Biosynthesis via carbocations: Theoretical studies on terpene formation

Tantillo, Dean J.

doi:10.1039/c1np00006c

Cited by 332 publications

(322 citation statements)

References 147 publications

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“…PP i charge stabilization in conjunction with carbocation shielding from remaining solvent water through an H-bond donor amino acid network constitutes a common catalytic trigger upon activesite closure. Requirements for charge stabilization and separation argue that ionized PP i is retained in the active site during the entire catalytic cascade suggested by previous reports (21,(26)(27)(28)(29)(30)(31)(32). The lack of essential Y residues results in hydroxylated products as in the case of CBTS, which suggests an amino acid-assisted mechanism that provide control for water-assisted quenching products.…”

Section: Discussionmentioning

confidence: 89%

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Identification of amino acid networks governing catalysis in the closed complex of class I terpene synthases

Schrepfer

Buettner

Goerner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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Class I terpene synthases generate the structural core of bioactive terpenoids. Deciphering structure-function relationships in the reactive closed complex and targeted engineering is hampered by highly dynamic carbocation rearrangements during catalysis. Available crystal structures, however, represent the open, catalytically inactive form or harbor nonproductive substrate analogs. Here, we present a catalytically relevant, closed conformation of taxadiene synthase (TXS), the model class I terpene synthase, which simulates the initial catalytic time point. In silico modeling of subsequent catalytic steps allowed unprecedented insights into the dynamic reaction cascades and promiscuity mechanisms of class I terpene synthases. This generally applicable methodology enables the active-site localization of carbocations and demonstrates the presence of an active-site base motif and its dominating role during catalysis. It additionally allowed in silico-designed targeted protein engineering that unlocked the path to alternate monocyclic and bicyclic synthons representing the basis of a myriad of bioactive terpenoids.computational biology | closed complex modeling | protein engineering | terpene synthases | terpene synthase catalysis

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Section: Discussionmentioning

confidence: 89%

“…Very recently, a hypothesis pointing to a possible involvement of electrostatic effects during the carbocation cascade of other terpene synthases has been proposed. These effects are thought to be mediated by the PP i anion coproduct that may be retained in the active site (21,24,(26)(27)(28)(29)(30)(31)(32).…”

mentioning

confidence: 99%

Identification of amino acid networks governing catalysis in the closed complex of class I terpene synthases

Schrepfer

Buettner

Goerner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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“…Quantum mechanics-only and quantum mechanics/molecular mechanics (QM/MM) calculations have provided important insights about the mechanisms of reactions catalyzed by terpene synthases (20)(21)(22)(23)(24). However, gas phase QM calculations cannot predict functions for specific terpene synthases in the absence of protein structures.…”

mentioning

confidence: 99%

Computational-guided discovery and characterization of a sesquiterpene synthase from Streptomyces clavuligerus

Chow

Tian

Ramamoorthy

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Terpenoids are a large structurally diverse group of natural products with an array of functions in their hosts. The large amount of genomic information from recent sequencing efforts provides opportunities and challenges for the functional assignment of terpene synthases that construct the carbon skeletons of these compounds. Inferring function from the sequence and/or structure of these enzymes is not trivial because of the large number of possible reaction channels and products. We tackle this problem by developing an algorithm to enumerate possible carbocations derived from the farnesyl cation, the first reactive intermediate of the substrate, and evaluating their steric and electrostatic compatibility with the active site. The homology model of a putative pentalenene synthase (Uniprot: B5GLM7) from Streptomyces clavuligerus was used in an automated computational workflow for product prediction. Surprisingly, the workflow predicted a linear triquinane scaffold as the top product skeleton for B5GLM7. Biochemical characterization of B5GLM7 reveals the major product as (5S,7S,10R,11S)-cucumene, a sesquiterpene with a linear triquinane scaffold. To our knowledge, this is the first documentation of a terpene synthase involved in the synthesis of a linear triquinane. The success of our prediction for B5GLM7 suggests that this approach can be used to facilitate the functional assignment of novel terpene synthases.T erpenoid compounds form a large group of natural products synthesized by many species of plants, fungi, and bacteria. To date, more than 70,000 of these compounds have been identified, comprising ∼25% of all of the known natural products (Dictionary of Natural Products database, dnp.chemnetbase.com/intro/ index.jsp). Terpenoids and molecules containing terpenoid fragments are produced from two basic five-carbon building blocks: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) (1, 2). IPP and DMAPP are then converted into a series of terpenoid diphosphate esters of increasing chain lengths by chain length selective polyprenyl diphosphate synthases to give geranyl diphosphate (GPP, C 10 ), farnesyl diphosphate (FPP, C 15 ), geranylgeranyl diphosphate (GGPP, C 20 ), and higher five-carbon homologs (3). These molecules are substrates for terpene synthases, which catalyze hydroxylation, elimination, cyclization, and rearrangement reactions to produce much of the structural diversity of terpenoid molecules found in nature (4, 5).The two main classes of terpene synthases (class I and class II) are distinguished from one another by the mechanisms they use to initiate carbocationic cyclization and rearrangement reactions and by their respective folds (6, 7). Class I terpene synthases use active site Mg 2+ ions to bind and activate the diphosphate moieties of their substrates as leaving groups to generate highly reactive allylic carbocations. In those terpene synthases that catalyze cyclization reactions, the carbocations alkylate distal double bonds in the hydrocarbon chain. The initial cycliza...

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“…76,[83][84][85][86] Complementing and enriching these studies, Prof Dean J Tantillo (U. C. Davis) has deepened the understanding of the mechanisms and energetics of terpene cyclization reactions through detailed quantum chemical calculations of the reaction pathways linking carbocationic intermediates and transition state structures for a wide variety of terpene synthase-catalyzed reactions. [87][88][89][90][91] In spite of the substantial progress in cloning terpene synthases, the search for additional terpene synthase genes was seriously hindered by the exceptionally low levels of mutual sequence similarity among known terpene synthases, thus thwarting the routine application of homology-based cloning methods to this class of microbial proteins. It occurred to me that it might be possible to find and then biochemically characterize microbial terpene synthases by using known terpene synthase sequences to query the then newly emerging microbial genome sequences.…”

Section: Enzymology and Molecular Genetics Of Natural Product Biosyntmentioning

confidence: 99%

Nature as organic chemist

Cane

2016

J Antibiot

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Figure 15 Stereospecific reduction of (2R)-2-methyl-3-ketopentanoyl-ACP by recombinant ketoreductase (KR) domains: EryKR6, from module 6 of the 6dEB synthase (DEBS); TylKR1, from module 1 of the tylactone synthase; EryKR1, from DEBS module 1; RifKR7, from module 7 of the rifamycin PKS. The (2R)-2-methyl-3-ketopentanoyl-ACP substrate is generated in situ by a reconstituted mixture of dissected PKS domains, Ery[KS6][AT6] (ketosynthase-acyl transferase didomain) and EryACP6 are both from DEBS module 6. Editorial

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Biosynthesis via carbocations: Theoretical studies on terpene formation

Abstract: This review describes applications of quantum chemical calculations in the field of terpene biosynthesis, with a focus on insights into the mechanisms of terpene-forming carbocation rearrangements arising from theoretical studies.

Cited by 332 publications

References 147 publications

Identification of amino acid networks governing catalysis in the closed complex of class I terpene synthases

Identification of amino acid networks governing catalysis in the closed complex of class I terpene synthases

Computational-guided discovery and characterization of a sesquiterpene synthase from Streptomyces clavuligerus

Nature as organic chemist

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