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TERUMI KAGAMIZONO, TAKUYA HAMAGUCHI, TSUTOMU ANDO, KOKO SUGAWARA, TAKA ...
1999 Volume 52 Issue 2 Pages
75-80
Published: February 25, 1999
Released on J-STAGE: September 19, 2008
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Phosphatoquinones A and B were isolated from the cultured broth of
Streptomyces sp. TA-0363 and their structures were elucidated by spectroscopic analyses. Phosphatoquinones A and B inhibited the protein tyrosine phosphatase activity prepared from human Ball-1 cells with IC
50 of 28 μM and 2.9 μM, respectively.
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FUMITAKA KUDO, YOSHIHIRO HOSOMI, HIDEYUKI TAMEGAI, KATSUMI KAKINUMA
1999 Volume 52 Issue 2 Pages
81-88
Published: February 25, 1999
Released on J-STAGE: September 19, 2008
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The biosynthesis of 2-deoxystreptamine, the central aglycon of a major group of clinically important aminoglycoside antibiotics, commences with the initial carbocycle formation step from D-glucose-6-phosphate to 2-deoxy-15-
cyllo-inosose. This crucial step is known to be catalyzed by 2-deoxy-
scyllo-inosose synthase, which has not yet been characterized so far. Reported in this paper is the first purification of 2-deoxy-
scyllo-inosose synthase from butirosin-producing.
Bacillus circulans SANK 72073 to electrophoretic homogeneity. The enzyme was isolated as a heterodimeric protein comprising from a 23 kDa- and a 42 kDa polypeptide chains. The
Km of the enzyme for D-glucose-6-phosphate was estimated to be 9.O × 10
-4M and that for NAD
+ 1.7 × 10
-4M,
kcat for D-glucose-6-phosphate being 7.3 × 10
-2s
-1. The presence of Co
2+ was essential for the enzyme activity, but Zn
2+ was totally inhibitory. While the reaction mechanisms are quite similar, 2-deoxy-
scyllo-inosose synthase appears to be distinct from dehydroquinate synthase in the shikimate pathway, with respect to the quaternary structure, metal ion requirement, and the kinetic parameters.
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KAREN AFFLECK, PHILIP J. SIDEBOTTOMC, PHILIP J. SIDEBOTTOM, NICHOLAS L ...
1999 Volume 52 Issue 2 Pages
89-95
Published: February 25, 1999
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We describe the discovery and properties of a prenylated
p-terphenyl metabolite of the fungus
Aspergillus candidus. The compound (
1) possesses potent cytotoxic activity against a range of tumour and other hyper-proliferative cell lines. Cell cycle analysis shows that in mouse keratinocyte (BALB/MK) cells treated with
1, the cell cycle is arrested in early S phase, indicative of an antimetabolite effect. Furthermore, cellular cytotoxicity can be reversed by addition of exogenous pyrimidine but not purine nucleosides to the cell culture medium. It is therefore likely that compound
1 selectively inhibits pyrimidine biosynthesis, and it is this property which accounts for its potent cytotoxic properties.
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THOMAS PAULULAT, AXEL ZEECK, JAN MIRKO GUTTERER, HANS-PETER FIEDLER
1999 Volume 52 Issue 2 Pages
96-101
Published: February 25, 1999
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The biosynthesis of polyketomycin was investigated by feeding
13C-labeled acetate and propionate to the growing cultures of
Streptomyces diastatochromogenes Tü 6028.
13C NMR spectral analysis demonstrated the polyketide origin of the aglycone and the dimethylsalicyloyl moieties. The
O-methyl group and 6-CH3 of the aglycone as well as 3B-CH
3 of L-axenose and 3C-CH
3 of the salicyloyl residue were labeled by feeding L-[methyl-
13C]methionine. Both deoxysugars emerged from D-glucose. The biosynthesis of the aglycone and the assembly of the glycoside are discussed. The polyketomycin producing strain may be a candidate for further exploration in combinatorial biosynthesis.
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CHRISTIANE BORMANN, ATTILA KÁLMÁNCZHELYI, RODERICK S&Uum ...
1999 Volume 52 Issue 2 Pages
102-108
Published: February 25, 1999
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The previously described
Streptomyces tendae nikC::aph mutant was used to mutasynthesize nikkomycins B
x and B
z. The mutant is deficient in L-lysine 2-aminotransferase, which transaminates lysine to form piperideine 2-carboxylate, the precursor of the peptidyl side chain of the biologically active nikkomycins I, J, X, and Z, and is therefore unable to produce these nikkomycins. The mutant accumulates the biologically inactive biosynthetic nucleoside precursors nikkomycins C
x and C
z. Resting cell cultures of the mutant fed with benzoic acid produced the biologically active nikkomycins B
x and B
z, which contain 2-amino-4-hydroxy-3-methyl-4-(4'-hydroxyphenyl)butanoic acid as the peptidyl side chain. The structures of nikkomycins B
x and B
z were confirmed by mass spectrometry and NMR. Nikkomycins B
x and B
z exhibit significantly higher pH stability than their analogues nikkomycins X and Z.
