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β-Ionone is a natural plant volatile compound, and it is the 9,10 and 9′,10′ cleavage product of β-carotene by the carotenoid cleavage dioxygenase. β-Ionone is widely distributed in flowers, fruits, and vegetables. β-Ionone and other apocarotenoids comprise flavors, aromas, pigments, growth regulators, and defense compounds; serve as ecological cues; have roles as insect attractants or repellants, and have antibacterial and fungicidal properties. In recent years, β-ionone has also received increased attention from the biomedical community for its potential as an anticancer treatment and for other human health benefits. However, β-ionone is typically produced at relatively low levels in plants. Thus, expressing plant biosynthetic pathway genes in microbial hosts and engineering the metabolic pathway/host to increase metabolite production is an appealing alternative. In the present review, we discuss β-ionone occurrence, the biological activities of β-ionone, emphasizing insect attractant/repellant activities, and the current strategies and achievements used to reconstruct enzyme pathways in microorganisms in an effort to to attain higher amounts of the desired β-ionone.

To help protect the environment as well as increase agricultural production, the use of synthetic herbicides must be reduced and replaced with plant-based bioherbicides. Elaeocarpus floribundus is a perennial, evergreen, and medium-sized plant grown in different areas of the world. The pharmaceutical properties and various uses of Elaeocarpus floribundus have been reported, but its allelopathic potential has not yet been explored. Thus, we carried out the present study to identify allelopathic compounds from Elaeocarpus floribundus. Aqueous MeOH extracts of Elaeocarpus floribundus significantly suppressed the growth of the tested species (cress and barnyard grass) in a dose- and species-dependent way. The three most active allelopathic substances were isolated via chromatographic steps and characterized as (3R)-3-hydroxy-β-ionone, cis-3-hydroxy-α-ionone, and loliolide. All three substances significantly limited the seedling growth of cress, and the compound (3R)-3-hydroxy-β-ionone had stronger allelopathic effects than cis-3-hydroxy-α-ionone and loliolide. The concentrations of the compounds required for 50% growth inhibition (I50 value) of the cress seedlings were in the range of 0.0001–0.0005 M. The findings of this study indicate that all three phytotoxic substances contribute to the phytotoxicity of Elaeocarpus floribundus.

Background One important metabolic engineering strategy is to localize the enzymes close to their substrates for improved catalytic efficiency. However, localization configurations become more complex the greater the number of enzymes and substrates is involved. Indeed, optimizing synthetic pathways by localizing multiple enzymes remains a challenge. Terpenes are one of the most valuable and abundant natural product groups. Phytoene, lycopene and β-carotene serve as common intermediates for the synthesis of many carotenoids and derivative compounds, which are hydrophobic long-chain terpenoids, insoluble in water and usually accumulate in membrane compartments. Results While β-ionone synthesis by β-carotene cleavage dioxygenase PhCCD1 and astaxanthin synthesis by β-carotene ketolase (CrtW) and β-carotene hydroxylase (CrtZ) differ in complexity (single and multiple step pathways), the productivity of both pathways benefited from controlling enzyme localization to the E. coli cell membrane via a GlpF protein fusion. Especially, the astaxanthin synthesis pathway comprises both CrtW and CrtZ, which perform four interchangeable reactions initiated from β-carotene. Up to four localization strategies of CrtW and CrtZ were exhaustively discussed in this work, and the optimal positioning strategy was achieved. CrtW and CrtZ were linked using a flexible linker and localized to the membrane via a GlpF protein fusion. Enzymes in the optimal localization configuration allowed a 215.4% astaxanthin production increase. Conclusions This work exploits a localization situation involving membrane-bound substrates, intermediates and multiple enzymes for the first time, and provides a workable positioning strategy to solve problems in similar circumstances.

To elucidate the significant influence of microorganisms on geographically dependent flavor formation by analyzing microbial communities and volatile flavor compounds (VFCs) in cigar tobacco leaves (CTLs) obtained from China, Dominica, and Indonesia. Microbiome analysis revealed that the predominant bacteria in CTLs were Staphylococcus , Aerococcus , Pseudomonas , and Lactobacillus , while the predominant fungi were Aspergillus , Wallemia, and Sampaiozyma . The microbial communities of CTLs from different origins differed to some extent, and the diversity and abundance of bacteria were greater than fungi. Metabolomic analysis revealed that 64 VFCs were identified, mainly ketones, of which 23 VFCs could be utilized to identify the geographical origins of CTLs. Sixteen VFCs with OAV greater than 1, including cedrol, phenylacetaldehyde, damascone, beta-damascone, and beta-ionone, play important roles in shaping the flavor profile of CTLs from different origins. Combined with the correlation analysis, bacterial microorganisms were more closely related to key VFCs and favored a positive correlation. Bacillus , Vibrio , and Sphingomonas were the main flavor-related bacteria. The study demonstrated that the predominant microorganisms were essential for the formation of key flavor qualities in CTLs, which provided a theoretical reference for flavor control of CTLs by microbial technology. Key points • It is the high OAV VFCs that determine the flavor profile of CTLs. • The methylerythritol phosphate (MEP) pathway and the carotenoid synthesis pathway are key metabolic pathways for the formation of VFCs in CTLs. • Microbial interactions influence tobacco flavor, with bacterial microorganisms contributing more to the flavor formation of CTLs. Graphical Abstract

