Bjerkandera adusta as a source of benzoic acid derivatives targeting 26S proteasome and cathepsins B&L

One of the main pathways involved in aging process is the proteostasis network, which is an assembly of protein degradation machines, molecular chaperones and stress response pathways that control the functionality of the proteome during protein synthesis, folding, trafficking and degradation. Ageing process is followed by a gradual dysfunction of the proteostasis network and this leads to proteome instability due to accumulation of damaged and/or misfolded proteins. The two main machineries of protein degradation in eukaryotic cells are the ubiquitin-proteasome and the autophagy-lysosome pathways [1], [2].

The aim of the present study was to investigate the strain CF-092983, identified as Bjerkandera adusta, as a potential source of natural products able to activate proteasome and/or lysosomal cathepsins and thus to contribute to the maintenance of protein homeostasis affected by several exogenous and/or endogenous factors.

Chemical investigation of the EtOAc L-L extract led to the isolation of four hydroxybenzoic acid derivatives [Fig. 1]. All the isolated compounds significantly enhanced the activity of cathepsins B and L. Additionally, compounds 1, 3 and 4, promoted the main degrading activity of the 26S proteasome at a final concentration of 5 μM. Moreover, using the crystal structure of the 26S proteasome, and of cathepsins B and L we run in-silico simulations to explore the possible binding mode of the active compounds.

Overall, the findings of this study further support the antioxidant and/or the potential anti-ageing effects of fungal extracts, and the fact that fungal natural products can be used as effective agents for promoting human health.

Fig. 1 Chemical structures of isolated compounds

• References

• 1 Koga H, Kaushik S, Cuervo AM. Protein homeostasis and aging: The importance of exquisite quality control. Ageing res rev 2011; 10 (02) : 205-215
• 2 Gumeni S, Trougakos IP. Cross talk of proteostasis and mitostasis in cellular homeodynamics, ageing, and disease. Oxid Med Cell Longevity 2016