Isoprenoid Compounds Research Articles

Does the novel fast-GC coupled with PTR-TOF-MS allow a significant advancement in detecting VOC emissions from plants?

Most plants produce and emit a wide blend of biogenic volatile organic compounds (BVOCs). Among them, many isoprenoids exhibit a high atmospheric reactivity toward OH radicals and ozone. In the last few years, Proton Transfer Reaction–Mass Spectrometry (PTR–MS) has been widely used in both field and laboratory determination of BVOCs, complementing the traditional methods using gas chromatography–mass spectrometry (GC–MS) for their identification in air and emission sources. This technical note reports a number of experiments carried out with a PTR- (Time-of-Flight) TOF-MS equipped with a prototype fast-GC system, allowing a fast separation of those isobaric isoprenoid compounds that cannot be identified by a direct PTR-TOF-MS analysis. The potential of this fast-GC system to adequately complement the information provided by PTR-TOF-MS was investigated by using the BVOC emissions of Quercus ilex and Eucalyptus camaldulensis as reliable testing systems, due to the different blend of isoprenoid compounds emitted and the different dependence of their emission from environmental parameters. While the oak species is a strong monoterpene emitter, the eucalyptus used is one of the few plant species emitting both isoprene and monoterpenes. The performances provided by the type of fast-GC used in the new PTR-TOF-MS instrument were also compared with those afforded by conventional GC–MS methods. The results obtained in this investigation showed that this new instrument is indeed a quick and handy tool to determine the contribution of isoprene and eucalyptol to m/z 69.070 and monoterpenes and (Z)-3-hexenal to m/z 81.070, integrating well the on-line information provided by PTR-TOF-MS. However, some limitations emerged in the instrument as compared to traditional GC–MS, which can only be solved by implementing the injection and separation processes.

Bakuchiol Is a Phenolic Isoprenoid with Novel Enantiomer-selective Anti-influenza A Virus Activity Involving Nrf2 Activation

Influenza represents a substantial threat to human health and requires novel therapeutic approaches. Bakuchiol is a phenolic isoprenoid compound present in Babchi (Psoralea corylifolia L.) seeds. We examined the anti-influenza viral activity of synthetic bakuchiol using Madin-Darby canine kidney cells. We found that the naturally occurring form, (+)-(S)-bakuchiol, and its enantiomer, (-)-(R)-bakuchiol, inhibited influenza A viral infection and growth and reduced the expression of viral mRNAs and proteins in these cells. Furthermore, these compounds markedly reduced the mRNA expression of the host cell influenza A virus-induced immune response genes, interferon-β and myxovirus-resistant protein 1. Interestingly, (+)-(S)-bakuchiol had greater efficacy than (-)-(R)-bakuchiol, indicating that chirality influenced anti-influenza virus activity. In vitro studies indicated that bakuchiol did not strongly inhibit the activities of influenza surface proteins or the M2 ion channel, expressed in Chinese hamster ovary cells. Analysis of luciferase reporter assay data unexpectedly indicated that bakuchiol may induce some host cell factor(s) that inhibited firefly and Renilla luciferases. Next generation sequencing and KeyMolnet analysis of influenza A virus-infected and non-infected cells exposed to bakuchiol revealed activation of transcriptional regulation by nuclear factor erythroid 2-related factor (Nrf), and an Nrf2 reporter assay showed that (+)-(S)-bakuchiol activated Nrf2. Additionally, (+)-(S)-bakuchiol up-regulated the mRNA levels of two Nrf2-induced genes, NAD(P)H quinone oxidoreductase 1 and glutathione S-transferase A3. These findings demonstrated that bakuchiol had enantiomer-selective anti-influenza viral activity involving a novel effect on the host cell oxidative stress response.

Road tunnel, roadside, and urban background measurements of aliphatic compounds in size-segregated particulate matter