The term ionone is derived from “iona” (Greek for violet) which refers to the violet scent and “ketone” due to its structure. Ionones can either be chemically synthesized or endogenously produced via asymmetric cleavage of β-carotene by β-carotene oxygenase 2 (BCO2). We recently proposed a possible metabolic pathway for the conversion of α-and β-pinene into α-and β-ionone. The differences between BCO1 and BCO2 suggest a unique physiological role of BCO2; implying that β-ionone (one of BCO2 products) is involved in a prospective biological function. This review focuses on the effects of ionones and the postulated mechanisms or signaling cascades involved mediating these effects. β-Ionone, whether of an endogenous or exogenous origin possesses a range of pharmacological effects including anticancer, chemopreventive, cancer promoting, melanogenesis, anti-inflammatory and antimicrobial actions. β-Ionone mediates these effects via activation of olfactory receptor (OR51E2) and regulation of the activity or expression of cell cycle regulatory proteins, pro-apoptotic and anti-apoptotic proteins, HMG-CoA reductase and pro-inflammatory mediators. α-Ionone and β-ionone derivatives exhibit anti-inflammatory, antimicrobial and anticancer effects, however the corresponding structure activity relationships are still inconclusive. Overall, data demonstrates that ionone is a promising scaffold for cancer, inflammation and infectious disease research and thus is more than simply a violet’s fragrance.

Background The GRAS and oleaginous yeast Yarrowia lipolytica ( Y. lipolytica ) is an attractive cell factory for the production of chemicals and biofuels. The production of many natural products of commercial interest have been investigated in this cell factory by introducing heterologous biosynthetic pathways and by modifying the endogenous pathways. However, since natural products anabolism involves long pathways and complex regulation, re-channelling carbon into the product of target compounds is still a cumbersome work, and often resulting in low production performance. Results In this work, the carotenogenic genes contained carB and bi-functional carRP from Mucor circinelloides and carotenoid cleavage dioxygenase 1 ( CCD1 ) from Petunia hybrida were introduced to Y. lipolytica and led to the low production of β-ionone of 3.5 mg/L. To further improve the β-ionone synthesis, we implemented a modular engineering strategy for the construction and optimization of a biosynthetic pathway for the overproduction of β-ionone in Y. lipolytica . The strategy involved the enhancement of the cytosolic acetyl-CoA supply and the increase of MVA pathway flux, yielding a β-ionone titer of 358 mg/L in shake-flask fermentation and approximately 1 g/L (~ 280-fold higher than the baseline strain) in fed-batch fermentation. Conclusions An efficient β-ionone producing GRAS Y. lipolytica platform was constructed by combining integrated overexpressed of heterologous and native genes. A modular engineering strategy involved the optimization pathway and fermentation condition was investigated in the engineered strain and the highest β-ionone titer reported to date by a cell factory was achieved. This effective strategy can be adapted to enhance the biosynthesis of other terpenoids in Y. lipolytica .

PurposeWe purified and characterized a novel ene-reductase (KaDBR1) from Kazachstania exigua HSC6 for the synthesis of dihydro-β-ionone from β-ionone.MethodsKaDBR1 was purified to homogeneity by ammonium sulfate precipitation and phenyl-Sepharose Fast Flow and Q-Sepharose chromatography. The purified enzyme was characterized by measuring the amount of dihydro-β-ionone from β-ionone with LC–MS analysis method.ResultsThe molecular mass of KaDBR1 was estimated to be 45 kDa by SDS-PAGE. The purified KaDBR1 enzyme had optimal activity at 60 °C and pH 6.0. The addition of 5 mM Mg2+, Ca2+, Al3+, Na+, and dithiothreitol increased the activity of KaDBR1 by 25%, 18%, 34%, 20%, and 23%, respectively. KaDBR1 favored NADH over NADPH as a cofactor, and its catalytic efficiency (kcat/Km) toward β-ionone using NADH was 8.1-fold greater than when using NADPH.ConclusionOwing to its unique properties, KaDBR1 is a potential candidate for the enzymatic biotransformation of β-ionone to dihydro-β-ionone in biotechnology applications.

