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Biomedical subjects

H Reichenbach

Publications and source records attributed to H Reichenbach.

At least 19 recordsLinked to original sources
PubMed2001

New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: isolation, structure elucidation, and SAR studies.

In addition to epothilones A (1) and B (2), 37 natural epothilone variants and epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/B2. Of these, only the 12,13-desoxyepothilones, epothilone C (14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and epothilones E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other epothilone variants were produced only in 1-100 microg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, epothilones containing an oxazole moiety (10-13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, epothilones I (30-35), and a ring contracted 14-membered macrolide, epothilone K (36), were found as very minor metabolites. The mutant strain, So ce90/D13, instead of macrolactones, produced short-chain carboxylic acids 40, 41, and 42 bearing the characteristic thiazole side chain. The structures of the new epothilones were elucidated on the basis of comprehensive NMR and MS data. The new epothilone variants were tested in a cytotoxicity assay with mouse fibroblasts (cell line L929), and structure-activity relationships were established. Several new natural epothilones showed activity comparable to 1 and 2, but in no case exceeded that of 2.

Animals↗
PubMed2001

Myxobacteria, producers of novel bioactive substances.

Myxobacteria are soil bacteria that move by gliding and have an astonishing life cycle culminating in fruiting body formation. In a research program at the Gesellshaft für Biotechnologische Forschung over the past 25 years the organisms have been shown to be a rich source of potentially useful secondary metabolites. So far about 80 different basic compounds and 450 structural variants have been characterized. Many of those compounds were new. It is particularly remarkable that myxobacteria specialize in mechanisms of action that are very rare with other producers. Thus 20 new electron transport inhibitors, 10 substances that act on the cytoskeleton, four inhibitors of nucleic acid polymerases, and one inhibitor of fungal acetyl-CoA carboxylase, a novel mechanism of action, have been found.

Actins↗
PubMed2001

Studies on the biosynthesis of epothilones: the PKS and Epothilone C/D monooxygenase.

Nonproducer mutants support the assumption that epothilones A and B are synthesized by the same polyketide synthase (PKS). The endproducts of the PKS, epothilones C and D, compete for the active site of a constitutively synthesized monooxygenase which is regulated by product inhibition. The postulated C-13 hydroxy-epothilones as direct precursors of epothilones C and D were not detected.

Binding Sites↗
PubMed2000

[Late diagnosis of Curschmann-Steinert myotonic dystrophy in a female patient with dilated cardiomyopathy and in her son].

A 41 year old woman presented with dyspnoea at rest and swollen legs in the emergency room of our centre. She reported a history of slowly progressing dyspnoea and oedema in the legs. Physical examination showed signs of biventricular congestive heart failure and dysmorphia of the face. Routine laboratory examination revealed elevated CK levels without significant elevations of the CK-MB isoform. ECG showed complete left bundle branch block and first degree atrioventricular block. Echocardiography and angiography showed markedly reduced left ventricular systolic function, the ejection fraction was 25%. Coronary angiography excluded CAD and there was no evidence for congenital or valvular heart disease. The patient also reported a history of a serious complication during emergency general anaesthesia and cataracts of both eyes. Because of the clinical and chemical findings, the history of cataracts and complications during general anaesthesia, a systemic congenital disease of the muscular tissue was suspected. Molecular studies revealed a trinucleotide amplification at the myotonic dystrophy locus 19q 13.3, so the diagnosis myotonic dystrophy Curschmann-Steinert was established. The sixteen year old son of the patient suffered from an at this time unknown disease with retardation, muscular weakness and myotonia of the face. The diagnosis myotonic dystrophy was evident because of the clinical signs and the family history.

Adolescent↗
PubMed2000

On the mechanism of action of the myxobacterial fungicide ambruticin.

The myxobacterial fungicide, ambruticin, kills the yeast, Hansenula anomala, with high efficacy (MIC 0.05 microg/ml), but only when the cells are growing. The earliest effect, observed almost immediately after the addition of the antibiotic, is a transient but substantial increase of intracellular glycerol, followed by an accumulation of triacylglycerols and free fatty acids. At about the time when free fatty acids accumulate, the cells become leaky to low molecular weight compounds. We assume that this leakage kills the cells. The mechanism of action of ambruticin thus appears to be the same as that of the phenylpyrroles, e.g., pyrrolnitrin, viz., interference with osmoregulation.

Antifungal Agents↗
PubMed2000

Studies on the biosynthesis of epothilones: the biosynthetic origin of the carbon skeleton.

The biosynthetic origin of the epothilone skeleton was studied by the incorporation of 13C and radioactively labeled precursors by Sorangium cellulosum So ce90. The carbon atoms are derived from acetate, propionate, the methyl group of S-adenosyl-methionine, and cysteine which also introduces the sulfur and nitrogen atoms. Epothilone biosynthesis starts with the formation of the thiazole part from acetate and cysteine. The incorporation of acetate or propionate units results in the formation of epothilones A and B, respectively. To introduce the epoxide function of epothilones A and B molecular oxygen is used.