Particulate matter samples were collected in a road tunnel in Lisbon (PM0.5, PM0.5–1, PM1–2.5, and PM2.5–10) and at two urban locations representing roadside and background stations (PM2.5 and PM2.5–10). Samples were analysed for organic and elemental carbon (OC and EC), n-alkanes, n-alkenes, hopanes, some isoprenoid compounds, and steranes. Particulate matter concentrations in the tunnel were 17–31 times higher than at roadside in the vicinity, evidencing an aerosol origin almost exclusively in fresh vehicle emissions. PM0.5 in the tunnel comprised more than 60% and 80% of the total OC and EC mass in PM10, respectively. Concentrations of the different aliphatic groups of compounds in the tunnel were up to 89 times higher than at roadside and 143 times higher than at urban background. Based on the application of hopane-to-OC or hopanes-to-EC ratios obtained in the tunnel, it was found that vehicle emissions are the dominant contributor to carbonaceous particles in the city but do not represent the only source of these triterpenic compounds. Contrary to what has been observed in other studies, the Σhopane-to-EC ratios were higher in summer than in winter, suggesting that other factors (e.g. biomass burning, dust resuspension, and different fuels/engine technologies) prevail in relation to the photochemical decay of triterpenoid hydrocarbons from vehicle exhaust.

Structure–activity analysis and antiprion mechanism of isoprenoid compounds

The prion strain-specific mechanism by which normal prion protein is converted to abnormal prion protein remains largely unknown. This study found that insect juvenile hormone III reduced abnormal prion protein levels only in cells infected with the RML prion. We conducted a structure–activity analysis using juvenile hormone III biosynthetic intermediates in the isoprenoid pathway. Both farnesol and geranylgeraniol, the most potent inhibitors of abnormal prion protein formation, behaved in an RML prion-dependent fashion. Neither of them modified cellular and cell surface prion protein levels. Events downstream of this pathway include cholesterol biosynthesis and protein prenylation. However, neither of these isoprenoid compounds modified lipid raft microdomains and cellular cholesterol levels and neither affected the representative prenylated protein expression levels of prenylation pathways. Therefore, these isoprenoid compounds are a new class of prion strain-dependent antiprion compounds. They are useful for exploring strain-specific prion biology.

Recent Advances in the Synthesis of Carotenoid-Derived Flavours and Fragrances.

Carotenoids are important isoprenoid compounds whose oxidative degradation produces a plethora of smaller derivatives, called apocarotenoids, which possess a range of different chemical structures and biological activities. Among these natural products, compounds having less than 15 carbon atoms in their frameworks are often relevant flavours or fragrances and their manufacturing represents an important economic resource for chemical companies. The strict correlation between stereochemical structure and odour has made the stereospecific synthesis of the latter biological active compounds increasingly important. In this review, the recent advances on the synthesis of the most relevant carotenoid-derived flavours and fragrances are discussed. In particular, the new synthetic methods that have given new and innovative perspectives from a scientific standpoint and the preparative approaches that might possess industrial importance are described thoroughly.

Carotenoid biosynthetic genes in Brassica rapa: comparative genomic analysis, phylogenetic analysis, and expression profiling.

BackgroundCarotenoids are isoprenoid compounds synthesized by all photosynthetic organisms. Despite much research on carotenoid biosynthesis in the model plant Arabidopsis thaliana, there is a lack of information on the carotenoid pathway in Brassica rapa. To better understand its carotenoid biosynthetic pathway, we performed a systematic analysis of carotenoid biosynthetic genes at the genome level in B. rapa.ResultsWe identified 67 carotenoid biosynthetic genes in B. rapa, which were orthologs of the 47 carotenoid genes in A. thaliana. A high level of synteny was observed for carotenoid biosynthetic genes between A. thaliana and B. rapa. Out of 47 carotenoid biosynthetic genes in A. thaliana, 46 were successfully mapped to the 10 B. rapa chromosomes, and most of the genes retained more than one copy in B. rapa. The gene expansion was caused by the whole-genome triplication (WGT) event experienced by Brassica species. An expression analysis of the carotenoid biosynthetic genes suggested that their expression levels differed in root, stem, leaf, flower, callus, and silique tissues. Additionally, the paralogs of each carotenoid biosynthetic gene, which were generated from the WGT in B. rapa, showed significantly different expression levels among tissues, suggesting differentiated functions for these multi-copy genes in the carotenoid pathway.ConclusionsThis first systematic study of carotenoid biosynthetic genes in B. rapa provides insights into the carotenoid metabolic mechanisms of Brassica crops. In addition, a better understanding of carotenoid biosynthetic genes in B. rapa will contribute to the development of conventional and transgenic B. rapa cultivars with enriched carotenoid levels in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1655-5) contains supplementary material, which is available to authorized users.

Natural phenolics greatly increase flax (Linum usitatissimum) oil stability.