Sichuan dark brick tea (Camellia sinensis) and Sichuan Fuzhuan brick tea have significantly different aroma characteristics although both of them have almost the same processing methods. Thus, these two types of tea were used as the research materials to determine the differences in their aroma compounds. The volatile compounds in the two types of tea were identified and quantified by headspace solid-phase microextraction coupled with gas chromatography–mass spectrometry (HS-SPME–GC–MS), results showed that they both had 37 common volatile compounds. Then the aroma-active components were identified by odour activity value (OAV). It was found that SFBT had 20 aroma-active components, of which β-ionone had the largest OAV (199547.72). SDBT has 21 aroma-active ingredients (including all 20 aroma-active components of SFBT), of which β-ionone again has the largest OAV (114800.66). Finally, the aroma profile differences between the two tea samples were studied by aroma profile tests, and the results showed that the main aroma differences of SDBT and SFBT were caused by β-ionone, epoxydihydrolinalool II, methyl salicylate, geranylacetone, nerolidol, benzaldehyde, benzyl acetate, nonanal, trans,trans-2,4-heptadienal and 1-octen-3-ol, in addition, defined SFBT’s ‘fungi flower aroma’ and SDBT’s ‘aged fragrance’ from the level of aroma monomer.

Background & aims 5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent for gastric cancer (GC), but its clinical efficacy is often limited by suboptimal antitumor activity and dose-related toxic side effects in patients. Combining natural compounds such as β-ionone (BI) with 5-FU has emerged as a promising strategy to enhance the therapeutic efficacy of GC chemotherapy while reducing the required dosage of 5-FU and mitigating its systemic toxicity. While BI exhibits anti-tumor activities, its synergy with 5-FU and the underlying mechanism are still unclear. This study was investigated the synergistic anti-tumor effects of BI and 5-FU in GC, focusing on the role of PAX6-mediated cell cycle arrest. Methods The effects of BI and 5-FU, alone or combined, on human GC cells (MKN45 cells and AGS cells) were assessed in vitro (MTT/MB assays, EdU flow cytometry, cell cycle analysis, spheroid formation, Western blot, immunofluorescence, co-immunoprecipitation, siRNA, and GSK-3β inhibitor - CHIR-99021) and in vivo (MKN45 cell xenografts in a BALB/c nude mouse model, tumor growth, HE/TUNEL staining, IHC, Western blot). Results BI significantly synergized with 5-FU to suppress the GC cell viability, DNA synthesis, tumor spheroid formation, and stemness. Their combination significantly induced the cell cycle arrest and significantly downregulated the expression of proliferating cell nuclear antigen (PCNA), cell cycle proteins, transcription factor PAX6, and GSK-3β proteins in MKN45 cells. Interaction between PAX6 and GSK-3β was confirmed by Co-IP. A GSK-3β inhibitor - CHIR-99,021 also altered the cell cycle distribution, recovrying effects of BI with 5-FU in MKN45 cells. In addition, BI combined with 5-FU potently inhibited MKN45 cell xenograft growth, increased apoptosis, and decreased the expression of PCNA, PAX6, and GSK-3β in MKN45 cell xenografts. Conclusions BI significantly enhances the efficacy of 5-FU against gastric cancer. This synergy is mechanistically linked to the inhibition of the transcription factor PAX6 and subsequent modulation of GSK-3β, leading to cell cycle arrest and inhibition of tumor progression. Graphical abstract

β-ionone, an apocarotenoid derived from a C40 terpenoid has an intense, woody smell and a low odor threshold that has been widely used in as an ingredient in food and cosmetics. Yarrowia lipolytica is a promising host for β-ionone production because of its oleaginous nature, its ability to produce high levels of acetyl-CoA (an important precursor for terpenoids), and the availability of synthetic biology tools to engineer the organism. In this study, β-carotene-producing Y. lipolytica strain XK17 was employed for β-ionone biosynthesis. First, we explored the effect of different sources of carotenoid cleavage dioxygenase (CCD) genes on β-ionone production. A high-yielding strain rUinO-D14 with 122 mg/L of β-ionone was obtained by screening promoters combined with rDNA mediated multi-round iterative transformations to optimize the expression of the CCD gene of Osmanthus fragrans. Second, to further develop a high-level production strain for β-ionone, we optimized key genes in the mevalonate pathway by multi-round iterative transformations mediated by non-homologous end joining, combined with a protein tagging strategy. Finally, the introduction of a heterologous oxidoreductase pathway enabled the engineered Y. lipolytica strain to use xylose as a sole carbon source and produce β-ionone. In addition, the potential for use of lignocellulosic hydrolysate as the carbon source for β-ionone production showed that the NHA-A31 strain had a high β-ionone productivity level. This study demonstrates that engineered Y. lipolytica can be used for the efficient, green and sustainable production of β-ionone.