Himeic acid

A new ubiquitin-activating enzyme (El) inhibitor himeic acid A 289 and two new related compounds, himeic acids B 290 and C 291, were isolated from a marine-derived fungus, Aspergillus sp. The formation of an El-ubiquitin (Ub) intermediate was 65% inhibited by 289 at the concentration of 50pM, while 290 and 291, showed little inhibitory activity even at lOOpM. 

Natural products have recently been shown to interfere with specific steps in both the ubiquitination and de-ubiquitination of proteins, effectively preventing their recognition and degradation by the 26S proteasome. Panepophenanthrin (20), isolated from the mushroom Panus radis and himeic acid A (21), isolated from a marine strain of Aspergillus sp., have been shown to interfere with the ubiquitin-activating function of El enzymes. In this ATP-driven process, an adenylated ubiquitin-AMP intermediate is first formed. This ubiquitin intermediate then forms an activated ubiquitin-Cys thioester in the active site of El. Both compounds have been shown to interfere with the formation of the adenylated ubiquitin-AMP intermediate that is required to form the activated ubiquitin thioester. 

Himeic add A is a y-pyrone, produced by the culture of an Aspergillus sp. assodated with Japanese mussels Mytilus edulis, which inhibits one of the three enzymes (El ubiq-uitin-adivating enzyme) involved in the ubiquitination of proteins. Himeic acids B and C, also isolated from the culture medium, are much less active (Tsrikamoto et al., 2005). 

Tsukamoto, S Hirota, H., Imachi, M., Eujimoro, M., Onuki, H.. Ohta, T, and Yokosawa, H. (2005) Himeic acid A a new ubiquitin-activating enzyme inhibitor isolated from a marine-derived fimgus, Aspergillus sp. Bioorg. Med. Chem. Lett., 15,191-194. 

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