BackgroundFlaxseed oil is characterized by high content of essential polyunsaturated fatty acids (PUFA) promoted as a human dietary supplement protecting against atherosclerosis. The disadvantage of the high PUFA content in flax oil is high susceptibility to oxidation, which can result in carcinogenic compound formation. Linola flax cultivar is characterized by high linoleic acid content in comparison to traditional flax cultivars rich in linolenic acid. The changes in fatty acid proportions increase oxidative stability of Linola oil and broaden its use as an edible oil for cooking. However one of investigated transgenic lines has high ALA content making it suitable as omega-3 source. Protection of PUFA oxidation is a critical factor in oil quality. The aim of this study was to investigate the impact of phenylpropanoid contents on the oil properties important during the whole technological process from seed storage to grinding and oil pressing, which may influence health benefits as well as shelf-life, and to establish guidelines for the selection of new cultivars.MethodsThe composition of oils was determined by chromatographic (GS-FID and LC-PDA-MS) methods. Antioxidant properties of secondary metabolites were analyzed by DPPH method. The stability of oils was investigated: a) during regular storage by measuring acid value peroxide value p-anisidine value malondialdehyde, conjugated dienes and trienes; b) by using accelerated rancidity tests by TBARS reaction; c) by thermoanalytical - differential scanning calorimetry (DSC).ResultsIn one approach, in order to increase oil stability, exogenous substances added are mainly lipid soluble antioxidants from the isoprenoid pathway, such as tocopherol and carotene. The other approach is based on transgenic plant generation that accumulates water soluble compounds. Increased accumulation of phenolic compounds in flax seeds was achieved by three different strategies that modify genes coding for enzymes from the phenylpropanoid pathway. The three types of transgenic flax had different phenylpropanoid profiles detected in oil, highly increasing its stability.ConclusionsWe found that hydrophilic phenylpropanoids more than lipophilic isoprenoid compounds determine oil stability however they can work synergistically. Among phenolics the caffeic acid was most effective in increasing oil stability.

Isoprene and isoprenoid compounds

This PubChem entry has information on chemical properties, biological interactions, and commercial sources for isoprene. This Wikipedia entry covers the biological and commercial sources of isoprene and also discusses briefly some of the details of isoprene biosynthesis. This webpage defines the terpenoid class of compounds and provides lnks to a relatively small number of specific terpenoid compounds. This database page lists important physiological isoprenoids and provides links to pages containing additional information. This page describes technology to produce isoprene by cyanobacteria using the MEP pathway. This interesting paper compares features of the chemical versus biological processes for making isoprene. The general conclusion is that the biological process is still more expensive than the chemical one, but it has good prospects in the long run. Isoprene contributes greatly to atmospheric aerosols. This paper describes modeling to follow isoprene and isoprene-derived chemical species as markers. There are two classes of hydroxymethylglutaryl-CoA reductases, a key enzyme in the synthesis of isoprenoid compounds, and this page describes class II enzymes which include those from bacteria as well as some archaea. This blog deals with some members of a certain class of hopanoids, which are one specific type of polycyclic isoprenoid compounds. This page contains a pathway map, in text and graphical form, for the cyclic isoprenoid compound limonene and information about the compounds and enzymes involved. This page contains a pathway map, in text and graphical form, for the acyclic isoprenoid alcohol geraniol and information about the compounds and enzymes involved. Geosmin is a bicyclic isoprenoid compound that is produced by Actinobacteria and is responsible for the earthy smell that is most noticeable following a rain after a long dry spell. The noticeable odor is due to the volatility of the compound and the sensitivity of the human nose to geosmin. This review describes isoprenoid compounds in general with a particular focus on their biosynthesis by microbial pathogens and the opportunities for new antibiotics by targeting the biosynthetic pathways. There are over 750 different carotenoids known and their estimated market value is approaching one billion dollars. This review deals with these compounds and recent research on their microbial production. This paper deals with an alternative to nucleic acid methods for monitoring microbial populations in which the ubiquitous microbial isoprenoid quinones are identified as markers for certain microbial types. This news article highlights recent findings showing that terpene biosynthesis by bacteria is more pervasive than previously thought. A bioinformatics approach revealed the widespread occurrence and a rich diversity of terpene synthases in prokaryotes. This article highlights how isoprenoid compounds are extremely important for the flavor and fragrance industry. This commercial website contains much useful information on the biosynthesis and properties of terpenoid compounds. This article extends our knowledge of the association between ectomycorrhizal fungi and and plants by showing that facets of the mutualistic association are mediated by isoprenoid compounds. This review discusses a wide variety of fungal sesquiterpenes and the potential significance of those compounds in nature.

