Kodaistatins, novel inhibitors of glucose-6-phosphate translocase T1 from Aspergillus terreus thom DSM 11247 : Isolation and structural elucidation

• Published in: Journal of antibiotics 2000-07, Vol.53 (7), p.677-686
• Main Authors: VERTESY, L, BURGER, H.-J, KENJA, J, KNAUF, M, KOGLER, H, PAULUS, E. F, RAMAKRISHNA, N. V. S, SWAMY, K. H. S, VIJAYAKUMAR, E. K. S, HAMMANN, P
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics (antibacterial agents, antifungal agents); Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents; Antiporters; Applied microbiology; Aspergillus - metabolism; Aspergillus terreus; aspulvinones; Biological and medical sciences; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - enzymology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Glucose-6-phosphate translocase 1; Inhibitory Concentration 50; Kodaistatins; Lactones - chemistry; Lactones - isolation & purification; Lactones - pharmacology; Liver - drug effects; Liver - enzymology; Magnetic Resonance Spectroscopy; Mass Spectrometry; Microbiology; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Molecular Structure; Monosaccharide Transport Proteins; Phosphotransferases - antagonists & inhibitors; Rats
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.53.677

Two novel compounds, kodaistatin A, C35H34O11, molecular weight 630, and kodaistatin C, C35H34O12, molecular weight 646, have been isolated from cultures of Aspergillus terreus Thom DSM 11247 by solid-phase extraction, size-exclusion chromatography, and various preparative HPLC steps. The use of a range of 2D NMR measurements, in particular 13C-13C correlation measurements, has led to the clarification of the structure of kodaistatin A. Kodaistatin C is a hydroxylated derivative of kodaistatin A. Both natural products contain hydroxylated aspulvinones and identical highly substituted polyketide units. An X-ray single crystal structure analysis of aspulvinon E demonstrated the z-configuration at the central double bond. The kodaistatins are effective inhibitors of the glucose-6-phosphate translocase component of the glucose-6-phosphatase system (EC 3.1.3.9), an enzyme system which is important for the control of blood glucose levels. The IC50 is 80 nM for kodaistatin A and 130 nM for kodaistatin C.