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KOICHI NONAKA, CHIEKO KUMASAKA, YOSHIHIRO OKAMOTO, FUMIO MARUYAMA, HIR ...
1999 Volume 52 Issue 2 Pages
109-116
Published: February 25, 1999
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Streptomyces hygroscopicus subsp.
aureolacrimosus SANK 60286 and SANK 60576 produce many kinds of milbemycins. Among them, milbemycin α
11, α
14, A
3, and A
4 have the most effective acaricidal activity. In this study, we investigated the terminal biosynthetic pathway to milbemycin α
14 and A
4 which accumulated as the final products in these strains. Using cerulenin, a specific inhibitor of fatty acid and polyketide biosynthesis, we conducted bioconversion experiments with cultures of several mutants, including milbemycin A
4- and α
14-producing strains. The byconversions of milbemycin β
6 to milbemycin A
4 and milbemycin A
4 to milbemycin α
14 could be identified. For the biosynthesis of milbemycin A
4 from milbemycin β
6 in the milbemycin A
4-high producing strain, there appeared to be two separate pathways exhibiting different sequences of furan ring formation and C-5 keto reduction steps.
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D. ABBANAT, W. MAIESE, M. GREENSTEIN
1999 Volume 52 Issue 2 Pages
117-126
Published: February 25, 1999
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Streptomyces rugosporus LL-42D005 was shown to produce the novel pyrroindomycin antibiotics. Production of pyrroindomycin (α) and chloro-pyrroindomycin (β) was characterized in a semi-defined fermentation medium containing glucose, casein, phosphate, vitamins and minerals. Accumulation of pyrroindomycin β increased with increasing concentrations of glucose, reaching maximum titers at approximately 5g/L glucose. Glucose concentrations greater than 7.5g/L decreased pyrroindomycin β yields. Inhibition of pyrroindomycin accumulation at higher glucose concentrations could be reversed by increasing the casein concentration. Ammonium chloride, arginine or glutamine could replace casein as the sole nitrogen source for growth and pyrroindomycin production. Glucose, fructose or mannitol were utilized as the sole carbon source, while sucrose, maltose, glycerol, corn oil and starch were poorly metabolized. Incubation of this isolate in a vitamin-deficient medium resulted in a delay in growth and pyrroindomycin production; this delay was eliminated by the addition of biotin. Addition of L-tryptophan to the medium resulted in the production of pyrroindomycin α as the major species.
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H. LEVERT, B. GRESSIER, C. BRUNET, T. DINE, M. LUYCKX, L. BALLESTER, F ...
1999 Volume 52 Issue 2 Pages
127-133
Published: February 25, 1999
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Dirithromycin is a 14-membered macrolide antibiotic, well known to yield high intragranulocytic levels after several hour exposure. We chose therefore to investigate oxidative metabolism after prolonged incubation periods with neutrophils.
Neutrophil generation of reactive oxygen species, represented by superoxide anion, was assessed after fMLP or
Staphylocoecus aureus-induced activation of the respiratory burst. Cellular uptake of the drug was assessed concurrently, in order to attempt a correlation with time-dependent modifications of the cellular oxidative status.
For 1 hour exposure time, a pro-oxidant effect was reported for lower concentrations, achievable during therapeutic administration, whereas the highest ones promoted a potent anti-oxidant effect. After prolonged incubation times, the anti-oxidant effect alone was reported, with time-dependent modifications of IC
50 values. These values could be correlated with intracellular accumulation of the drug. The anti-inflammatory activity reported here for high dirithromycin concentrations, could be nevertheless clinically relevant, since dirithromycin cellular uptake extends beyond 4 hours.
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KANEO KANOH, SINKICHI KOHNO, JUN KATADA, JUNKO TAKAHASHI, ISAO UNO
1999 Volume 52 Issue 2 Pages
134-141
Published: February 25, 1999
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(-)-Phenylahistin, a fungal diketopiperazine metabolite composed of phenylalanine and isoprenylated dehydrohistidine, arrested cells in mitosis and inhibited the proliferation of A549 cells. The microtubule network in A549 cells was disrupted by (-)-phenylahistin, which also inhibited the polymerization of both microtubule protein from bovine brain and phosphocellulose-purified tubulin
in vitro. Competitive binding studies indicated that (-)-phenylahistin interacted with the colchicine binding site on tubulin but not with the vinblastine binding site.