Major bioactive metabolites from marine fungi: A Review.

Biologists and chemists of the world have been attracted towards marine natural products for the last five decades. Approximately 16,000 marine natural products have been isolated from marine organisms which have been reported in approximately 6,800 publications, proving marine microorganisms to be a invaluable source for the production of novel antibiotic, anti tumor, and anti inflammatory agents. The marine fungi particularly those associated with marine alga, sponge, invertebrates, and sediments appear to be a rich source for secondary metabolites, possessing Antibiotic, antiviral, antifungal and antiyeast activities. Besides, a few growth stimulant properties which may be useful in studies on wound healing, carcinogenic properties, and in the study of cancers are reported. Recent investigations on marine filamentous fungi looking for biologically active secondary metabolites indicate the tremendous potential of them as a source of new medicines. The present study reviews about some important bioactive metabolites reported from marine fungal strains which are anti bacterial, anti tumour and anti inflammatory in action. It highlights the chemistry and biological activity of the major bioactive alkaloids, polyketides, terpenoids, isoprenoid and non-isoprenoid compounds, quinones, isolated from marine fungi.

Bioactive Compounds from Marine Invertebrates for Potential Medicines - An Overview

The present review deals with the bioactive compounds of the marine non-chordates. The potent medicinal usage of the bioactive compounds viz. steroids, terpenoids, isoprenoid and non-isoprenoid compounds, quinones, brominated compounds, nitrogen heterocyclics and nitrogen-sulphur heterocyclics from marine non-chordates have been compiled. Various literatures survey revealed that the bioactive compounds isolated in recent past from the marine poriferans, cnidarians, annelids, arthropods, molluscs and echinoderms could be rich sources of therapeutic agents having antibacterial, antiinflamatory, anticarcinogenic properties. In overall, the present study will be benefitted to know global drug discovery researches on bioactive compounds from marine organisms for students, scholars, scientists, pharmaceutical sector, and government regulating authorities as new challenging technology in clinical applications through medicines.

Reduction of fatty acid flux at low temperature led to enhancement of β-carotene biosynthesis in recombinant Saccharomyces cerevisiae

Transferring the recombinant S. cerevisiae T73-63 from 30 °C to 4 °C resulted in 41.4% increment of β-carotene concentration (3.96mg/g dry cell weight) relative to that of 30 °C, which was accompanied with the accumulation of fatty acid and ergosterol. The comparisons of the transcriptional levels of mevalonate pathway genes indicated that the expressions of HMG1, ERG9, ERG19, ERG20 and IDI1 at 4 °C were all higher than those of 30 °C, respectively. This suggested that increased transcriptions of mevalonate pathway genes contribute to the improvement of β-carotene production at low temperature. We also found that supplementation of 30mg/L triclosan, an inhibitor of fatty acid synthesis, led to further 28.3% enhancement of β-carotene concentration (4.94mg/g DCW), which was 18.8% higher than that of 30 °C with the same concentration of triclosan. The higher expressional levels of HMG, ERG19 and ERG20 and the simultaneous increment of ergosterol content (17.8%) suggested that more carbon source was transferred from fatty acid synthesis to mevalonate pathway under the circumstance of appropriately blocking fatty acid synthesis at low temperature (4 °C), which resulted in a higher increment of β-carotene production compared to that of 30 °C. The results of this study collectively suggest that the combination of reducing temperature and adding fatty acid synthesis inhibitors is a potential approach to improve the production of desirable isoprenoid compounds such as carotenoids.

Geranylgeranylacetone suppresses colitis‑related mouse colon carcinogenesis.

Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. GGA protects a variety of cells and tissues against numerous stresses via induction of heat shock protein (HSP)70, and it has recently been reported to protect mice from experimental ulcerative colitis (UC). However, it is unknown whether GGA exhibits a preventive effect on UC-associated neoplasia. In the present study, we evaluated the preventive effects of GGA on colitis-related carcinogenesis in the mouse colon. Mice were administered 1,2-dimethylhydrazine (DMH) subcutaneously three times within a week, followed by 2cycles of dextran sulfate sodium (DSS) (each cycle, 3% DSS for 7days and then distilled water for 14days) and they were sacrificed 28days after the completion of the 2cycles. The mice were divided into the following groups according to the diet received during the experiment: groupA, which received a standard diet and served as a disease control; groupB, which received a diet mixed with 0.25% GGA; groupC, which received a diet mixed with 0.5% GGA; groupD, which received a diet mixed with 1.0% GGA; groupE, which received a diet mixed with 2.0% GGA; and groupF, which received a diet containing no agents, including DSS and served as a normal control. The incidence of neoplasia was assessed. The expression of inducible nitric oxide synthase (iNOS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also determined. In addition, the expression of HSP70 in the colon tissues was determined by immunohistochemistry and western blot analysis. The mean number of tumors was 16.6, 11.0, 9.4, 5.8, 5.4 and0 in groupsA-F, respectively. GGA significantly suppressed the occurrence of neoplasia in a dose-dependent manner. GGA treatment enhanced the expression of HSP70 and suppressed the oxidative damage in the background mucosa (i.e. lesion-free colon). These results suggest that GGA could be useful in the prevention of UC-associated neoplasia.

Bioactive Compounds from Marine Invertebrates for Potential Medicines - An Overview

The present review deals with the bioactive compounds of the marine non-chordates. The potent medicinal usage of the bioactive compounds viz. steroids, terpenoids, isoprenoid and non-isoprenoid compounds, quinones, brominated compounds, nitrogen heterocyclics and nitrogen-sulphur heterocyclics from marine non-chordates have been compiled. Various literatures survey revealed that the bioactive compounds isolated in recent past from the marine poriferans, cnidarians, annelids, arthropods, molluscs and echinoderms could be rich sources of therapeutic agents having antibacterial, antiinflamatory, anticarcinogenic properties. In overall, the present study will be benefitted to know global drug discovery researches on bioactive compounds from marine organisms for students, scholars, scientists, pharmaceutical sector, and government regulating authorities as new challenging technology in clinical applications through medicines.

Isoprenoid drugs, biofuels, and chemicals--artemisinin, farnesene, and beyond.

Isoprenoids have been identified and used as natural pharmaceuticals, fragrances, solvents, and, more recently, advanced biofuels. Although isoprenoids are most commonly found in plants, researchers have successfully engineered both the eukaryotic and prokaryotic isoprenoid biosynthetic pathways to produce these valuable chemicals in microorganisms at high yields. The microbial synthesis of the precursor to artemisinin--an important antimalarial drug produced from the sweet wormwood Artemisia annua--serves as perhaps the most successful example of this approach. Through advances in synthetic biology and metabolic engineering, microbial-derived semisynthetic artemisinin may soon replace plant-derived artemisinin as the primary source of this valuable pharmaceutical. The richness and diversity of isoprenoid structures also make them ideal candidates for advanced biofuels that may act as "drop-in" replacements for gasoline, diesel, and jet fuel. Indeed, the sesquiterpenes farnesene and bisabolene, monoterpenes pinene and limonene, and hemiterpenes isopentenol and isopentanol have been evaluated as fuels or fuel precursors. As in the artemisinin project, these isoprenoids have been produced microbially through synthetic biology and metabolic engineering efforts. Here, we provide a brief review of the numerous isoprenoid compounds that have found use as pharmaceuticals, flavors, commodity chemicals, and, most importantly, advanced biofuels. In each case, we highlight the metabolic engineering strategies that were used to produce these compounds successfully in microbial hosts. In addition, we present a current outlook on microbial isoprenoid production, with an eye towards the many challenges that must be addressed to achieve higher yields and industrial-scale production.

