Thielavins as Glucose-6-phosphatase (G6Pase) Inhibitors: Producing Strain, Fermentation, Isolation, Structural Elucidation and Biological Activities

High-throughput screening of microbial extracts using rat hepatic microsomal glucose-6-phosphatase (G6Pase) led us to find thielavin B as a G6Pase inhibitor with inhibition of glucose output from glucagon-stimulated hepatocytes. Further searching for more potent analogs identified 11 new thielavins...

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Published in:Journal of antibiotics 2002/11/25, Vol.55(11), pp.941-951
Main Authors: SAKEMI, SHINICHI, HIRAI, HIDEO, ICHIBA, TOSHIO, INAGAKI, TAISUKE, KATO, YOSHINAO, KOJIMA, NAKAO, NISHIDA, HIROYUKI, PARKER, JANICE C., SAITO, TOSHIYUKI, TONAI-KACHI, HIROKO, VANVOLKENBURG, MARIA A., YOSHIKAWA, NOBUJI, KOJIMA, YASUHIRO
Format: Article
Language:English
Subjects:
Animals
Benzoates - chemistry
Benzoates - isolation & purification
Benzoates - pharmacology
Biological and medical sciences
Chaetomium - metabolism
Chemical Phenomena
Chemistry, Physical
Chromatography, High Pressure Liquid
Enzyme Inhibitors - pharmacology
Fermentation
General and cellular metabolism. Vitamins
Glucagon - pharmacology
Glucose - metabolism
Glucose-6-Phosphatase - antagonists & inhibitors
Hepatocytes - drug effects
Hepatocytes - metabolism
Hydrolysis
Hydroxybenzoates - chemistry
Hydroxybenzoates - isolation & purification
Hydroxybenzoates - pharmacology
Magnetic Resonance Spectroscopy
Medical sciences
Microsomes, Liver - enzymology
Molecular Structure
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Spectrometry, Mass, Fast Atom Bombardment
Structure-Activity Relationship
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Summary:High-throughput screening of microbial extracts using rat hepatic microsomal glucose-6-phosphatase (G6Pase) led us to find thielavin B as a G6Pase inhibitor with inhibition of glucose output from glucagon-stimulated hepatocytes. Further searching for more potent analogs identified 11 new thielavins F-P in addition to the known thielavins A and B from a fungus Chaetomium carinthiacum ATCC 46463. Thielavin G showed the strongest activity as a G6Pase inhibitor (IC50=0.33μM), while the IC50 of thielavin B was 5.5μM. According to the structureactivity relationship, including authentic thielavins C, D and 3 partial hydrolysates from thielavins A and B, 3 benzoic acid-units and carboxylic acid functions are essential for G6Pase inhibition.
ISSN:0021-8820
1881-1469
DOI:10.7164/antibiotics.55.941