Inherent atomic mobility changes in carbocation intermediates during the sesterterpene cyclization cascade

Abstract

We previously showed that the regio- and stereoselectivity in terpene-forming reactions are determined by the conformations of the carbocation intermediates, which reflect the initial conformation of the substrate, geranylfarnesyl diphosphate (GFPP). However, it remains unclear how the initial conformation of GFPP is controlled, and which part(s) of the GFPP molecule are important for its fixation inside the substrate-binding pocket. Here, we present the first detailed analysis of the inherent atomic mobility in carbocation intermediates during sesterterpene biosynthesis. We identified two methyl groups as the least mobile of all the carbons of the carbocation intermediates in the first half of the cyclization cascade. Our analysis suggests that these two methyl groups are critical for the preorganization of GFPP in the biosynthetic pathways leading to sesterfisherol and quiannulatene.

Theoretical Study of Natural Product Biosynthesis Using Computational Chemistry

“…Comparing the three dimensional (3D) structures obtained by DFT calculations, it is clear that these differences in regioselectivity are due to the initial conformation of the substrates 17,18) (Fig. 4).…”

Research Progress on Fungal Sesterterpenoids Biosynthesis

“…The regioselectivity and stereoselectivity in terpene formation reactions are determined by the conformations of carbocation intermediates that mirror the initial conformation of GFPP [ 46 ]. By calculating the intrinsic atomic mobility of the carbon positive ion intermediate during the enzymatic catalysis of sesterterpenes ( 28 and 44 ), Sato et al found that the two methyl groups (C20 and C23) remained unchanged during the first half of the cyclization cascade.…”

“…By calculating the intrinsic atomic mobility of the carbon positive ion intermediate during the enzymatic catalysis of sesterterpenes ( 28 and 44 ), Sato et al found that the two methyl groups (C20 and C23) remained unchanged during the first half of the cyclization cascade. It is also suggested that the 28 and 44 enzyme-catalyzed process is divided into three stages: (I) formation of the 5/12/5 tricycles, (II) conformational change and hydrogen transfer, and (III) ring rearrangement to form the 5-6-8-5 ring system [ 46 ].…”