento & purificación , Citratos/aislamiento & purificación , Ácidos Hidroxámicos/aislamiento & purificación , Myxococcales/clasificación , Fenómenos Químicos , Química Física , Citratos/química , Ácidos Hidroxámicos/química , Myxococcales/metabolismoRESUMEN
Myxothiazol, a potent inhibitor of the cytochrome bc1 oxidoreductase, was shown by the use of flow cytometry to block reversibly the late G1/S phase of the cell cycle of human lymphoblastic T-cell line Jurkat (clone 886) at concentrations of 0.5 microgram/ml. These observations are compared to those of other drugs, such as antimycin, which effect the respiratory chain, and with O2-deficiency.
Asunto(s)
Antifúngicos/farmacología , Ciclo Celular/efectos de los fármacos , Naranja de Acridina , Citometría de Flujo , Humanos , Interfase/efectos de los fármacos , Leucemia de Células T , Metacrilatos , Tiazoles/farmacología , Células Tumorales CultivadasRESUMEN
A new natural saframycin was discovered in the culture broth of the myxobacterium, Myxococcus xanthus strain Mx x48. The fermentation and isolation of the antibiotic are described. The name, saframycin Mx1, is proposed. The compound appears to interact with cellular DNA.