Biosynthetic Mechanism of Lanosterol: Cyclization

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

doi:10.1002/ange.201501986

Cited by 8 publications

(11 citation statements)

References 37 publications

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“…Computational approaches have been used to refine the mechanistic sequence proposed in Figure 84 , as recently reviewed by Hess, Wu, and colleagues. 463 Given that oxidosqualene cyclase is a potential target for cholesterol-lowering drugs, a deeper understanding of the molecular details of catalysis may facilitate the design of potent and selective inhibitors. Intriguingly, inhibitors of oxidosqualene cyclase may also be useful in cancer chemotherapy.…”

Section: Class II Terpenoid Cyclasesmentioning

confidence: 99%

Structural and Chemical Biology of Terpenoid Cyclases

2017

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The year 2017 marks the twentieth anniversary of terpenoid cyclase structural biology: a trio of terpenoid cyclase structures reported together in 1997 were the first to set the foundation for understanding the enzymes largely responsible for the exquisite chemodiversity of more than 80000 terpenoid natural products. Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that more than half of the substrate carbon atoms undergo changes in bonding and hybridization during a single enzyme-catalyzed cyclization reaction. The past two decades have witnessed structural, functional, and computational studies illuminating the modes of substrate activation that initiate the cyclization cascade, the management and manipulation of high-energy carbocation intermediates that propagate the cyclization cascade, and the chemical strategies that terminate the cyclization cascade. The role of the terpenoid cyclase as a template for catalysis is paramount to its function, and protein engineering can be used to reprogram the cyclization cascade to generate alternative and commercially important products. Here, I review key advances in terpenoid cyclase structural and chemical biology, focusing mainly on terpenoid cyclases and related prenyltransferases for which X-ray crystal structures have informed and advanced our understanding of enzyme structure and function.

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Section: Class II Terpenoid Cyclasesmentioning

confidence: 99%

Structural and Chemical Biology of Terpenoid Cyclases

2017

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“…All the QM/MM simulations were run with QChem4.0 40 and Tinker 41 programs. The whole protocol is transplanted from our previous studies and has been carefully validated [42][43][44] . Additional a The values in parentheses refer to statistics in the highest bin.…”

Section: Methodsmentioning

confidence: 99%

Structural studies reveal flexible roof of active site responsible for ω-transaminase CrmG overcoming by-product inhibition

Tang

Zhu

et al. 2020

Commun Biol

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Amine compounds biosynthesis using ω-transaminases has received considerable attention in the pharmaceutical industry. However, the application of ω-transaminases was hampered by the fundamental challenge of severe by-product inhibition. Here, we report that ωtransaminase CrmG from Actinoalloteichus cyanogriseus WH1-2216-6 is insensitive to inhibition from by-product α-ketoglutarate or pyruvate. Combined with structural and QM/MM studies, we establish the detailed catalytic mechanism for CrmG. Our structural and biochemical studies reveal that the roof of the active site in PMP-bound CrmG is flexible, which will facilitate the PMP or by-product to dissociate from PMP-bound CrmG. Our results also show that amino acceptor caerulomycin M (CRM M), but not α-ketoglutarate or pyruvate, can form strong interactions with the roof of the active site in PMP-bound CrmG. Based on our results, we propose that the flexible roof of the active site in PMP-bound CrmG may facilitate CrmG to overcome inhibition from the by-product.

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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. 49 The above-discussed closed protein conformation of the wild type would shield reactive carbocation intermediates from the solvent. Otherwise, it will be unfavorable for intermediate stabilization and may result in premature quenching of the reaction.…”

Section: ■ Introductionmentioning

confidence: 99%

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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Biosynthetic Mechanism of Lanosterol: Cyclization

Cited by 8 publications

References 37 publications

Structural and Chemical Biology of Terpenoid Cyclases

Structural and Chemical Biology of Terpenoid Cyclases

Structural studies reveal flexible roof of active site responsible for ω-transaminase CrmG overcoming by-product inhibition

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

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