Ein neues Alkaloid aus dem Mycel einesClaviceps purpurea-Stammes. Zur Biogenese von Ergocristin

Summary A new alkaloid from the lyophilized mycelia of aClaviceps purpurea strain, N-[N-(d-Lysergyl)-l-valyl]-l-phenylalanyl-d-prolin-lactam, has been isolated and characterized. From its fast methanolysis it is deduced that the previously reported N-(d-Lysergyl)-l-valinmethylester is actually an artefact. The biogenetic significance and its possible role in biogenesis of Ergocristine is discussed.     

The chemistry of the polymyxin antibiotics

Zusammenfassung Die Chemie der Polymyxine, einer Klasse von basischen Polypeptid-Antibiotika, begann 1954, als durch Gegenstromverteilung erstmals ein definierter Vertreter, das Polymyxin B₁ in reiner Form isoliert werden konnte (L. C.Craig). Partialhydrolyse mit Mineralsäuren führte zum Schluss, dass es sich um Cyclohepta- oder Cyclooctapeptide mit Seitenketten handelt, die, -Diaminobuttersäure (Dab) enthalten (W.Hausmann).Amidartige Verknüpfung der Seitenkette mit einer Fettsäure [(+)-6-Methyloctansäure (MOA) oder 6-Methylheptansäure (IOA)] (S.Wilkinson) verleiht diesen Antibiotika den Charakter von Invertseifen. Sie sind besonders gegen gramnegative Erreger wirksam. Schwierigkeiten bereiteten die Aufklärung der Verknüpfungsweise der Seitenkette (- oder-) und die Beantwortung der Frage, ob das Molekül nebend-Phenylalanin in der Ringsequenz noch einend-, -Diaminobuttersäurerest in Nachbarschaft zur Fettsäure in der Seitenkette enthält. Synthetische Versuche mitd-, -Diaminobuttersäure an dieser Stelle führten zu hochaktiven Produkten, die aber mit natürlichem Polymyxin B₁ nicht identisch waren. Entscheidende Fortschritte wurden mit dem bakteriellen Enzym Nagarse (T.Suzuki) erzielt, das schrittweise die Seitenkette bis zum Ringpeptid abbaut. Dabei ergab sich, dass den Polymyxinen die allgemeine Struktur eines Cycloheptapeptides mit-verknüpfter Seitenkette zukommt (Figur 4).Die Polymyxine B₁ E₁ (Colistin A) sowie Circulin A unterscheiden sich voneinander nur durch eine Variation in der gleichen Dipeptidsequenz des 7-gliedrigen Ringes. Die im Polymyxin B₁ vorhandene Dipeptidsequenzd-Phe-l-Leu ist in Polymyxin E₁ (Colistin A) durchd-Leu-l-Leu und in Circulin A durchd-Leu-Ll-Ile ersetzt. Im Polymyxin D₁ ist neben dem Ersatz der entsprechenden Sequenz durchl-Leu-l-Thr noch ein, -Diaminobuttersäurerest der Seitenkette durch eind-Serin ausgetauscht. Die entsprechenden Verbindungen mit dem Index 2 unterscheiden sich von denjenigen mit dem Index 1 durch einen Austausch der (+)-6-Methyloctansäure durch 6-Methylheptansäure.Die Struktur von Polymyxin B₁ E₁ und Circulin A konnte durch Totalsynthese gesichert werden (K.Vogler). Weitere Fortschritte in der Erforschung der Natur der noch unbekannten Vertreter sind in Kürze zu erwarten.     

Sur le mycoside Cm,nouveau peptido-glycolipide isolé deMycobacterium marianum

Summary Mycoside C_m, m.p. 198–200° []_D = – 31° (CHCl₃), a new peptido-glycolipid isolated fromMycobacterium marianum, has the approximate molecular formula C₁₀₈H₁₈₅N₇O₂₈ and gives on hydrolysis seven molecules ofd-amino acids (oned-phenylalanine, threed-allo-threonine, threed-alanine), three molecules of 6-deoxyhexoses (one 6-deoxy-talose of as yet undetermined configuration and two molecules of 3,4-di-O-methyl-l-rhamnose); the lipid moiety of mycoside C_m is a hydroxy-acid of approximate formula C₅₀H₉₆O₃; three O-acetyl groups are also present. The preliminary formula (I) is proposed for mycoside C_m.

