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Biomedical subjects

H G Floss

Publications and source records attributed to H G Floss.

155 records · Page 9Linked to original sources
PubMedDate not supplied

Studies on the biosynthesis of antibiotics.

In the framework of studies on the biosynthesis of several antibiotics, specifically asukamycin, acarbose, reductiomycin, actinorhodin, and granaticin, a variety of different approaches to biosynthetic problems are illustrated. These include multiple labeling with stable isotopes in conjunction with modern methods of nmr analysis, as illustrated by the development of a new triple-quantum 2D-INADEQUATE experiment for biosynthetic studies, the use of stereochemical probes, as illustrated by the synthesis and stereochemical analysis of chiral [13C, 2H]malonate, and combinations of genetic and chemical approaches, as illustrated by examples of the production of new hybrid antibiotics by genetic engineering.

Anti-Bacterial Agents↗
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Biosynthesis of the ansamycin antibiotic ansatrienin (mycotrienin) by Streptomyces collinus.

The biosynthesis of ansatrienin (mycotrienin) has been studied in radioactive and stable isotope feeding experiments with Streptomyces collinus Tü 1892. The m-C7N unit of the ansa ring is efficiently and specifically derived from 3-amino-5-hydroxybenzoic acid; shikimic acid is not incorporated into this part of the molecule but does label the cyclohexanecarboyxlic acid moiety, providing all seven of its carbon atoms. Incorporation of methionine confirms origin of the methoxy group by transmethylation. The D-alanine moiety is derived directly from D-alanine rather than L-alanine. The terminal steps in the conversion of shikimic acid into cyclohexanecarboyxlic acid seem to be sequential reduction of 2,5-dihydrobenzoic acid and cyclohexene-1-carboxylic acid as evidenced by feeding experiments and the detection of a new ansatrienin containing a 1-cyclohexene instead of the cyclohexane moiety.

Chemical Phenomena↗
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Production of 'hybrid' antibiotics by genetic engineering.

The recent development of molecular cloning systems in Streptomyces has made possible the isolation of biosynthetic genes for some of the many antibiotics produced by members of this important genus of bacteria. Such clones can now be used to test the idea that novel antibiotics could arise through the transfer of biosynthetic genes between streptomycetes producing different antibiotics. The likelihood of a 'hybrid' compound being produced must depend on the substrate specificities of the biosynthetic enzymes, about which little is known. In attempts to demonstrate hybrid antibiotic production, we therefore began with strains producing different members of the same chemical class of compounds in order to maximize the chance of success. Here we report the production of novel compounds by gene transfer between strains producing the isochromanequinone antibiotics actinorhodin, granaticin and medermycin. These experiments were made possible by the recent cloning of the whole set of genes for the biosynthetic pathway of actinorhodin from Streptomyces coelicolor A3(2) (ref. 8). We believe that this represents the first report of the production of hybrid antibiotics by genetic engineering.

Anthraquinones↗
PubMedDate not supplied

Further studies on the biosynthesis of granaticin.

Experiments with cerulenin-inhibited cultures of S. violaceoruber showed conversion of dihydrogranaticin (II) into granaticin (I), but not vice versa, confirming an earlier conclusion that II is the biosynthetic precursor of I. Feeding of CH3(13)C18O2Na followed by 13C-NMR analysis of the product by the 18O shift method indicated the expected incorporation of 18O at carbons 1, 11 and 13 of I and showed that the oxygen of the pyran ring originates from C-3 and not from C-15. Analysis of I biosynthesized from 13C2H3COONa by 13C[1H, 2H] triple resonance NMR spectroscopy showed the incorporation of one atom of deuterium each at C-2 and C-4. C-16 carried a maximum of 2, not 3, atoms of deuterium. These results are discussed in terms of biosynthetic mechanisms.

Acetates↗
PubMedDate not supplied

[Biosynthesis of ergot alkaloids. Some new results on an old problem (Review)].

The biosynthetic pathway leading from L-tryptophan, mevalonic acid and methionine to the tetracyclic ergoline ring system of the ergot alkaloids in Claviceps species is reviewed. This pathway entails many mechanistically intriguing features. Recent studies are also discussed which reveal the stereochemical course of the isoprenylation of tryptophan and of the N-methylation of dimethylallyltryptophan (DMAT) and which shed some light on the likely steps leading from the open-chain precursors, N-methyl-DMAT to the tricyclic intermediate, chanoclavine-1. Finally, some plans are outlined to probe the evolutionary relationship of ergot alkaloid biosynthesis in fungi to that in higher plants of the family Convolvulaceae.

Biological Evolution↗
PubMedDate not supplied

Shikimic acid and quinic acid are not mutagenic in the Ames assay.

Shikimic acid, reported to cause tumors in mice, and its close structural analog, quinic acid, both ubiquitous constituents of higher plants, were found not be be mutagenic in the Ames assay when tested with and without the rat liver microsomal activation system.

Animals↗
PubMedDate not supplied

Purification and properties of anthranilate synthetase from the ergot fungus, Claviceps spec., strain SD 58.

A three-enzyme complex containing anthranilate synthetase, phosphoribosyl anthranilate isomerase and indole-3-glycerol phosphate synthetase was partially purified from Claviceps spec., strain SD 58. The anthranilate synthetase activity of the enzyme complex was quite unstable unless glutamine, MgCl2, TRIS and, most importantly, glycerol were included in the extraction buffer. The three-enzyme complex showed a molecular weight of 400,000 when estimated using Sephadex gel filtration, and a molecular weight of 200,000 when using sucrose density gradient centrifugation. At least two bands of anthranilate synthetase were detected on disc gel electrophoresis. An enzyme complex containing phosphoribosyl anthranilate synthetase and indoleglycerol phosphate synthetase, but no anthranilate synthetase, was isolated from Claviceps. This enzyme complex had an apparent molecular weight of 165,000 as estimated by sucrose gradient centrifugation. Anthranilate synthetase is inhibited by L-tryptophan and elymoclavine, the terminal ergot alkaloid produced by this strain of Claviceps. No differences could be detected between the enzyme complexes isolated from 2-day-old growing mycelia and from 6-day-old alkaloid-producing mycelia of the organism.

Age Factors↗