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Substrate inhibition of enzymes can be a major obstacle to the production of valuable chemicals in engineered microorganisms. Here, we show substrate inhibition of lycopene cyclase as the main limitation in carotenoid biosynthesis in Yarrowia lipolytica . To overcome this bottleneck, we exploit two independent approaches. Structure-guided protein engineering yields a variant, Y27R, characterized by complete loss of substrate inhibition without reduction of enzymatic activity. Alternatively, establishing a geranylgeranyl pyrophosphate synthase-mediated flux flow restrictor also prevents the onset of substrate inhibition by diverting metabolic flux away from the inhibitory metabolite while maintaining sufficient flux towards product formation. Both approaches result in high levels of near-exclusive β-carotene production. Ultimately, we construct strains capable of producing 39.5 g/L β-carotene at a productivity of 0.165 g/L/h in bioreactor fermentations (a 1441-fold improvement over the initial strain). Our findings provide effective approaches for removing substrate inhibition in engineering pathways for efficient synthesis of natural products. Substrate inhibition has not been widely studied in the context of synthetic biology and metabolic engineering. Here, the authors report removal of lycopene substrate inhibition by two different strategies and enable high carotenoid productivity in Yarrowia lipolytica .

Niosomes are employed for their improved physical properties and stability and as a controlled delivery system. However, their large-scale production and different preparation methods affect their physical properties. The microfluidic method represents a novel approach to the preparation of niosomes that enables precise control and decreases the preparation time and steps compared to alternative methods. The UVB protection and anti-hyperpigmentation activities of lycopene-loaded niosomes prepared by microfluidic (MF) and novel conventional thin-film hydration (THF) methods were compared. Extract powders from tomatoes (T), carrots (C), and mixed red vegetables (MR) were utilized to prepare lycopene-rich extract-entrapped niosomes. The resulting niosome formulations were characterized by particle size, polydispersity index (PDI), zeta potential, FT-IR spectra, entrapment efficiency, lycopene-release profile, permeation, and stability. The lycopene extract–niosome formulations were evaluated for their potential to provide UVB protection to human keratinocytes (HaCaT) and for their anti-melanogenesis effects on B16F10 melanoma cells. The results indicated that niosomes prepared by the MF method exhibited high uniformity and homogeneity (reflected by a low PDI value) and maintained smaller sizes when processed through a chip utilizing a hydrodynamic flow-focusing (HFF) platform compared to THF niosomes. The release kinetics of all lycopene–niosome formulations followed the Korsmeyer–Peppas model. The FT-IR spectra indicated that lycopene was incorporated into the niosome bilaminar membrane. Moreover, niosomes obtained from MF demonstrated enhanced stability during heating–cooling cycles, along with high UVB protection and anti-melanogenesis effects. Therefore, these developed niosome preparation methods could be effectively applied to topical products.

  This study aimed to explore whether allicin (ALC) and lycopene (LP) could offer protection against the harmful effects of methotrexate (MTX), a type of chemotherapy drug known for its severe side effects, on the heart of rats. In this experiment, seven groups of rats ( n  = 7) were used. The first group was given saline as a control vehicle, the second group was given ALC at a dosage of 20 mg/kg orally, the third group was given LP at a dosage of 10 mg/kg orally, and the fourth group was given MTX at a dosage of 20 mg/kg intraperitoneally on the 15 th day of the experiment. The remaining three groups received treatments, including ALC + MTX, LP + MTX, and ALC + LP + MTX. After the administration of MTX, the concentrations of serum cardiac biomarkers, such as Creatine kinase (CK), Lactate dehydrogenase (LDH), and creatine kinase-myoglobin binding (CK-MB) were found to increase. Also, MTX caused a notable rise in malondialdehyde (MDA) levels and significant declines in the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in the heart tissues of rats. In addition, MTX caused alterations in the cardiac histopathology and enhanced the caspase-3 expression in the cardiac tissues, indicating the occurrence of apoptosis. The antioxidant properties of ALC and/or LP were effectively reduced cardiac toxicity and apoptosis induced by MTX. The administration of ALC and/or LP was found to alleviate these effects caused by MTX.