ХИМИЧЕСКИЙ СОСТАВ ЛИПИДОВ ЛИСТОСТЕБЕЛЬНЫХ МХОВ – ТОРФООБРАЗОВАТЕЛЕЙ ЭВТРОФНЫХ БОЛОТ ЗАПАДНОЙ СИБИРИ И АЛТАЯ

The paper describes the molecular composition of lipids in three samples of leafy moss ( Aulacomnium palustre, Warnstorfia fluitans and Calliergon giganteum ). Acyclic compounds such as normal and isoprenoid alkanes, isoprenoid alkenes, carboxylic acids and their esters, alcohols, aldehydes, normal and isoprenoid ketones were identified. Cyclic structures comprised of bi-, tri- and tetracyclic polycycloaromatic hydrocarbons (PAHs), bicyclic and pentacyclic terpenoids, steroids and tocopherols were detected. It was shown that carboxylic acids and n-alkanes with the dominance of C 27 homologue prevail among the organic compounds identified in mosses. It was found that A. palustre is characterized by a reduced content of isoprenoid compounds, alcohols, ketones and high content of unsaturated acids, pentacyclic terpenoids and aldehydes. A. palustre also differs from W. fluitans and C. giganteum in the composition of steroids. The sesquiterpenoid eremophilene was detected in A. palustre, but it is absent in the other mosses. The content of lycopadiene, carboxylic acids, n-alkanes, fit-2-ene, aldehydes, esters, squalene, diploptene, α-tocopherol and triphenyl phosphates is higher in W. fluitans in comparison to C. giganteum .

Enhanced production of bioactive isoprenoid compounds from cell suspension cultures of Artemisia annua L. using β-cyclodextrins.

Plant cell cultures as valuable tools for the production of specific metabolites can be greatly improved by the application of elicitors including cyclodextrins (CDs) for enhancing the yields of the desired plant compounds. Here the effects of 2,6-dimethyl-β-cyclodextrins (DIMEB) on the production of carotenoids and quinones from Artemisia annua L. cell suspension cultures were investigated. The addition of 50 mM DIMEB induced an early increase of intracellular carotenoid and quinone contents, which could be observed to a higher extent for lutein (10-fold), Q9 (3-fold) and Q10 (2.5-fold). Real Time PCR analysis revealed that the expression of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) gene in DIMEB treated cell cultures after three days was 2.5-fold higher than in untreated samples, thus suggesting that the DIMEB induced increase of carotenoids and quinones could be due to the induction of the plastidial isoprenoid biosynthetic route. In addition, the DIMEB treatment induced an enhanced release of carotenoids and quinones into the culture medium of A. annua cell suspension cultures possibly due to the ability of CDs to form inclusion complexes with hydrophobic molecules.

Synthetic biology applications in industrial microbiology

Synthetic biology applications in industrial microbiology

Overexpression of erg20 gene encoding farnesyl pyrophosphate synthase has contrasting effects on activity of enzymes of the dolichyl and sterol branches of mevalonate pathway in Trichoderma reesei.

The mevalonate pathway is the most diverse metabolic route resulting in the biosynthesis of at least 30,000 isoprenoid compounds, many of which, such as sterols or dolichols, are indispensable for living cells. In the filamentous fungus Trichoderma of major biotechnological interest isoprenoid metabolites are also involved in the biocontrol processes giving the mevalonate pathway an additional significance. On the other hand, little is known about genes coding for enzymes of the mevalonate pathway in Trichoderma. Here, we present cloning and functional analysis of the erg20 gene from Trichoderma reesei coding for farnesyl pyrophosphate (FPP) synthase (EC 2.5.1.10), an enzyme located at the branching point of the mevalonate pathway. Expression of the gene in a thermosensitive erg20-2 mutant of Saccharomyces cerevisiae impaired in the FPP synthase activity suppressed the thermosensitive phenotype. The same gene overexpressed in T. reesei significantly enhanced the FPP synthase activity and also stimulated the activity of cis-prenyltransferase, an enzyme of the dolichyl branch of the mevalonate pathway. Unexpectedly, the activity of squalene synthase from the other, sterol branch, was significantly decreased without, however, affecting ergosterol level.

Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds.

Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines’ release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

δ-Deuterium isotope effects as probes for transition-state structures of isoprenoid substrates.

The biosynthetic pathways to isoprenoid compounds involve transfer of the prenyl moiety in allylic diphosphates to electron-rich (nucleophilic) acceptors. The acceptors can be many types of nucleophiles, while the allylic diphosphates only differ in the number of isoprene units and stereochemistry of the double bonds in the hydrocarbon moieties. Because of the wide range of nucleophilicities of naturally occurring acceptors, the mechanism for prenyltransfer reactions may be dissociative or associative with early to late transition states. We have measured δ-secondary kinetic isotope effects operating through four bonds for substitution reactions with dimethylallyl derivatives bearing deuterated methyl groups at the distal (C3) carbon atom in the double bond under dissociative and associative conditions. Computational studies with density functional theory indicate that the magnitudes of the isotope effects correlate with the extent of bond formation between the allylic moiety and the electron-rich acceptor in the transition state for alkylation and provide insights into the structures of the transition states for associative and dissociative alkylation reactions.