Computational Studies on Biosynthetic Carbocation Rearrangements Leading to Quiannulatene: Initial Conformation Regulates Biosynthetic Route, Stereochemistry, and Skeleton Type

Abstract

The results of quantum chemical calculations on the mechanism of the carbocation cascade of reactions in the biosynthetic pathways leading to the pentacyclic sesterterpenes quiannulatene and sesterfisherol provide reasonable answers to several persistent mechanistic questions in sesterterpene biosynthesis, including: 1) the reaction pathways of the multicyclic ring system construction and skeletal rearrangements, 2) the mechanism of triquinane skeleton formation, which requires more complicated rearrangements than previously proposed, 3) the stereochemistry of the final carbocation intermediate, and 4) the determining factor of biosynthetic selection for either 5/6/4/6/5 or 5/6/5/5/5 pentacyclic skeleton formation. This in‐depth mechanistic study on sesterterpene biosynthesis revealed that the shape of the final product and the type of triquinane skeleton formed are regulated by the stereochemistry and conformation of the common starting material, geranylfarnesyl diphosphate (GFPP).

Molecular Basis for Sesterterpene Diversity Produced by Plant Terpene Synthases

“…It has been proposed that the initial conformation of GFPP, which is fixed in the catalytic pocket of different sester-TPSs, determines the sesterterpene cyclization mechanism (type A or type B; shown in Figure 2 [ Sato et al., 2018 ]). To test the effects of Trp 335 and Ser 503 on GFPP accommodation in type-B sester-TPSs, we replaced these two amino acids in AtTPS06 with Gly and Phe, both individually and simultaneously.…”

“…Compared with the extensive studies on mono-, sesqui-, and di-TPSs, there are only a few studies on sester-TPSs from plants and fungi ( Chiba et al., 2013 , Matsuda et al., 2015 , Matsuda et al., 2016 , Ye et al., 2015 , Chai et al., 2016 , Bian et al., 2017 , Huang et al., 2017 , Huang et al., 2018 , Shao et al., 2017 ). Two early-stage cyclization mechanisms of GFPP in the catalytic pocket of sester-TPSs have been proposed, namely, type A, C 1 -IV-V (cyclization between the C 1 cation, the C 14 –C 15 olefin [the fourth double bond, IV] and the C 18 –C 19 olefin [the fifth double bond, V]) and type B, C 1 -III-IV (cyclization between the C 1 cation, the C 10 –C 11 olefin [the third double bond, III], and the C 14 –C 15 olefin [the fourth double bond, IV]) ( Minami et al., 2018 , Sato et al., 2018 ). However, the amino acid(s) determining the difference between type-A sester-TPS and type-B sester-TPS remains largely unknown.…”

DFT Study on the Biosynthesis of Verrucosane Diterpenoids and Mangicol Sesterterpenoids: Involvement of Secondary-Carbocation-Free Reaction Cascades

“…Next, we discuss in detail the biosynthesis of mangicol-type sesterterpenoids. Only a few C20/C25 terpenoids based on 5,11-bicyclic systems, such as ophiobolin, 34 , 35 cotylenin A, 36 and fusicoccadiene, 37 have been reported, 38 in contrast to those derived from 5,15-systems, such as quiannulatene, 5 , 39 sesterfisherol, 40 , 41 (+)-astellatene, 42 , 43 arathanadiene derivatives, sestermobaraenes, 44 and aspergildienes. 45 In the present study, IM8 was adopted as the simplest chemical model ( Figure 4 ).…”

“…However, the mechanistic issues are extremely difficult to resolve fully by means of experimental studies alone, since terpene cyclization is a domino-type reaction occurring inside a single enzyme (“black box”). We recently established a powerful combination of quantum-chemical calculations with the artificial force induced reaction (AFIR) method 2 , 3 to unveil complicated biosynthetic pathways/mechanisms, such as those leading to trichobrasilenol, 4 quiannulatene, 5 and cyclooctatin. 6 , 7 In general, experimental and theoretical studies indicate that a terpene biosynthesis involves a sophisticated exothermic cascade of reactions, in which carbocation intermediates are converted into more stable intermediates such as allyl cations, tertiary (3°) carbocations, and cycloalkylcarbinyl cations.…”

Zwei Sesterterpen‐Syntasen aus Lentzea atacamensis demonstrieren die Rolle der Konformationsvariabilität in der Terpenbiosynthese

“…Die Bedeutung der Konformationen von Substrat und Zwischenstufen bei Terpencyclisierungen wurde auch in früheren computerchemischen Studien hervorgehoben. [55,56] Darüber hinaus wurde eine einzigartige thermische [1,5]sigmatrope Umlagerung, die an die Vitamin D 3 -Biosynthese erinnert, beobachtet und durch Isotopenmarkierungsexperimente und Berechnungen vollständig erklärt. Trotz der geringen Sequenzidentität von 40 % zwischen LaLDS und der Sestermobaraen-Synthase SmTS1 [5] produzieren beide als Nebenprodukt Sestermobaraen F, was einmal mehr zeigt, wie schwierig strukturelle Vorhersagen für die Produkte von Terpensynthasen anhand ihrer Aminosäuresequenzen sind.…”