Substrate specificities of E- and Z-farnesyl diphosphate synthases with substrate analogs

Nagaki, Masahiko; Ichijo, Takumi; Kobashi, Rikiya; Yagihashi, Yusuke; Musashi, Tohru; Kawakami, Jun; Ohya, Norimasa; Gotoh, Tetsuo; Sagami, Hiroshi

doi:10.1016/j.molcatb.2012.04.006

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…Interestingly, a chiral center is created during elongation reactions with 4-methyl-IPP and its configuration depends on the E - or Z -configuration of the C 6 substrate. , The introduction of chirality into the so far nonchiral terpenoid building block repertoire adds another level of complexity to terpene biosynthesis pathways.…”

Section: Resultsmentioning

confidence: 99%

Expanding the Isoprenoid Building Block Repertoire with an IPP Methyltransferase from Streptomyces monomycini

et al. 2019

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Many synthetic biology approaches aim at expanding the product diversity of enzymes or whole biosynthetic pathways. However, the chemical structure space of natural product forming routes is often restricted by the limited cellular availability of different starting intermediates. Although the terpene biosynthesis pathways are highly modular, their starting intermediates are almost exclusively the C 5 units IPP and DMAPP. To amplify the possibilities of terpene biosynthesis through the modification of its building blocks, we identified and characterized a SAM-dependent methyltransferase converting IPP into a variety of C 6 and C 7 prenyl pyrophosphates. Heterologous expression in Escherichia coli not only extended the intracellular prenyl pyrophosphate spectrum with mono-or dimethylated IPP and DMAPP, but also enabled the biosynthesis of C 11 , C 12 , C 16 , and C 17 prenyl pyrophosphates. We furthermore demonstrated the general high promiscuity of terpenoid biosynthesis pathways toward uncommon building blocks by the E. coli-based production of polymethylated C 41 , C 42 , and C 43 carotenoids. Integration of the IPP methyltransferase in terpene synthesis pathways enables an expansion of the terpenoid structure space beyond the borders predetermined by the isoprene rule which indicates a restricted synthesis by condensation of C 5 units.

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Section: Resultsmentioning

confidence: 99%

Expanding the Isoprenoid Building Block Repertoire with an IPP Methyltransferase from Streptomyces monomycini

et al. 2019

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“…The stereochemistry of the final molecule in this case would be determined by whether the methyl-IPP molecule was E or Z. The substrate E-4-methyl-IPP would yield S-4-methyl-GPP, and Z-4-methyl-IPP would yield R-4-methyl-GPP, as demonstrated in previous studies with FPP synthase and synthetic substrates (Tanetoshi Koyama et al 1980;Nagaki et al 2012).…”

Section: Isotope Labeling Of Methylated Compounds and Identification Of Longchain Methyl-terpenesmentioning

confidence: 69%

“…Interestingly, the use of either (Z)-or (E)-4-methyl-IPP as substrate generates specifically (R) or (S) configurations of the C11 and C16 prenyl diphosphates. This phenomenon was already described using synthetic substrates in assays with prenyl transferases from pig liver (Tanetoshi Koyama et al 1980;Nagaki et al 2012). The possibility of enzymatically creating chiral molecules according to the configuration of the substrate offered encompasses an attractive approach for the pharmaceutical industry, which is in constant pursuit of enzymatic technologies for delivering enantiopure products, especially generics (Blaser 2013).…”

Section: In Vitro Assays With Mt From S Monomycinimentioning

confidence: 95%

“…Several FPP analogues were shown to be accepted by a farnesyl transferase involved in protein prenylation, in a study searching for enzymatic reaction inhibitors (Subramanian et al 2012). When focusing on prenyl transferases, studies have been made with prenyl pyrophosphates analogues showing high promiscuity of these enzymes towards a variety of uncommon substrates and products (Tanetoshi Koyama et al 1980;Nagaki et al 2012) Different strains of E. coli were employed according to the type of experiment to be performed. The strains and their specific genomic notations are described on Table 4.…”

Section: Motivationmentioning

confidence: 99%

“…Analog dazu wurde gezeigt, dass eine Farnesyltransferase, die an der Proteinprenylierung beteiligt ist, XXII verschiedene FPP-Analoga akzeptiert(Subramanian et al 2012). Mehre Studien mit synthetischen Prenylpyrophosphat-Analoga zeigten die Promiskuität von Prenyltransferasen, sowohl hinsichtlich der Substrate als auch der Produkte (TanetoshiKoyama et al 1980;Nagaki et al 2012). Die Promiskuität solcher Enzyme kann genutzt werden, um eine breitere synthetische Produktvielfalt des Terpen-Biosynthesewegs zu erreichen, indem unnatürliche oder unkonventionelle Vorstufen verwendet werden.…”

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Investigation of non-canonical terpene biosynthesis

Drummond¹

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Terpenes are one of the largest and most diverse class of natural products, produced by organisms from all kingdoms of life and with important applications in the pharma, flavor and fragrance industries. Well-known examples of terpenes are the pharmaceuticals artemisinin and taxol, the flavor and fragrance compounds menthol, santalol and sclareol, the structural material polyisoprene and the biofuel precursor farnesene. The methods and results presented in this work offer a variety of ways to modify terpene precursors for the creation of new terpene molecules. The application of these methodologies in well-established production systems could lead to the production of new substances, with applications in the industrial fields of pharmaceuticals, flavors and fragrances, and biofuels.

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Effiziente chemoenzymatische Synthese von Dihydroartemisinaldehyd

et al. 2017

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Artemisinin aus der Pflanze Artemisia annua ist das wirkungsvollste Arzneimittel zur Behandlung von Malaria. Die Sesquiterpen-Cyclase Amorphadien-Synthase,e in Cytochrom-abhängiges CYP450 und eine Aldehyd-Reduktase wandeln in der PflanzeF arnesyl-Diphosphat (FDP) in Dihydroartemisinaldehyd (DHAAl) um, welches ein Schlüssel-zwischenprodukt in der Biosynthese von Artemisinin und eine halbsynthetische Vorstufe in der chemischen Synthese des Arzneimittels ist. Hier berichtenw ir über einen chemoenzymatischen Prozess,der in der Lage ist, DHAAl nur mithilfe der Sesquiterpen-Synthase aus einem gezielt synthetisierten, hydroxylierten FDP-Derivat herzustellen. Dieser Prozess,der die natürlicheS equenz aus Cyclisierung von FDP und Oxidation des Kohlenwasserstoffs umkehrt, stellt eine wesentliche Verbesserung der DHAAl-Synthese dar und zeigt das Potenzial neuer Substrate in der Terpen-Synthase-katalysierten Synthese hochwertiger Naturstoffe auf.

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Substrate specificities of E- and Z-farnesyl diphosphate synthases with substrate analogs

Cited by 8 publications

References 21 publications

Expanding the Isoprenoid Building Block Repertoire with an IPP Methyltransferase from Streptomyces monomycini

Expanding the Isoprenoid Building Block Repertoire with an IPP Methyltransferase from Streptomyces monomycini

Investigation of non-canonical terpene biosynthesis

Effiziente chemoenzymatische Synthese von Dihydroartemisinaldehyd

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