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Monoterpenes, comprising hydrocarbons, are the largest class of plant secondary metabolites and are commonly found in essential oils. Monoterpenes and their derivatives are key ingredients in the design and production of new biologically active compounds. This review focuses on selected aliphatic, monocyclic, and bicyclic monoterpenes like geraniol, thymol, myrtenal, pinene, camphor, borneol, and their modified structures. The compounds in question play a pivotal role in biological and medical applications. The review also discusses anti-inflammatory, antimicrobial, anticonvulsant, analgesic, antiviral, anticancer, antituberculosis, and antioxidant biological activities exhibited by monoterpenes and their derivatives. Particular attention is paid to the link between biological activity and the effect of structural modification of monoterpenes and monoterpenoids, as well as the introduction of various functionalized moieties into the molecules in question.

Monoterpenes have wide applications in the food, cosmetics, and medicine industries and have recently received increased attention as advanced biofuels. However, compared with sesquiterpenes, monoterpene production is still lagging in Saccharomyces cerevisiae . In this study, geraniol, a valuable acyclic monoterpene alcohol, was synthesized in S. cerevisiae . We evaluated three geraniol synthases in S. cerevisiae , and the geraniol synthase Valeriana officinalis (tVoGES), which lacked a plastid-targeting peptide, yielded the highest geraniol production. To improve geraniol production, synthesis of the precursor geranyl diphosphate (GPP) was regulated by comparing three specific GPP synthase genes derived from different plants and the endogenous farnesyl diphosphate synthase gene variants ERG20 G ( ERG20 K197G ) and ERG20 WW ( ERG20 F96W-N127W ), and controlling endogenous ERG20 expression, coupled with increasing the expression of the mevalonate pathway by co-overexpressing IDI1 , tHMG1 , and UPC2-1 . The results showed that overexpressing ERG20 WW and strengthening the mevalonate pathway significantly improved geraniol production, while expressing heterologous GPP synthase genes or down-regulating endogenous ERG20 expression did not show positive effect. In addition, we constructed an Erg20p(F96W-N127W)-tVoGES fusion protein, and geraniol production reached 66.2 mg/L after optimizing the amino acid linker and the order of the proteins. The best strain yielded 293 mg/L geraniol in a fed-batch cultivation, a sevenfold improvement over the highest titer previously reported in an engineered S. cerevisiae strain. Finally, we showed that the toxicity of geraniol limited its production. The platform developed here can be readily used to synthesize other monoterpenes.

Background: Hemolysis and eryptosis of red blood cells (RBCs) contribute to chemotherapy-induced anemia, a marker of poor prognosis. Geraniol (GER) is an anticancer acyclic monoterpene alcohol found in several plant extracts, but a dearth of evidence exists regarding the potential toxicity of GER in RBCs. Methods: Hemolysis and eryptosis were evaluated using colorimetric and fluorescence-assisted cell-sorting methods, respectively. Phosphatidylserine (PS) exposure, loss of volume, and intracellular Ca[sup.2+] were measured by annexin-V-FITC, forward scatter (FSC), and Fluo4/AM staining. Cells were also examined by electron microscopy to identify membrane blebbing and by the Westergren method to assess erythrocyte sedimentation rate (ESR). Results: In a concentration-responsive fashion, GER induced hemolysis and PS exposure in addition to elevated ESR. GER-induced cell death was characterized by reduced FSC, membrane blebs, and increased Fluo4 fluorescence. Ca[sup.2+] deprivation prevented eryptosis, whereas concurrent Ca[sup.2+] deprivation and membrane depolarization prevented hemolysis, eryptosis, and cell shrinkage. Furthermore, whereas inhibition of cyclooxygenase (COX), casein kinase 1α (CK1α), or Rac1 GTPase ameliorated eryptosis and hemolysis, the latter was only prevented by caspase, nitric oxide synthase, or serine palmitoyltransferase inhibition. Exclusive reversal of eryptosis was rather only achieved in the presence of either caffeine or adenine. Conclusions: GER is a novel stimulator of hemolysis and eryptosis, an activity mediated through membrane hyperpolarization following Ca[sup.2+] elevation. In parallel, GER seems to involve the COX/CK1α/Rac1 GTPase axis to trigger its cytotoxic effects. Targeting the identified mechanisms in combination therapy may attenuate the off-target toxicity of GER and enhance its specificity to cancer cells.