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60ème communication sur les constitutants des Mycobactéries; 59ème comm. voir: ref. 7.

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Ce travail a bénéficié d'une subvention de la Fondation Waksman pour le développement des Études microbiologiques en France, et d'une subvention du National Institute of Allergy and Infectious Diseases (Grant E 28 38).     

Antagonism of prostaglandin-induced cyclic AMP accumulation in the rat anterior pituitary in vitro by somatostatin analogues

Summary The PGE₂-induced cyclic AMP accumulation in the rat anterior pituitary in vitro is inhibited by [desamino¹]-, [desamino¹] [descarboxy¹⁴] and [d-Lys⁴]-somatostatin similarly to somatostatin, while the [descarboxy¹⁴]-somatostatin exhibits reduced activity; [d-Lys⁹]-somatostatin is ineffective at a higher concentration.The authors acknowledge the technical assistance ofG. Alexander. F. Bellini, D. Mangerel andJ. Rochon and thank Dr.G. Schilling and his associates for the analytical data.     

Metabolism of the neuromodulator d-serine

Over the past years, accumulating evidence has indicated that d-serine is the endogenous ligand for the glycine-modulatory binding site on the NR1 subunit of N-methyl-d-aspartate receptors in various brain areas. d-Serine is synthesized in glial cells and neurons by the pyridoxal-5′ phosphate-dependent enzyme serine racemase, and it is released upon activation of glutamate receptors. The cellular concentration of this novel messenger is regulated by both serine racemase isomerization and elimination reactions, as well as by its selective degradation catalyzed by the flavin adenine dinucleotide-containing flavoenzyme d-amino acid oxidase. Here, we present an overview of the current knowledge of the metabolism of d-serine in human brain at the molecular and cellular levels, with a specific emphasis on the brain localization and regulatory pathways of d-serine, serine racemase, and d-amino acid oxidase. Furthermore, we discuss how d-serine is involved with specific pathological conditions related to N-methyl-d-aspartate receptors over- or down-regulation.     

Avilamycin

Summary A strain ofStreptomyces viridochromogenes produced a new crystalline antibiotic, Avilamycin, related to but not identical with Curamycin and Exfoliatin. Avilamycin, C₆₃H₉₄O₃₅Cl₂, gave on solvolytic degradation the following products: dichloroisoeverninic acid, 2-deoxy-d-rhamnose, 2,6-di-O-methylmannose, 4-O-methylfucose,l-lyxose and 3,5-diacetoxy--caprolactone.     

Die Einlagerung von radioaktivem Schwefel in die Flügel von Acrididen nach Applikation von35S-Natriumsulfat-und35S-l-Cystinlösungen

Summary Psophus stridulus L. andOedipoda coerulescens L. were fed or injected with solutions of Na ₂ ³⁵ SO₄ and³⁵S-l-cystine. The radioactive radiation pattern of the wings was found to depend on the time of application. Differences in radiation intensity were found to correspond to the red, blue and dark areas.     

Reinigung von F-antigen

Summary F-antigens are glycoproteins with s ₂₀ ^c , 0.1M NaCl=5.4 and a main component in SDS-polyacrylamide of molecular weight of 40,000. Separation of F-antigens is described; with the methods used they are indistinguishable.

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Arbeit mit Unterstützung des Schweizerischen Nationalfonds zur Förderung der wissenschaftlichen Forschung (Kredit Nr. 5254.3). Herrn Dr.H. Mosimann danke ich für die Hilfe bei der analytischen Ultrazentrifugation, Frl.U. Kohler für Mitarbeit und Herstellung der Skizzen.     