Carbon↗
PubMed2000

Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties.

New cytostatic compounds, tubulysins, were isolated from the culture broth of strains of the myxobacteria Archangium gephyra and Angiococcus disciformis. The compounds are peptides partly consisting of unusual amino acids and are distantly related to the dolastatins. The tubulysins were not active against bacteria and only little against fungi, but showed high cytostatic activity against mammalian cell lines with IC50 values in the picomolar range. An incubation with 50 ng/ml tubulysin A led to a complete disappearance of the microtubuli network of the cells within 24 hours. The more active tubulysin D induced multipolar spindles: At 0.5 ng/ml all mitotic cells showed more than four spindle poles.

Animals↗
PubMed1999

De novo complete trisomy 5p: clinical report and FISH studies.

We describe a de novo trisomy 5p in a 1-year-old severely retarded boy. The complete short arm of chromosome 5 segregated as an additional marker chromosome in all metaphases. The marker was identified as 5p by conventional cytogenetic techniques (GTG, GBG, CBG) and molecular cytogenetic techniques (whole chromosome-painting probe, probes for the cri-du-chat region and the centromere, and additionally high-resolution multicolor banding using a chromosome 5-specific DNA probe cocktail). The clinical findings were similar to the established trisomy 5p phenotype including macrocephaly, facial abnormalities, tracheobronchial defects with subsequent respiratory infections, hypotonia, and psychomotor retardation. To the best of our knowledge this is the first description of an isolated complete 5p trisomy without involvement of the aberrant chromosome in any structural chromosomal rearrangements.

Centromere↗
PubMed1999

Prenatal detection of a giant bilateral thoracic vascular lesion: prognostic evaluation and genetic aspects.

We describe a giant bilateral vascular mass in the skin of the chest diagnosed by ultrasound investigation in a fetus of 20 gestational weeks. Ultrasound and colour Doppler investigations detected no signs of early congestive heart failure but rapid and excessive enlargement of the vascular mass. Indications of increased fetal blood volume were found. The fetus had additional minor anomalies. Early in utero manifestation suggests a severe vascular malformation.

Amniocentesis↗
PubMed1999

Effects of rhizopodin and latrunculin B on the morphology and on the actin cytoskeleton of mammalian cells.

The effects of the novel myxobacterial compound rhizopodin on mammalian cells were studied and compared with those of latrunculin B. Both substances induced adherently growing L929 mouse fibroblasts and PtK2 potoroo kidney cells to produce long, narrow, branched extensions or runners. Rhizopodin was more efficient than latrunculin B in that respect (minimal inhibitory concentration with L929 cells 5 nM vs 50 nM), and, in contrast to latrunculin B, its effects were permanent. Rhizopodin-treated cells became much larger than normal cells and were multinucleate, yet stayed alive and biochemically active for several weeks. Latrunculin B-treated cells returned to a quasi-normal state within 3-4 days. But latrunculin B acted faster, with the first effects becoming visible almost immediately upon the addition of the drug, while the first rhizopodin effects were seen 10 min later. Both substances caused reorganization of the actin cytoskeleton. When 100 nM rhizopodin was added to PtK2 cells, the stress fibers began to decay after just 10 min and had disappeared completely after about 3 h. Later there was a gradual restitution of F-actin. Long F-actin fibers were seen within the runners, and only there; in fact, these fibers may be responsible for the development and extension of the runners. The microtubuli network adjusted itself to the new cell morphology, but was not directly impaired by the compound.

Actins↗
PubMed1999

The correlation between morphological and phylogenetic classification of myxobacteria.

In order to determine whether morphological criteria are suitable to affiliate myxobacterial strains to species, a phylogenetic analysis of 16S rDNAs was performed on 54 myxobacterial strains that represented morphologically 21 species of the genera Angiococcus, Archangium, Chondromyces, Cystobacter, Melittangium, Myxococcus, Polyangium and Stigmatella, five invalid species and three unclassified isolates. The analysis included 12 previously published sequences. The branching pattern confirmed the deep trifurcation of the order Myxococcales. One lineage is defined by the genera Cystobacter, Angiococcus, Archangium, Melittangium, Myxococcus and Stigmatella. The study confirms the genus status of 'Corallococcus', previously 'Chondrococcus', within the family Myxococcaceae. The second lineage contains the genus Chondromyces and the species Polyangium ('Sorangium') cellulosum, while the third lineage is comprised of Nannocystis and a strain identified as Polyangium vitellinum. With the exception of a small number of strains that did not cluster phylogenetically with members of the genus to which they were assigned by morphological criteria ('Polyangium thaxteri' Pl t3, Polyangium cellulosum ATCC 25531T, Melittangium lichenicola ATCC 25947T and Angiococcus disciformis An d1), the phenotypic classification should provide a sound basis for the description of neotype species in those cases where original strain material is not available or is listed as reference material.

