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Concertedness and Activation Energy Control by Distal Methyl Group during Ring Contraction/Expansion in Scalarane-type Sesterterpenoid Biosynthesis.

Salmahyritisol A, similan A, and hippospongide A, which are scalarane-type sesterterpenoids, feature 6/6/5/7/5 pentacyclic skeletons. Although their biosyntheses have been previously proposed to involve a unique skeletal rearrangement reaction, the detailed reaction mechanism remains unclear as none of the corresponding biosynthetic enzymes for this reaction have been reported. Herein, we investigated this skeletal rearrangement reaction using computational techniques, which revealed the following four key features: (i) the distal 24-Me substituent controls both the concertedness and activation energy of this transformation, (ii) enzymes are not responsible for the observed regioselectivity of C12-C20 bond formation, (iii) stereoselectivity is enzyme-regulated, and (iv) protonation is a key step in this skeletal rearrangement process. These new findings provide insight into the C-ring-contraction and D-ring-expansion mechanisms in scalarane-type sesterterpenoid biosyntheses.