Traversing the fungal terpenome

Quin, Maureen B.; Flynn, Christopher; Schmidt‐Dannert, Claudia

doi:10.1039/c4np00075g

Cited by 296 publications

(284 citation statements)

References 250 publications

(482 reference statements)

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“…The putative mechanism for formation of the carbon skeleton for cucumene is closely related to those suggested for linear and angular triquinane sesquiterpenes (39). A key step in all of these pathways is the 1,11 ring closure of the trans-farnesyl cation to give a trans-humulyl cation.…”

Section: Discussionmentioning

confidence: 84%

“…A 2D structure for compound 1 was published when this manuscript was in the final stage of preparation (15). The authors named the sesquiterpene iso-hirsutene; however, we prefer cucumene, in recognition of the proposal that the methyl substitution patterns of the two carbon skeletons arise from nontrivial differences in the mechanisms for their formation (39).…”

Section: Resultsmentioning

confidence: 99%

“…Although a different reaction channel was originally proposed for pentalenene, recent isotopically sensitive branching experiments suggest that the protoilludyl cation is also the precursor for formation of the pentalenane skeleton (33,36). The protoilludyl cation is a likely intermediate in the formation of cucumene (39).…”

Section: Discussionmentioning

confidence: 99%

“…For example, presilphiperfolan-8β-ol synthase catalyzes the highly selective seven-step transformation of FPP to presilphiperfolan-8β-ol (39,43). Each of these steps is exquisitely sensitive to the steric and electrostatic environment of the active site, and single mutations are often sufficient to substantially alter the structures of the products.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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.

View full text Add to dashboard Cite

show abstract

“…Arguably, terpenes represent the largest and structurally most diverse class of natural products with over 55,000 members so far described, including monoterpenes, sesquiterpenes, and diterpenes. These molecules are generated via terpene cyclases, a highly sophisticated class of enzymes that turns simple linear and achiral precursor molecules with high enantioselectivity into usually polycyclic terpene hydrocarbons or alcohols with often multiple stereogenic centres (Degenhardt et al, 2009, Quin et al, 2014, Dickschat, 2016. The initial products can be further converted into highly functionalised and bioactive molecules such as mycotoxins by oxidations, acylations and other modifications.…”

Section: Introductionmentioning

confidence: 99%