Identification of a major cytokinin in coconut milk

A major cytokinin found in coconut milk was isolted by using the tobacco callus growth-promoting assay as a guide during purification. The structure of the factor was determined to be 14-O-{3-O-[-d-galactopyranosyl-(12)--d--galactopyranosyl-(13)--L-arabinofuranosyl]-4-O-(-L-arabinofuranosyl)--d-galactopyranosyl}-trans-zeatin riboside [G₃A₂-ZR] by various NMR techniques, including heteronuclear multiple bond connectivity by 2D multiple quantum NMR (HMBC), as well as mass spectroscopy and sugar analysis. The optimum concentration of G₃A₂-ZR for cytokinin activity in the tobacco callus assay was estimated to be 5×10^–6 M, so that G₃A₂-ZR is one order of magnitude more potent than 1,3-diphenylurea and one order less potent than zeatin riboside. At least 20% of the cytokinin activity of coconut milk could be attributed to G₃A₂-ZR.     

Regulation ofL-valine absorption by opioids interacting withμ-receptors in rabbit ileum

In intact tissue, [d-Ala²,MePhe⁴, Gly-ol⁵] enkephalin (10^–5 M;-ligand), diminsihed short-circuit current (I_sc) and increased water, Na⁺ and Cl^– net fluxes in vitro under open circuit conditions; it also inhibitedL-valine absorption andL-valine-dependent variations of short-circuit current (I_{sc, val}). Naloxone (10^–6 M) antagonized these effects. In the absence of the muscularis and myenteric plexus this enkephalin or morphine (-ligand) reduced I_sc and I_{sc, val}. These enkephalin effects occurred at different times. Different concentrations of enkephalin were tested for their effects on I_{sc, val}. [d-Ala²,d-Leu⁵] enkephalin (mainly a -ligand) significantly decreased I_sc but not I_{sc, val}. The reduction ofL-valine absorption does not depend on the effects on basal ion transport. Interaction of opioids with-receptors located in the submucosal plexus and/or in the epithelial cell accounts for this reduction. This enkephalin effect seems to be at least partially under the control of the myenteric plexus.     

l-Methionin als Regulator der Spannung von Collagen

Summary Collagen fibres produce tension in hypermolar salt solutions such as 5M NaClO₄. This tension can be increased by formaldehyde 0.035M (or more). These reactions are reversible in 0.15M NaCl and can be repeated many times.l-Methionine in 0.01M solution inhibits the reversal. It is supposed that this effect is caused by inhibition of the aldol-aldimin reaction which restitutes the crosslink in the collagen fibre.     

Beziehungen zwischen laccase- und peroxidaseartigen Isoenzymen von Basidiomyceten

Summary Phenoloxidases of 30 wood-rotting fungi were separated by isoelectric focusing. It turned out that apparent peroxidasic activity of the crude extracts of certain species is not necessarily atributable to peroxidases but to the special properties of certain laccase isoenzymes, which may be uninfluenced, inhibited, or activated by H₂O₂. These interactions differ in certain species for intra- and extracellular forms of the same isoenzyme.

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Wir danken den technischen Mitarbeitern unseres Lehrstuhls, besonders FräuleinK. Kuprat, für ihre Unterstützung und der DFG für Sachmittel.     

Synthesis of L-4-amino-3-isoxazolidinone,the unnatural stereoisomer of cycloserine and its antibiotic activity

Zusammenfassung Eine direkte Synthese vonl- undd-Cycloserin ausl- undd-Serin wurde beschrieben. Die bakteriostatischen Effekte der drei Formen von Cycloserin (d-,l-unddl-) aufE. coli in synthetischem Medium wurden verglichen.     

Quantitativer Nachweis eines Abbaus von Zellulose und Lignin in der rollkranken Rebe

Summary In leafroll-diseased grapevines, lignine and cellulose decompose anomalously. Therefore leaves and shoots of these vines curl characteristically down and inward. As a specific intermediate product, 4-methyl-d-glucuronic acid has been identified. The decomposition increases proportionally to the progress of the infection.     

Stéréochimie d'acides grasα-hydroxylés isolés d'une souche deStreptomyces

Summary A strain ofStreptomyces contains a mixture (ca. 3:1) of 2d-hydroxy-12l-methyltetradecanoic and 2d-hydroxy-13-methyltetradecanoic acids; it has the same properties as a similar mixture prepared by synthesis.

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11e Communication sur la chimie des micro-organismes; 10e communication:C. Lacave, J. Asselineau etR. Toubiana, Europ. J. Biochem.2, 37 (1967).     

