- Squalene-Hopene Cyclase: On the Polycyclization Reactions of Squalene Analogues Bearing Ethyl Groups at Positions C-6, C-10, C-15, and C-19
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Squalene-hopene cyclase (SHC) has been found to convert acyclic squalene into 6,6,6,6,5-fused pentacyclic triterpenes hopene and hopanol. The enzymatic reactions of squalene analogues bearing ethyl groups in lieu of methyl groups at positions C-6, C-10, C-15, and C-19 have been examined to investigate whether the larger ethyl substituents (a C1 unit increment) are accepted as substrates and to investigate how these substitutions affect polycyclization cascades. Analogue 6-ethylsqualene 19a did not cyclize, which indicates 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 6:6:1:2. The production of tetra- and pentacyclic scaffolds suggests that the reaction cavity for D-ring formation site is somewhat loosely packed and can accept the 19-ethyl group, and that 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 domains for the 10- and 15-methyl binding sites are tightly packed and cannot fully accommodate the Et substituents. The cyclization pathways followed by the ethyl-substituted substrates in the presence of SHC and lanosterol and β-amyrin synthases are compared.
- Takahashi, Kazunari,Sasaki, Yusuke,Hoshino, Tsutomu
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- Two concise enantioselective total syntheses of (-)-glabrescol implicate alternative biosynthetic pathways starting from squalene
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The C2-symmetric (-)-glabrescol was synthesized in two steps from (10S,11R)-dihydroxy-10,11-dihydrosqualene or squalene with 50% or 10% overall yields, respectively. These highly efficient and biomimetic syntheses employed a base-promoted middl
- Yang, Peng,Li, Pei-Fang,Qu, Jin,Tang, Liang-Fu
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experimental part
p. 3932 - 3935
(2012/10/08)
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- Squalene-hopene cyclase: Insight into the role of the methyl group on the squalene backbone upon the polycyclization cascade. Enzymatic cyclization products of squalene analogs lacking a 26-methyl group and possessing a methyl group at C(7) or C(11)
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To provide deep insight into the polycyclization reaction of squalene, some analogs were synthesized and incubated with the cell-free homogenates of the recombinant Escherichia coli encoding the wild-type squalene cyclase. The presence of C(6)-Me leads to an efficient polycyclization cascade. Substitution of the C(14)-H and the C(18)-H with a methyl group halted the polycylization reaction at the tricyclic ring stage having a 6/6/6-fused ring system and the tetracycle with a 6/6/6/6-fused ring, respectively, both of which were produced according to a Markovnikov closure. Replacement of the C(7)-H and the C(11)-H with a methyl group led to no cyclization. These results, in conjunction with our previous reports, indicated that the methyl positions are important for bringing to completion of the normal polycylization reaction and further demonstrated that the precise steric bulk size at the methyl positions of squalene is critical to the correct folding and the strong binding of the substrate to the squalene cyclase.
- Nakano, Shin-Ichi,Ohashi, Shumi,Hoshino, Tsutomu
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p. 2012 - 2022
(2007/10/03)
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- Importance of the methyl group at C(10) of squalene for hopene biosynthesis and novel carbocyclic skeletons with 6/5 + 5/5 + (6) ring system(s)
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Squalene-hopene cyclase (matrix presented) Incubation of (6E,10E,14E,18E)-2,6,10,19,23-pentamethyl-tetracosa-2,6,10,14,18,22-hexaene with Alicyclobacillus acidocaldarius hopene cyclase afforded four products having two types of carbocyclic skeletons, i.e., two hopane products and two products having an unprecedented carbocyclic skeleton of 6/5 + 5/5 +6 pentacyclic and 6/5 + 5/5 tetracyclic ring systems. The former two hopane skeletons were formed from the bioconversion of C(15)-desmethylsqualene and the latter two skeletons from that of C(10)-desmethylsqualene.
- Hoshino, Tsutomu,Ohashi, Shumi
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p. 2553 - 2556
(2007/10/03)
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- New cyclization mechanism for squalene: A ring-expansion step for the five-membered C-ring intermediate in hopene biosynthesis
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Three triterpenes having the 6/6/5-fused tri- and 6/6/6/5-fused tetracyclic skeletons were isolated from an incubation mixture of the mutated F601A enzyme, these products being in accordance with a Markovnikov closure. Successful trapping of the tricyclic
- Hoshino, Tsutomu,Kouda, Masanori,Abe, Takamasa,Ohashi, Shumi
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p. 2038 - 2041
(2007/10/03)
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- Epoxidation of Carbon-Carbon Double Bonds in Terpenes by Linoleic Acid Hydroperoxides
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Epoxidation of C=C double bonds in terpenes is achieved by reaction with linoleic acid hydroperoxides (LOOH) exemplified with caryophyllene (3), methyl farnesoate (5) and squalene (8).Linoleic acid (9S)-hydroperoxide was obtained by reaction of linoleic acid (1) with lipoxygenase present in tomato homogenisate.When 18O2-labeled (9S)-LOOH (2) was used 18O was found in the terpene epoxide.While 3 is converted under physiological conditions regioselectivity in high yield into its 4,5-epoxide 4, the yield of epoxidized products from long-chain molecules, e.g. squalene (8), decreases strongly and no regioselectivity was observed. - Key Words: Terpenes/ Epoxides/ Linoleic acid derivatives/ Hydroperoxides/ Labeled compounds, 18O2
- Meyer, Werner,Spiteller, Gerhard
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p. 1253 - 1256
(2007/10/02)
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- Stereospecific Synthesis of Squalenoid Epoxide Vinyl Ethers as Inhibitors of 2,3-Oxidosqualene Cyclase
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The stereospecific synthesis of squalenoid epoxide vinyl ethers with an isopentyloxy group is described.The synthesis involves the preparation of the C22 squalenoid aldehyde bromohydrin (15) by a new method via a one-step cleavage of lipophilic epoxides using periodic acid in diethyl ether, and the preparation of (1-isopentyloxyethyl)diphenylphosphine oxide (24).The structure of this compound has been confirmed by X-ray analysis.The configuration of vinyl ethers, synthesized using a Wittig-Horner reaction, has been determined by (13)C n.m.r.Biological results show that vinyl ethers (5) and (27) are competitive inhibitors of 2,3-oxidosqualene cyclase from rat liver.
- Ceruti, Maurizio,Viola, Franca,Dosio, Franco,Cattel, Luigi,Bouvier-Nave, Pierrette,Ugliengo, Piero
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p. 461 - 470
(2007/10/02)
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