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KATSUNORI KANAZAWA, HIROSHI NOUDA, YOSHIHIRO SUMITA, MAKOTO SUNAGAWA
1999 Volume 52 Issue 2 Pages
142-149
Published: February 25, 1999
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The antagonism of the antipseudomonal activity of ceftazidime by meropenem (
1a) was much less than those by imipenem (
2a) and panipenem (
2b). To reveal the major structural features of carbapenem compounds responsible for the antagonism, we investigated the structure-activity relationships of carbapenems to their antagonism of the antipseudomonal activity of ceftazidime and to their β-lactamase-inducibility in
P. aeruginosa. The antagonistic effect of
la was less than that of desmethyl-meropenem (
1b). Two other meropenem-analogues (
3,
4), with the highly basic C-2 side chain, showed greater antagonistic effects than that of
la, which has a weakly basic C-2 side chain. The β-lactamase-inducibility of
1a in
P. aeruginosa was lower than those of
2a,
1b and
4. These results indicated that the antagonism of the antipseudomonal activity of ceftazidime by carbapenems was due to the induction of β-lactamase in
P. aeruginosa. As a result of the study on the structure-activity relationships, we clarified that the introduction of a 1β-methyl group and/or the reduction of the basicity (cationic character) of the C-2 side chain in carbapenem skeleton decreased the antagonistic effect of carbapenems on the antipseudomonal activity of ceftazidime resulted mainly from the decreasing the β-lactamase inducibility.
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MAKOTO YANAI, SHIGERU HIRAMOTO
1999 Volume 52 Issue 2 Pages
150-159
Published: February 25, 1999
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Both (
R)- and (
S)-3-hydroxy-13-methyltetradecanoic acids were prepared
via a lipasecatalyzed enantioselective acylation. The total synthesis of N-4909 and its diastereomer were achieved by a coupling of either (
R)- or (
S)-3-hydroxy-13-methyltetradecanoic acid moiety with a hexapeptide moiety and by a cyclization with HATU (
O-(7-azabenzotriazoll-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate) and HOAt (1-hydroxy-7-azabenzotriazole) in a high dilution condition. The
R configuration of 3-hydroxy-13-methyltetradecanoic acid was found to be important for stimulating the activity of apolipoprotein E secretion in human hepatoma Hep G2 cells.
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HIROSHI TOMODA, CHIKAKO MATSUSHIMA, NORIKO TABATA, ICHIJI NAMATAME, HA ...
1999 Volume 52 Issue 2 Pages
160-170
Published: February 25, 1999
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The effect of thirteen different fungal azaphilones, which have a common 6-isochromane-like ring, was tested on cholesteryl ester transfer protein (CETP) activity
in vitro. Chaetoviridin B showed the most potent inhibitory activity with an IC
50 value of <6.2 μM, followed by sclerotiorin with an IC
50 value of 19.4 μM. Rotiorin, chaetoviridin A and rubrorotiorin had moderate inhibitory activity (IC
50; 30-40 μM), but others showed very weak or no inhibitory activity. The relationship between the structures and their inhibitory activity indicated that the presence of an electrophilic ketone(s) and/or enone(s) at both C-6 and C-8 positions in the isochromane-like ring is essential for eliciting CETP inhibitory activity. The transfer activity of both CE and TG was inhibited by sclerotiorin to approximately the same extent (IC
50: 14.4 and 10.3 μM, respectively). A model of the reaction suggested that sclerotiorin reacts with a primary amine of amino acids such as lysine in the protein to form a covalent bond.
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CHIKARA SHINOHARA, KEIJI HASUMI, TOSHIHIRO CHIKANISHI, TADASHI KIKUCHI ...
1999 Volume 52 Issue 2 Pages
171-174
Published: February 25, 1999
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MASAMICHI NAKAKOSHI, KEN-ICHI KIMURA, NOBORU NAKAJIMA, MAKOTO YOSHIHAM ...
1999 Volume 52 Issue 2 Pages
175-177
Published: February 25, 1999
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MASAO TSUKAMOTO, SHIGERU NAKAJIMA, KUMIKO MUROOKA, HAJIME SUZUKI, MIOK ...
1999 Volume 52 Issue 2 Pages
178-181
Published: February 25, 1999
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KAZUHIRO YOSHIKAWA, YUJI NAKAYAMA, MAKI HAYASHI, TSUTOMU UNEMOTO, KENI ...
1999 Volume 52 Issue 2 Pages
182-185
Published: February 25, 1999
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MIHO HORIKAWA, TADAHIDE NORO, YUTO KAMEI
1999 Volume 52 Issue 2 Pages
186-189
Published: February 25, 1999
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IAN C. PARSONS, JEREMY R. EVERETT, MICHAEL S. PACEY, JOHN C. RUDDOCK, ...
1999 Volume 52 Issue 2 Pages
190-192
Published: February 25, 1999
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GEONSEEK RYU, SI-KWAN KIM
1999 Volume 52 Issue 2 Pages
193-197
Published: February 25, 1999
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TSUKASA KOIWA, TAKAYUKI NAKANO, SENJI TAKAHASHI, HIROYUKI KOSHINO, MIK ...
1999 Volume 52 Issue 2 Pages
198-200
Published: February 25, 1999
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YUZURU MIKAMI, KATSUKIYO YAZAWA, AKIRA NEMOTO, HISAYUKI KOMAKI, YASUSH ...
1999 Volume 52 Issue 2 Pages
201-202
Published: February 25, 1999
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