Effets d'analogues du chloramphénicol sur la différenciation de l'∄uf de l'oursinParacentrotus lividus

Summary The effects ofl-threo-chloramphenicol and thiophenicol on the differentiation of sea-urchin eggs are compared with those exerted byd-threo-chloramphenicol. Onlyd-threo-chloramphenicol caused vegetalization;l-threo-chloramphenicol inhibited development. These effects resemble those of nitrobenzene. Thiophenicol, differing fromd-threo-chloramphenicol by replacing the nitro group with a methylsulphonyl group, slows down development at high concentrations. The effects of chloramphenicol on oxidative phosphorylation and synthesis of proteins are discussed. It is suggested that both the steric configuration typed-threo of the side chain and the presence of a nitro group are necessary for the vegetalizing activity.     

Steroidal sapogenins. XXX stereochemistry of the side chain

Zusammenfassung Die optischen Drehungen einiger 20, 25d; 20, 25l; 20, 25d; und 20, 25-l-Sapogenine wurden bestimmt. Die ersten drei Serien gaben übereinstimmend linksdrehende Werte, aber die letztere Gruppe erwies sich als rechtsdrehend.Die Struktur der vier Serien der Sapogenine folgte aus der Analyse dieser Befunde. Der mögliche Mechanismus bei der Entstehung dieser Verbindungen aus Pseudosapogeninen wurde besprochen. Die Autoren gelangen zum Schluss, dass sterische Faktoren an C₂₀ und C₂₅ die Richtung der Ringschliessung beeinflussen.

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Steroidal sapogenins. XXX stereochemistry of the side chain

     

The molecular basis for scent discrimination: Response to nitrobenzene-d5 of honey bees (Apis mellifera L.) conditioned with nitrobenzene

Zusammenfassung Honigbienen,Apis mellifera L., wurden dressiert, Zuckersirup an Stellen zu sammeln die mit Nitrobenzol markiert waren. Wenn Nitrobenzol oder Nitrobenzol-d ₅ zur Auswahl standen, konnten die Bienen nicht zwischen diesen Analogen unterscheiden. Dieses Ergebnis stimmt mit der Überlegung überein, dass die Chemorezeptormechanismen mit Elektronenmustern odereffekten zusammenhängen und nicht auf Oszillations-und Rotationsfrequenz, Dipolmoment oder anderen Masseneffekten an Molekülen beruhen.

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Acknowledgment: Dr.R. L. Feltham, Chemistry Dept., andK. R. Armstrong, Lunar and Planetary Lab., University of Arizona, obtained the far-IR-spectra.Othon Ziehl assisted in bioassays.     

Curamycin. II. Structure of the hydrolysis products ‘curacin’ and ‘d-curamicose’

Zusammenfassung Curacin, die chlorhaltige Fraktion der milden Hydrolyse des Antibiotikums Curamycin, wurde durch ihre chemischen und physikalischen Eigenschaften als 4-O-Dichlor-iso-everninyl-2-deoxy-d-rhamnose aufgeklärt. Ausserl-Lyxose und 4-O-Methyl-d-fucose besitzt auch das Curamycin ein drittes Monosaccharid,d-Curamicose, welches als 2,6-Di-O-methyl-d-mannose identifiziert wurde.     

d-Ribosylated Tau forms globular aggregates with high cytotoxicity

Although the glycation of Tau that is involved in paired helical filament formation in Alzheimer’s disease has been widely studied, little attention has been paid to the role of d-ribose in the glycation of Tau. Here, we show that Tau is rapidly glycated in the presence of d-ribose, resulting in oligomerization and polymerization. Glycated derivatives appeared after 24 h incubation. Western blotting indicated the formation of advanced glycation end-products (AGEs) during initial stages of glycation. Thioflavin T-positive (ThT-positive) aggregations that appeared from day 4 indicated the globular-like features. Atomic force microscopy revealed that the surface morphology of ribosylated Tau40 was globular-like. Kinetic studies suggested that d-ribosylated Tau is slowly oligomerized and rapidly polymerized with ThT-positive features. Moreover, d-ribosylated Tau aggregates were highly toxic to SHSY5Y cells and resulted in both apoptosis and necrosis. This work has demonstrated that d-ribose reacted with Tau protein rapidly, producing ThT-positive aggregations which had high cytotoxicity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.