Mounting evidence from clinical and epidemiological studies suggests that lycopene, the most abundant carotenoid in tomatoes, may be beneficial in the prevention or treatment of some important diseases. Ripe tomato peels are the richest source of lycopene, but the use of conventional solvent extraction methods without pretreatment of the plant material results in very poor recovery. The reason lies in the localization of lycopene in the plant tissue and the low permeability of the latter to solvent molecules. In this paper, a mixture design procedure was used to formulate solvent mixtures allowing the recovery of lycopene from non-pretreated tomato peels. Two ternary systems were investigated: (a) n-hexane–ethanol–acetone and (b) ethyl lactate–ethanol–acetone. Optimization of the ternary mixture composition led to a recovery of over 90% of the lycopene present in the peels. The high extraction efficiency was explained in terms of lycopene affinity combined with the ability to swell the plant material. A tomato oleoresin with high antioxidant activity and a lycopene content of about 13% (w/w) was also produced. Overall, the results indicate that highly effective solvents for direct recovery of lycopene from tomato peels can be easily prepared by a mixture design approach.

The current study was undertaken to assess the attenuating potential of lycopene against Dithane toxicity in Allium cepa L. roots. A. cepa bulbs were arranged in 6 groups. The control group was treated with tap water while the other groups were treated with 215 mg/L lycopene, 430 mg/L lycopene, 500 mg/L Dithane, 500 mg/L Dithane + 215 mg/L lycopene and 500 mg/L Dithane + 430 mg/L lycopene, respectively. When the treatments were completed, growth inhibition, biochemical, genotoxicity and meristematic cell injury analyses were performed. Lycopene did not cause any toxic effect when applied alone. While rooting percentage, root elongation, weight gain and mitotic index (MI) decreased in response to Dithane exposure, the frequency of micronucleus (MN) and chromosomal abnormalities (CAs) in addition to malondialdehyde (MDA) level and the catalytic activities of superoxide dismutase (SOD) and catalase (CAT) increased. Dithane promoted fragment, sticky chromosome, vagrant chromosome, unequal distribution of chromatin, bridge, nucleus bud and reverse polarization formation in meristem cells. Dithane also provoked meristematic cell injuries, including indistinct appearance of vascular tissue, epidermis cell damage and flattened cell nucleus. Lycopene mitigated all damage types, depending on the lycopene dose applied with Dithane. Hence, the data analysis revealed that lycopene provides exceptional antioxidant protection against the fungicide Dithane, which has devastating toxic potential.

Tomatoes are well known for their impressive nutritional value among vegetables. However, the industrial processing of tomatoes generates a significant amount of waste. Specifically, 10% to 18% of the raw materials used in tomato processing become waste. This waste can seriously affect ecosystems, such as freshwater bodies, wetlands, rivers, and other natural environments, if not properly managed. Interestingly, tomato waste, specifically the skin, contains lycopene, a potent antioxidant and antimutagenic that offers a range of health benefits. This makes it a valuable ingredient in industries such as food and cosmetics. In addition, researchers are exploring the potential of lycopene in the treatment of various types of cancer. This systematic review, guided by the PRISMA 2020 methodology, examined studies exploring the possibility of tomato peel as a source of lycopene and carotenoids for cancer treatment. The findings suggest that tomato peel extracts exhibit promising anticancer properties, underscoring the need for further investigation of possible therapeutic applications. The compiled literature reveals significant potential for using tomato peel to create new cancer treatments, which could potentially revolutionize the field of oncology. This underscores the importance of continued research and exploration, emphasizing the urgency and importance of the scientific community’s contribution to this promising area of study.

As an antioxidant, lycopene has acquired importance as it prevents autoxidation of fats and related products. Tomatoes are an important agricultural product that is a great source of lycopene. It contains many vitamins and minerals, fiber, and carbohydrates and is associated with various positive effects on health. The antioxidant potential of tomatoes is substantially explained with lycopene compounds. Diet is a major risk factor for heart diseases which is shown as the most important cause of death in the world. It has been observed that the lycopene taken in the diet has positive effects in many stages of atherosclerosis. The serum lipid levels, endothelial dysfunction, inflammation, blood pressure, and antioxidative potential are mainly affected by lycopene. These natural antioxidants, which can also enhance the nutritional value of foods, may lead to new ways if used in food preservation. In this review study, the antioxidant potential and cardiovascular protection mechanism of lycopene are discussed.

