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A complement inhibitor produced by Stachybotrys complementi, nov. sp. K-76, a new species of fungi imperfecti
Abstract:
A complement inhibitor, K-76, was isolated and purified from the culture supernatant of a fungus, Stachybotrys complementi, nov. sp. K-76, isolated from soil of Ishigaki Island, Okinawa. K-76 is a sesquiterpene compound and it can be oxidized to a monocarboxylic derivative (K-76 COOH), the sodium salt of which is very soluble and much less toxic than K-76. K-76 and K-76 COOH both inhibited complement activation by either the classical or alternative pathway. They inhibited generation of the factor chemotactic to human polymorphonuclear leukocytes from human serum by aggregated immunoglobulin. When sensitized erythrocytes were treated with complement in the presence of K-76 COOH, the resulting unlysed cells were found to be in the state of EACl, 4b, 2a, 3b. Thus K-76 COOH is considered to block mainly the C5 intermediate step. K-76 COOH did not inhibit any proteases or esterases tested, except when tested at high concentration.
Insights
A novel fungus yielded K-76, a sesquiterpene complement inhibitor. Its derivative, K-76 COOH, effectively blocks complement activation at the C5 step with reduced toxicity.
Area of Science:
- Immunology
- Natural Products Chemistry
Background:
- The complement system is crucial for innate immunity.
- Inhibitors of complement activation are valuable research tools and potential therapeutics.
- Natural products offer diverse chemical structures for biological activity.
Purpose of the Study:
- To isolate and characterize a novel complement inhibitor from a fungal source.
- To investigate the mechanism of action of the isolated compound and its derivative.
- To evaluate the potential of these compounds in modulating immune responses.
Main Methods:
- Fungal culture and isolation of K-76 from Stachybotrys complementi.
- Chemical characterization of K-76 as a sesquiterpene.
- Oxidation of K-76 to its monocarboxylic derivative, K-76 COOH.
- Assays for complement inhibition (classical and alternative pathways).
- Chemotaxis assays using human polymorphonuclear leukocytes.
- Analysis of complement-mediated erythrocyte lysis.
Main Results:
- K-76, a sesquiterpene, was isolated from Stachybotrys complementi.
- K-76 COOH, a less toxic derivative, was synthesized.
- Both K-76 and K-76 COOH inhibited classical and alternative complement pathways.
- Inhibition of chemotactic factor generation was observed.
- K-76 COOH primarily blocked complement at the C5 intermediate step.
Conclusions:
- K-76 and its derivative K-76 COOH are potent inhibitors of complement activation.
- K-76 COOH exhibits a specific inhibitory action at the C5 step.
- These compounds represent promising leads for further investigation in immunology and drug development.