Biosynthetic Mechanism of Lanosterol: Cyclization

Chen, Nanhao; Wang, Shenglong; Smentek, Lidia; Hess, B. Andes; Wu, Ruibo

doi:10.1002/anie.201501986

Cited by 48 publications

(53 citation statements)

References 37 publications

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“…As we know, the low dielectric, that is hydrophobic environment, is necessary for this kind of cyclization reaction in which involves proton/carbocation immigration in our previous study . The above-discussed closed protein conformation of the wild type would shield reactive carbocation intermediates from the solvent.…”

Section: Results and Discussionmentioning

confidence: 85%

Molecular Dynamics Simulations Elucidate Conformational Dynamics Responsible for the Cyclization Reaction in TEAS

Zhang

Chen

2016

J. Chem. Inf. Model.

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The Mg-dependent 5-epi-aristolochene synthase from Nicotiana tabacum (called TEAS) could catalyze the linear farnesyl pyrophosphate (FPP) substrate to form bicyclic hydrocarbon 5-epi-aristolochene. The cyclization reaction mechanism of TEAS was proposed based on static crystal structures and quantum chemistry calculations in a few previous studies, but substrate FPP binding kinetics and protein conformational dynamics responsible for the enzymatic catalysis are still unclear. Herein, by elaborative and extensive molecular dynamics simulations, the loop conformation change and several crucial residues promoting the cyclization reaction in TEAS are elucidated. It is found that the unusual noncatalytic NH2-terminal domain is essential to stabilize Helix-K and the adjoining J-K loop of the catalytic COOH-terminal domain. It is also illuminated that the induce-fit J-K/A-C loop dynamics is triggered by Y527 and the optimum substrate binding mode in a "U-shape" conformation. The U-shaped ligand binding pose is maintained well with the cooperative interaction of the three Mg(2+)-containing coordination shell and conserved residue W273. Furthermore, the conserved Arg residue pair R264/R266 and aromatic residue pair Y527/W273, whose spatial orientations are also crucial to promote the closure of the active site to a hydrophobic pocket, as well as to form π-stacking interactions with the ligand, would facilitate the carbocation migration and electrophilic attack involving the catalytic reaction. Our investigation more convincingly proves the greater roles of the protein local conformational dynamics than do hints from the static crystal structure observations. Thus, these findings can act as a guide to new protein engineering strategies on diversifying the sesquiterpene products for drug discovery.

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Section: Results and Discussionmentioning

confidence: 85%

Molecular Dynamics Simulations Elucidate Conformational Dynamics Responsible for the Cyclization Reaction in TEAS

Zhang

Chen

2016

J. Chem. Inf. Model.

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“…457 The effect of this action is to polarize the squalene scaffold and results in epoxide at the end serving as an electrophilic functional group. Oxidosqualene cyclases then catalyze the cascade of cyclization steps, starting from a pre-chair-boat-chair configuration, to form the proposed protosterol cation intermediate ( 640 ).…”

Section: Cyclization Via Epoxidationmentioning

confidence: 99%

Oxidative Cyclization in Natural Product Biosynthesis

et al. 2016

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Oxidative cyclizations are important transformations that occur widely during natural product biosynthesis. The transformations from acyclic precursors to cyclized products can afford morphed scaffolds, structural rigidity and biological activities. Some of the most dramatic structural alterations in natural product biosynthesis occur through oxidative cyclization. In this review, we examine the different strategies used by Nature to create new intra-(inter-)-molecular bonds via redox chemistry. The review will cover both oxidation- and reduction-enabled cyclization mechanisms, with an emphasis on the former. Radical cyclizations catalyzed by P450, nonheme iron, α-KG dependent oxygenases and radical SAM enzymes are discussed to illustrate the use of molecular oxygen and S-adenosylmethionine to forge new bonds at unactivated sites via one-electron manifolds. Nonradical cyclizations catalyzed by flavin-dependent monooxygenases and NAD(P)H-dependent reductases are covered to show the use of two-electron manifolds in initiating cyclization reactions. The oxidative installation of epoxides and halogens into acyclic scaffolds to drive subsequent cyclizations are separately discussed as examples of “disappearing” reactive handles. Lastly, oxidative rearrangement of rings systems, including contractions and expansions will be covered.

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“…It is a tetracyclic triterpenoid that is synthesized in plants, animals, and yeast . It is also an intermediate in the biosynthesis of cholesterol . Lanosterol inhibits the formation of paraneoplastic lesions in the colon of rat .…”

Section: Introductionmentioning

confidence: 99%

“…1 It is also an intermediate in the biosynthesis of cholesterol. 2 Lanosterol inhibits the formation of paraneoplastic lesions in the colon of rat. 3 A side chain derivative of lanosterol (3β-hydroxy-5α-lanosta-8,24-diene) acts as an inhibitor of Δ24 (25) sterol methyltransferase.…”

Section: ■ Introductionmentioning

confidence: 99%

Solubility of Lanosterol in Organic Solvents and in Water–Alcohol Mixtures at 101.8 kPa

Forciniti

2020

J. Chem. Eng. Data

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Lanosterol is a sterol derivative whose physicochemical properties are poorly understood. Pure lanosterol (>95%) was isolated from a crude product (54.6%) by a newly developed C18 reverse-phase high-performance liquid chromatography (HPLC) method. Purity and structure were confirmed by gas chromatography–mass spectrometry (GC–MS). The melting temperature and fusion enthalpy were determined to be 408.27 K and 23.61 kJ/mol, respectively. The solubility of lanosterol was measured in methanol, ethanol, isopropanol, n-propanol, acetonitrile, acetone, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, water, water–methanol, water–isopropanol, and water–ethanol binary systems using a static equilibrium setup from 277.09 to 338.78 K. The solid phases were characterized by X-ray diffraction and by scanning differential calorimetry. The solubility of lanosterol increases with an increase in temperature. The mole fraction of lanosterol in organic solvents has a minimum of 3.0 × 10–5 in methanol at 277.78 K and a maximum of 0.0048 in n-propanol at 318.93 K. The solubilities of lanosterol in organic solvents were correlated by the modified Apelblat equation and by the Wilson, NRTL, and UNIQUAC models. Furthermore, the binary water–alcohol systems were correlated by the Apelblat–Jouyban–Acree and the van’t Hoff–Jouyban–Acree models.

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Biosynthetic Mechanism of Lanosterol: Cyclization

Cited by 48 publications

References 37 publications

Molecular Dynamics Simulations Elucidate Conformational Dynamics Responsible for the Cyclization Reaction in TEAS

Molecular Dynamics Simulations Elucidate Conformational Dynamics Responsible for the Cyclization Reaction in TEAS

Oxidative Cyclization in Natural Product Biosynthesis

Solubility of Lanosterol in Organic Solvents and in Water–Alcohol Mixtures at 101.8 kPa

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