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Fungal Δ9-fatty acid desaturase: a unique enzyme at the core of lipid metabolism in Aspergillus fumigatus and a promising target for the search for antifungal strategies

Summary

Certain dangerous fungal infections like aspergillosis are difficult to treat because current antifungal drugs have significant side effects or the fungi are developing resistance. Scientists have discovered that a specific enzyme called Δ9-fatty acid desaturase, which fungi need to make fats for their cell membranes, has a unique structure different from human cells. This structural difference offers a new opportunity to design antifungal drugs that could kill fungi without harming human cells, potentially providing safer and more effective treatments for serious fungal infections.

Background

Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans are leading fungal pathogens causing life-threatening deep mycosis in immunocompromised patients. Lipid metabolism is crucial for fungal growth, with membrane fluidity regulated by the ratio of saturated and unsaturated fatty acids. The Δ9-fatty acid desaturase enzyme is essential for synthesizing monounsaturated fatty acids with cis double bonds at the C9 position.

Objective

This review summarizes current information on Δ9-FA desaturase in fungal pathogens, focusing on Aspergillus fumigatus. The authors examine the unique structural organization of this enzyme and its implications for catalytic mechanisms, exploring its potential as a chemotherapeutic antifungal target with less toxicity concerns than current treatments.

Results

Δ9-FA desaturases are essential for fungal viability and unique in possessing a C-terminal cytochrome B5 (CytB5) domain fused to the desaturase domain, distinguishing them from mammalian orthologs where CytB5 is a separate protein. AlphaFold3 modeling revealed the N-terminal desaturase domain shows structural similarity to human SCD1 with conserved catalytic features, while the C-terminal CytB5 domain retains electron transfer capabilities.

Conclusion

The unique fusion organization of fungal Δ9-FA desaturases presents a novel therapeutic target distinct from mammalian enzymes. Targeting either the catalytic site or the fusion CytB5 domain offers promising strategies for developing selective antifungal agents with reduced toxicity concerns compared to current treatments targeting ergosterol.
  • Published in:mBio,
  • Study Type:Review,
  • Source: PMID: 40569070
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