ABSTRACT
Cytochrome P450sca-2 from Streptomyces carbophilus catalyzes the hydroxylation of ML-236B sodium salt to pravastatin sodium, a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase. HMG-CoA reductase is a key enzyme in cholesterol biosynthesis. Crystals of the protein were obtained by the vapour-diffusion method, using ammonium sulfate as a precipitant. The crystals belong to the trigonal space group P3121 (or its enantiomorph, P3221) with unit-cell dimensions a = 103.5, c = 79.8 A. Assuming the presence of one molecule in the asymmetric unit, the calculated value of Vm is 2.68 A3 Da-1. A native data set was collected to a resolution of 2.2 A.
Subject(s)
Cytochrome P-450 Enzyme System/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Mixed Function Oxygenases/chemistry , Pravastatin/biosynthesis , Streptomyces/enzymology , Crystallization , Crystallography, X-Ray , Cytochrome P-450 Enzyme System/isolation & purification , Cytochrome P-450 Enzyme System/metabolism , Mixed Function Oxygenases/isolation & purification , Mixed Function Oxygenases/metabolism , Protein Conformation , X-Ray DiffractionABSTRACT
A novel acyl-CoA : cholesterol acyltransferase (ACAT) inhibitor, designated epi-cochlioquinone A has been isolated from the fermentation broth of Stachybotrys bisbyi SANK 17777. The molecular formula, physicochemical properties, NMR spectroscopic analysis and X-ray crystallographic analysis revealed that this compound was a stereoisomer of cochlioquinone A, which has been previously reported as a nematocidal agent. It inhibited ACAT activity in an enzyme assay using rat liver microsomes with an IC50 value of 1.7 microM. However, it showed about 10-fold less potent inhibitory effect on plasma lecithin cholesterol acyltransferase (LCAT) than on ACAT. In addition, it inhibited in vivo cholesterol absorption in rats by 50% at 75 mg/kg.
Subject(s)
Benzoquinones/isolation & purification , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Antinematodal Agents , Benzoquinones/chemistry , Benzoquinones/pharmacology , Fermentation , Male , Microsomes, Liver/drug effects , Molecular Structure , Rats , Rats, Sprague-Dawley , Stachybotrys , StereoisomerismABSTRACT
Novel heparanse inhibitors, A72363 A-1, A-2, and C, were isolated from the culture filtrate of Streptomyces nobilis SANK 60192 by column chromatography on various resinous adsorbents, followed by preparative anion exchange HPLC. Spectroscopic studies revealed that they are diastereomers of siastatin B, a neuraminidase inhibitor.
Subject(s)
Enzyme Inhibitors/isolation & purification , Fermentation , Glucuronidase , Glycoside Hydrolases/antagonists & inhibitors , Piperidines/isolation & purification , Streptomyces/metabolism , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Streptomyces/classificationSubject(s)
Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Lactams , Microbial Sensitivity Tests , Molecular Structure , Mupirocin/analogs & derivatives , Mupirocin/chemistry , Mupirocin/isolation & purification , Mupirocin/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Thiomarinol, an antimicrobial antibiotic, was isolated from the culture broth of a marine bacterium, Alteromonas rava sp. nov. SANK 73390. Its structure was deduced as a hybrid composed of a pseudomonic acid analogue and holothin by NMR spectral analysis and chemical degradation. Antimicrobial activity against Gram-positive and Gram-negative bacteria of thiomarinol was stronger than both of pseudomonic acids and pyrrothine antibiotics.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Gram-Negative Aerobic Bacteria/chemistry , Mupirocin/analogs & derivatives , Anti-Bacterial Agents/chemistry , Chemical Phenomena , Chemistry, Physical , Fermentation , Gram-Negative Aerobic Bacteria/metabolism , Lactams , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Mupirocin/chemistry , Mupirocin/isolation & purification , Mupirocin/pharmacologyABSTRACT
New inositol-1,4,5-trisphosphate (InsP3) agonists, adenophostins A(1) and B(2), were isolated from the culture broth of Penicillium brevicompactum SANK 11991 and SANK 12177. Its structures were related to adenine nucleotides. The agonistic activity of adenophostins A or B for binding to the InsP3 receptor was higher than InsP3 itself.
Subject(s)
Adenine/analogs & derivatives , Adenosine/analogs & derivatives , Calcium Channels/drug effects , Inositol 1,4,5-Trisphosphate/metabolism , Penicillium/chemistry , Receptors, Cytoplasmic and Nuclear/drug effects , Adenosine/chemistry , Adenosine/isolation & purification , Adenosine/metabolism , Animals , Calcium Channels/metabolism , Chromatography, High Pressure Liquid , Fermentation , Inositol 1,4,5-Trisphosphate Receptors , Mice , Receptors, Cytoplasmic and Nuclear/metabolismABSTRACT
Three metabolites were isolated from the culture broth of an actinomycete strain identified as Streptomyces platensis SANK 60191, that induce the production of colony-stimulating factors (CSFs) by stromal cell line KM-102 at ED50 concentrations from 40 to 200 ng/ml. The compounds induced quantities of granulocyte CSF (G-CSF) and granulocyte-macrophage CSF (GM-CSF) comparable to those induced by interleukin-1, a strong CSF inducer. These metabolites were called leustroducsins (A, B and C) and were later found to be structurally related to phoslactomycins. This is the first report of CSF inducing activity by members of the phoslactomycin class.
Subject(s)
Bone Marrow/drug effects , Fatty Acids, Unsaturated/isolation & purification , Granulocyte Colony-Stimulating Factor/biosynthesis , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Streptomyces/chemistry , Antifungal Agents/pharmacology , Bone Marrow/metabolism , Cell Line , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/pharmacology , Fermentation , Humans , Lactones/chemistry , Lactones/isolation & purification , Lactones/pharmacology , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/isolation & purification , Organophosphorus Compounds/pharmacology , Pyrones , Structure-Activity RelationshipABSTRACT
A strain of actinomycetes identified as Pseudonocardia compacta subsp. helvetica produced new glycopeptide antibiotics, helvecardins A and B. They were isolated from culture broth mainly by affinity chromatography of D-alanyl-D-alanine and preparative HPLC. The physico-chemical properties of helvecardins A and B showed that they resemble each other. Though helvecardin A was structurally related to beta-avoparcin, it clearly differed in the presence of an O-methyl moiety in its NMR spectrum.