Geraniol 10-hydroxylase (G10H) is one of the important regulatory cytochrome P450 monooxygenase, which is involved in the biosynthesis of monoterpene alkaloids. However, G10H is not characterized at the enzymatic or at the regulatory aspect in B. monnieri. In the present study, we have identified two transcripts of BmG10H (BmG10H-1 and BmG10H-2) and characterized the methyl jasmonate (MeJA) and wound responsive BmG10H-1 transcript from B. monnieri. BmG10H-1 showed induced expression after 3 h of MeJA and wounding treatment in the shoot. Yeast purified recombinant BmG10H-1 protein is enzymatically active, having Vmax of 0.16 μMsec-1 μg-1 protein and catalyzes the hydroxylation of geraniol to 10-hydroxy geraniol. The BmG10H-1 promoter was isolated by using the genome walking method. BmG10H-1 promoter can drive GUS expression in transgenic Arabidopsis thaliana. GUS activity of MeJA and wound-treated Arabidopsis seedlings were found to be increased as compared to the control untreated seedlings, whereas no GUS activity was found in deleted MeJA responsive and W-box cis-elements. This shows that the BmG10H-1 promoter contains functional MeJA (TGACG) and wound responsive (TGA CCT ) cis-elements. Further, shoot specific and MeJA responsive recombinant BmMYB35 protein was purified, which binds with the MYB recognition cis-element (TGGTTA) present in the BmG10H-1 promoter and transcriptionally activates the reporter gene in yeast. In conclusion, the characterization of MeJA and wound responsive aBmG10H-1 provides novel information about its transcriptional regulation by binding with MYB transcription factor in B. monnieri.

Geraniol derived from essential oils of various plant species is widely used in the cosmetic and perfume industries. It is also an essential trait of the pleasant smell of rose flowers. In contrast to other monoterpenes which are produced in plastids via the methyl erythritol phosphate pathway, geraniol biosynthesis in roses relies on cytosolic NUDX1 hydrolase which dephosphorylates geranyl diphosphate (GPP). However, the metabolic origin of cytosolic GPP remains unknown. By feeding Rosa chinensis “Old Blush” flowers with pathway-specific precursors and inhibitors, combined with metabolic profiling and functional characterization of enzymes in vitro and in planta, we show that geraniol is synthesized through the cytosolic mevalonate (MVA) pathway by a bifunctional geranyl/farnesyl diphosphate synthase, RcG/FPPS1, producing both GPP and farnesyl diphosphate (FPP). The downregulation and overexpression of RcG/FPPS1 in rose petals affected not only geraniol and germacrene D emissions but also dihydro-β-ionol, the latter due to metabolic cross talk of RcG/FPPS1-dependent isoprenoid intermediates trafficking from the cytosol to plastids. Phylogenetic analysis together with functional characterization of G/FPPS orthologs revealed that the G/FPPS activity is conserved among Rosaceae species. Site-directed mutagenesis and molecular dynamic simulations enabled to identify two conserved amino acids that evolved from ancestral FPPSs and contribute to GPP/FPP product specificity. Overall, this study elucidates the origin of the cytosolic GPP for NUDX1-dependent geraniol production, provides insights into the emergence of the RcG/FPPS1 GPPS activity from the ancestral FPPSs, and shows that RcG/FPPS1 plays a key role in the biosynthesis of volatile terpenoid compounds in rose flowers.

Geraniol is a monoterpenic alcohol with a pleasant rose-like aroma, known as an important ingredient in many essential oils, and is used commercially as a fragrance compound in cosmetic and household products. However, geraniol has a number of biological activities, such as antioxidant and anti-inflammatory properties. In addition, numerous in vitro and in vivo studies have shown the activity of geraniol against prostate, bowel, liver, kidney and skin cancer. It can induce apoptosis and increase the expression of proapoptotic proteins. The synergy of this with other drugs may further increase the range of chemotherapeutic agents. The antibacterial activity of this compound was also observed on respiratory pathogens, skin and food-derived strains. This review discusses some of the most important uses of geraniol.

Background Iridoids represent the primary pharmacologically active constituents in Morinda officinalis , a traditional Chinese medicinal herb, and exhibit diverse pharmacological properties with broad applications in the pharmaceutical, chemical, and cosmetic industries. Geraniol synthase (GES), encoded by MoGES , catalyzes the conversion of geranyl diphosphate (GPP) to geraniol, representing a critical rate-limiting step in iridoid biosynthesis. Nevertheless, the regulatory mechanism of MoGES expression remains uncharacterized. Results In this study, a 1598 bp promoter region of MoGES (designated as ProMoGES) was cloned from M. officinalis and systematically functionally characterized. Bioinformatics analysis revealed ProMoGES contains core elements (37 TATA-boxes, 40 CAAT-boxes) and cis-acting elements responsive to light, hormones, and abiotic stresses. Promoter truncation assays using a GUS reporter system demonstrated that all fragments drove GUS expression in both Nicotiana benthamiana and Arabidopsis thaliana , and the promoter activity exhibited a non‑monotonic trend with the P3 fragment showing peak activity as the fragment length decreased. The ProMoGES promoter exhibited stronger activity than the CaMV35S promoter in M. officinalis , driving 1.56-fold higher eGFP expression, which confirms its function as a potent endogenous promoter. ProMoGES-mediated MoGES expression was significantly induced by methyl jasmonate (MeJA), low temperature, and light, but suppressed by heat and salt stress. Furthermore, MoDREB6 functions as a negative regulator that suppresses MoGES expression by binding to the DRE/CRT element within the ProMoGES promoter. Conclusions The functional characterization of ProMoGES offers a valuable and potent endogenous promoter tool for future genetic engineering and metabolic manipulation in M. officinalis . This study also provides novel insights into the transcriptional regulatory mechanisms underlying iridoid biosynthesis.

