3 years ago

Squalene-hopene cyclase: on the polycyclization reactions of squalene analogs bearing ethyl groups at positions C-6, C-10, C-15 and C-19

Yusuke Sasaki, Tsutomu Hoshino, kazunari Takahashi
Squalene-hopene cyclase (SHC) converts acyclic squalene into the 6,6,6,6,5-fused pentacyclic triterpene hopene and hopanol. Enzymatic reactions of squalene analogs bearing ethyl groups in lieu of methyl groups at positions C-6, C-10, C-15 and C-19 were examined in order to investigate whether the larger ethyl-substituents (C1-unit increment) are accepted as substrates and to investigate how these substitutions affect polycyclization cascades. Analog 6-ethylsqualene 19a was not cyclized, indicating that substitution with the bulky group at C-6 completely inhibited the polycyclization reaction. In contrast, 19-ethylsqualene 19b afforded a wide spectrum of cyclization products, including mono-, bi-, tetra-, and pentacyclic products in a ratio of 6:6.3:1:2. Production of tetra- and pentacyclic scaffolds suggests that the reaction cavity for the D-ring formation site is somewhat loosely packed and can accept the 19-ethyl group, and a robust hydrophobic interaction exists between the 19-ethyl group and the binding site. In contrast to 19b, 10-ethylsqualene 20a and 15-ethylsqualene 20b afforded mainly mono- and bicyclic products, that is, the polycyclization cascade terminated prematurely at the bicyclic reaction stage. Therefore, the catalytic domain for the 10- and 15-methyl binding sites are tightly packed and cannot fully accommodate the Et substituents. The cyclization pathways of ethyl-substituted substrates are compared between SHC and lanosterol and β-amyrin synthases.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/ejoc.201800010

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