Bacterial Typing Techniques↗
PubMed1999

Melithiazols, new beta-methoxyacrylate inhibitors of the respiratory chain isolated from myxobacteria. Production, isolation, physico-chemical and biological properties.

New antibiotic compounds, melithiazols, were isolated from the culture broth of strains of the myxobacteria Melittangium lichenicola, Archangium gephyra, and Myxococcus stipitatus. The compounds belong to the group of beta-methoxyacrylate (MOA) inhibitors and are related to the myxothiazols. The melithiazols show high antifungal activity, but are less toxic than myxothiazol A and its methyl ester in a growth inhibition assay with mouse cell cultures. The melithiazols inhibit NADH oxidation by submitochondrial particles from beef heart. Melithiazol A blocks the electron transport within the bc1-segment (complex III) and causes a red shift in the reduced spectrum of cytochrome b.

Acrylates↗
PubMed1998

The chondramides: cytostatic agents from myxobacteria acting on the actin cytoskeleton.

BACKGROUND: Chondramides are cyclodepsipeptides produced by strains of the myxobacterium, Chondromyces crocatus. These peptides, which have been reported to inhibit yeast and mammalian cell proliferation, are related to jasplakinolide, which has been isolated from marine sponges of the genus Jaspis and has been shown to interfere with the actin cytoskeleton (a structural component of cells that helps maintain their shape and is involved in processes, such as cell division and cell locomotion). We studied the effects of the chondramides (A, B, C, and D) on tumor cell growth, on cytoskeletal structure, and on actin polymerization in vitro and compared these effects with those of cytochalasin D and jasplakinolide. METHODS: Cell proliferation was measured by means of tetrazolium salt reduction assays. Effects on the cytoskeleton were studied by use of fluorescence techniques, and actin polymerization in vitro was measured by means of viscosimetry. RESULTS: Proliferation of tested tumor cell lines was inhibited by the chondramides. Concentrations that inhibited proliferation by 50% (IC50 values) ranged from 3 to 85 nM and were of the same order of magnitude as those found for cytochalasin D and jasplakinolide. Fluorescence staining of potoroo cells incubated with chondramides A and B showed that organization of the actin cytoskeleton was disrupted; however, the microtubule system was not affected. Viscosimetric measurement showed that, depending on the experimental conditions, chondramide A induced or accelerated actin polymerization in vitro. CONCLUSION: The chondramides--unlike jasplakinolide--can be produced in large amounts by fermentation, and, similar to jasplakinolide, they appear to have antiproliferative activity against carcinoma cell lines by targeting the actin cytoskeleton.

Actins↗
PubMed1998

Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS, OMIM #107480) is a rare autosomal-dominant malformation syndrome with a combination of anal, renal, limb and ear anomalies. Cytogenetic findings suggested that the gene mutated in TBS maps to chromosome 16q12.1, where SALL1 (previously known as HSAL1), a human homologue of spalt (sal), is located. SAL is a developmental regulator in Drosophila melanogaster and is conserved throughout evolution. No phenotype has yet been attributed to mutations in vertebrate sal-like genes. The expression patterns of sal-like genes in mouse, Xenopus and the fish Medaka, and the finding that Medaka sal is regulated by Sonic hedgehog (Shh; ref. 11), prompted us to examine SALL1 as a TBS candidate gene. Here we demonstrate that SALL1 mutations cause TBS in a family with vertical transmission of TBS and in an unrelated family with a sporadic case of TBS. Both mutations are predicted to result in a prematurely terminated SALL1 protein lacking all putative DNA binding domains. TBS therefore represents another human developmental disorder caused by mutations in a putative C2H2 zinc-finger transcription factor.

Abnormalities, Multiple↗
PubMed1998

Apicularens A and B, new cytostatic macrolides from Chondromyces species (myxobacteria): production, physico-chemical and biological properties.

A novel macrolide, apicularen A, was produced by several species of the genus Chondromyces. Initially it was discovered by bioassay-guided RP-HPLC-fractionation of culture extracts of Chondromyces robustus, strain Cm a13. Apicularen A showed no antimicrobial activity, but was highly cytotoxic for cultivated human and animal cells, with IC50 values ranging between 0.1 and 3 ng/ml. A cometabolite of apicularen A, the N-acetylglucosamine glycoside apicularen B, was distinctly less cytotoxic with IC50 values between 0.2 and 1.2 microg/ml, and showed weak activity against a few Gram-positive bacteria. Apicularen A is chemically closely related to the salicylihalamides A and B from the marine sponge Haliclona sp.

Animals↗