The regioselective hydration of carbon–carbon double bonds to generate alcohols is a fundamental reaction in synthetic organic chemistry, offering pathways to valuable secondary and tertiary alcohols. Biocatalysis using hydratase enzymes, which add water to a double bond, provides a selective and sustainable alternative to traditional chemical methods. This study investigates the potential of Escherichia coli to hydrate the monoterpene geraniol in whole-cell biotransformation systems. Through a targeted knockout approach using the Keio collection, fumarases were identified as key contributors to geraniol hydration. Overexpression studies further revealed that FumA and FumB overexpression substantially enhanced geraniol hydration activity at the terminal alkene, suggesting promiscuity towards this non-native substrate. This result indicates an expanded substrate scope of class I fumarases beyond their established role in fumarate metabolism. By establishing a link between geraniol hydration and specific genes, we aim to extend the enzymatic toolbox for monoterpene transformations. Utilizing the inherent regioselectivity and atom economy of fumarases, the potential of fumarases as efficient biocatalysts in terpene modification could open new avenues to advance applications in green chemistry and biocatalysis.

The prominent cultivation of lemongrass (Cymbopogon spp.) relies on the pharmacological incentives of its essential oil. Lemongrass essential oil (LEO) carries a significant amount of numerous bioactive compounds, such as citral (mixture of geranial and neral), isoneral, isogeranial, geraniol, geranyl acetate, citronellal, citronellol, germacrene-D, and elemol, in addition to other bioactive compounds. These components confer various pharmacological actions to LEO, including antifungal, antibacterial, antiviral, anticancer, and antioxidant properties. These LEO attributes are commercially exploited in the pharmaceutical, cosmetics, and food preservations industries. Furthermore, the application of LEO in the treatment of cancer opens a new vista in the field of therapeutics. Although different LEO components have shown promising anticancer activities in vitro, their effects have not yet been assessed in the human system. Hence, further studies on the anticancer mechanisms conferred by LEO components are required. The present review intends to provide a timely discussion on the relevance of LEO in combating cancer and sustaining human healthcare, as well as in food industry applications.

Key messageComprehensive transcriptome analysis of leaf and root tissues of Nothapodytes nimmoniana unravels several putative pathway genes, transcription factors and CYPs related to camptothecin (CPT) biosynthesis. Additionally, post-transcriptional suppression by artificial microRNA (aMIR) of NnCYP76B6 (geraniol 10-hydroxylase) suggests its role in CPT biosynthesis. Tissue-specific LC-MS/MS analysis revealed the presence of secologanin as the central intermediate of MIA pathway in N. nimmoniana.Nothapodytes nimmoniana is a rich source of potent anticancer drug camptothecin (CPT) whose biosynthetic pathway is unresolved due to the lack of genomic and transcriptomic information. Present investigation entails deep transcriptome analysis of N. nimmoniana which led to identification of putative pathway genes and regulatory components involved in CPT biosynthesis. Using Illumina HiSeq 2500 sequencing platform a total of 31,172,889 (6.23 Gb) and 31,218,626 (6.24 Gb) raw reads were generated from leaf and root wood, respectively. These were assembled de novo into 138,183 unique contigs. Additionally, 16 cytochrome P450 transcripts related to secondary metabolism were also identified. Further, transcriptome data pool presented 1683 putative transcription factors of which transcripts corresponding to WRKY TFs were the most abundant (14.14%). A total of 2741 transcripts were differentially expressed out of which 478 contigs showed downregulation in root wood and 2263 contigs were up-regulated. Further, comparative analyses of 17 genes involved in CPT biosynthetic pathway were validated by qRT-PCR. On basis of intermediates, two distinct seco-iridoid pathways are involved in the biosynthesis of monoterpene indole alkaloids either through multiple isomers of strictosidinic acid or strictosidine. Tissue-specific LC-MS/MS analysis revealed the presence of secologanin as the central intermediate of MIA pathway in N. nimmoniana. Geraniol-10 hydroxylase (NnCYP76B6) an important enzyme in CPT biosynthesis which specifically shunts geraniol into the secologanin pathway was also cloned from the trancriptome resource. In planta transient expression of NnCYP76B6 showed a significant enhancement in mRNA transcript levels coincident with enhanced CPT accumulation. Further, artificial microRNA (aMIR) mediated downregulation of NnCYP76B6 resulted in reduction of mRNA transcript levels as well as CPT content in comparison to control. These empirical results suggest a plausible regulatory role for NnCYP76B6 in CPT biosynthesis and also establish a valuable repository for deciphering various structural, rate limiting and regulatory genes of CPT biosynthetic pathway.