Clavaric acid

Clavaric acid, a tetracyclic triterpenoid hydroxymethylglutyrate (Figure 25), was isolated from Clavariadelphus truncatus, a fungus collected from Cercedilla, Madrid, Spain. The compound was isolated by using Sephadex LH20 and reverse phase HPLC and the structure was elucidated using standard 2D NMR methods and mass spectrometry [116]. 

The difference in the activity of clavaric acid against FPTase with different peptide substrates (namely, Ras-CVIM versus Ras-CVLS) was attributed to the 20-fold difference in values for the two substrates against the enzyme. Clavaric acid is more potent when Ras-CVLS is used as a substrate when compared to Ras-CVIM. This is not surprising since... 

Similar to cembranolide, clavaric acid was competitive with respect to the Ras-peptide substrate Kj = 1.4 jM) and non- and/or un-competitive with FPP despite having a negatively charged carboxyl group. This is only the second example of a non-nitrogenous FPTase inhibitor that is competitive with peptide substrate. These two (cembranolide and clavaric acid) structurally distinct compounds show remarkably similar profiles of the mechanism of FPTase inhibition [117]. 

In summary, clavaric acid is a non-nitrogenous compound that inhibits FPTase by competing with Ras-peptide. This led to the identification, design and synthesis of very potent inhibitors that compete with either of the two enzyme substrates (ie., corticosteroids and des-A steroids). 

There were only three examples of natural products that mechanistically are Ras competitive inhibitors of FPTase. These include the pentapeptide pepticinnamins, and the terpenoids cembranolide and clavaric acid. There was no surprise about the Ras competitive activity of pepticinnamins but the Ras competitive activities of cembranolide and clavaric acid were certainly surprising. Clavaric acid led to the discoveries of a number of steroidal inhibitors that were competitive with either of the two substrates. 

Godio RP, Fouces R, Martin IF (2007) A squalene epoxidase is involved in biosynthesis of both the antitumor compound clavaric acid and sterols in the basidiomycete H. sublateritium. Chem Biol 14 1334-1346... 

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