The genetic diversity of cultivated crops is limited, largely as a result of domestication bottlenecks and the selective pressures imposed during modern breeding. An introgression cross was initiated by mating bitter apple (Citrullus colocynthis), as a wild founder parent, with ‘Charleston Grey’ watermelon (Citrullus lanatus) commercial cultivar, focused on identifying and utilizing trait-enhancing alleles from crop wild relative (CWR). Successful crosses resulted in diverse families, including F[sub.1] hybrids, F[sub.2] population, and backcross (BC) progenies. The study revealed substantial variation among the founder parents and their derived progeny in plant growth and major agronomic fruit traits, highlighting the value of this genetic diversity for breeding programs and demonstrating the potential of Citrullus introgression lines to enhance desired traits in cultivated watermelon. Morphological analysis demonstrated that F[sub.1] progeny resembled the maternal parent for the majority of investigated fruit traits. A considerable proportion of the introgression progeny in the F[sub.2] generation outperformed both parents in total soluble solids and lycopene content, suggesting that crop wild relatives hold strong breeding value through beneficial allelic recombination. BC[sub.1] siblings were closer to the wild watermelon, which is presumably maternally controlled through plastome and mitogenome in crosses between cultivated watermelon and wild bitter apple, which is expected to be retained in successive backcrosses. The study uncovers novel alleles of CWR that preserve extensive genetic variation that is essential for enhancing resilience traits in current breeding lines. These introgression-derived resources provide a critical platform for advancing genetic studies and enhancing crop resilience.

Enzymatic reactions in living cells are highly dynamic but simultaneously tightly regulated. Enzyme engineers seek to construct multienzyme complexes to prevent intermediate diffusion, to improve product yield, and to control the flux of metabolites. Here we choose a pair of short peptide tags (RIAD and RIDD) to create scaffold-free enzyme assemblies to achieve these goals. In vitro, assembling enzymes in the menaquinone biosynthetic pathway through RIAD–RIDD interaction yields protein nanoparticles with varying stoichiometries, sizes, geometries, and catalytic efficiency. In Escherichia coli , assembling the last enzyme of the upstream mevalonate pathway with the first enzyme of the downstream carotenoid pathway leads to the formation of a pathway node, which increases carotenoid production by 5.7 folds. The same strategy results in a 58% increase in lycopene production in engineered Saccharomyces cerevisiae . This work presents a simple strategy to impose metabolic control in biosynthetic microbe factories. Metabolic enzymes often form supramolecular complexes to improve product yield. Here the authors use short peptide tags to create scaffold-free assemblies and synthetic metabolic nodes.

Large-scale data acquisition and analysis are often required in the successful implementation of the design, build, test, and learn (DBTL) cycle in biosystems design. However, it has long been hindered by experimental cost, variability, biases, and missed insights from traditional analysis methods. Here, we report the application of an integrated robotic system coupled with machine learning algorithms to fully automate the DBTL process for biosystems design. As proof of concept, we have demonstrated its capacity by optimizing the lycopene biosynthetic pathway. This fully-automated robotic platform, BioAutomata, evaluates less than 1% of possible variants while outperforming random screening by 77%. A paired predictive model and Bayesian algorithm select experiments which are performed by Illinois Biological Foundry for Advanced Biomanufacturing (iBioFAB). BioAutomata excels with black-box optimization problems, where experiments are expensive and noisy and the success of the experiment is not dependent on extensive prior knowledge of biological mechanisms. Existing efforts have been focused on one of the elements in the automation of the design, build, test, and learn (DBTL) cycle for biosystems design. Here, the authors integrate a robotic system with machine learning algorithms to fully automate the DBTL cycle and apply it in optimizing the lycopene biosynthetic pathway.