Predicting pathways for terpene formation from first principles – routes to known and new sesquiterpenes

Isegawa, Miho; Maeda, Satoshi; Tantillo, Dean J.; Morokuma, Keiji

doi:10.1039/c3sc53293c

Cited by 33 publications

(66 citation statements)

References 55 publications

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“…The AFIR has been applied most extensively to organo and organometallic catalysis, in combination with quantum chemical calculations 52–64. The other applications are: gas‐phase reactions;65–67 enzyme catalysis;68 domino reactions;69 and metal‐cluster catalysis 70,71. It has also been applied to electronic excited states and geometries of the seam of crossing between two electronic states 72–75.…”

Section: Introductionmentioning

confidence: 99%

Artificial Force Induced Reaction (AFIR) Method for Exploring Quantum Chemical Potential Energy Surfaces

Maeda

Harabuchi

Takagi

et al. 2016

The Chemical Record

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161

167

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In this account, a technical overview of the artificial force induced reaction (AFIR) method is presented. The AFIR method is one of automated reaction path search methods developed by the authors, and has been applied extensively to a variety of chemical reactions such as organocatalysis, organometallic catalysis, and photoreactions.There are two modes in the AFIR method, i.e., multi-component mode (MC-AFIR) and

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Section: Introductionmentioning

confidence: 99%

Artificial Force Induced Reaction (AFIR) Method for Exploring Quantum Chemical Potential Energy Surfaces

Maeda

Harabuchi

Takagi

et al. 2016

The Chemical Record

Self Cite

161

167

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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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“…There are some related works as AFIR [23]/GRRM, RetroRules [22], and Biotransformer [21]. Isegawa et al [45] had made computational simulations predicting pathways for terpene formation from a humulyl cation and other intermediate molecules using AFIR [23]/GRRM of which the chemical results align with ours, which allowed for a cross-confirmation. Compared to this work, the AFIR [23]/GRRM approach is a fundamentally distinct approach because it uses both a different data structure to design molecules and applies artificial forces between two or more reacting molecules.…”

Section: Discussionmentioning

confidence: 55%

“…Table 1 shows an overview of some features of the 2Path-Sesquiterpenes and its related works. [45] Internal AFIR/GRRM Sesquiterpenes Internal -RetroRules [22] SMART SMIRKS General -RetroRules BioTransformer [21] SMART SMIRKS General -MetXBioDB…”

Section: Discussionmentioning

confidence: 99%

Exploring Plant Sesquiterpene Diversity by Generating Chemical Networks

et al. 2019

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Plants produce a diverse portfolio of sesquiterpenes that are important in their response to herbivores and the interaction with other plants. Their biosynthesis from farnesyl diphosphate depends on the sesquiterpene synthases that admit different cyclizations and rearrangements to yield a blend of sesquiterpenes. Here, we investigate to what extent sesquiterpene biosynthesis metabolic pathways can be reconstructed just from the knowledge of the final product and the reaction mechanisms catalyzed by sesquiterpene synthases. We use the software package MedØlDatschgerl (MØD) to generate chemical networks and to elucidate pathways contained in them. As examples, we successfully consider the reachability of the important plant sesquiterpenes β -caryophyllene, α -humulene, and β -farnesene. We also introduce a graph database to integrate the simulation results with experimental biological evidence for the selected predicted sesquiterpenes biosynthesis.

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Predicting pathways for terpene formation from first principles – routes to known and new sesquiterpenes

Cited by 33 publications

References 55 publications

Artificial Force Induced Reaction (AFIR) Method for Exploring Quantum Chemical Potential Energy Surfaces

Artificial Force Induced Reaction (AFIR) Method for Exploring Quantum Chemical Potential Energy Surfaces

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

Exploring Plant Sesquiterpene Diversity by Generating Chemical Networks

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