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Rationally engineering santalene synthase to readjust the component ratio of sandalwood oil.

ABSTRACT: Plant essential oils (PEOs) are widely used in cosmetic and nutraceutical industries. The component ratios of PEOs determine their qualities. Controlling the component ratios is challenging in construction of PEO biotechnological platforms. Here, we explore the catalytic reaction pathways of both product-promiscuous and product-specific santalene synthases (i.e., SaSSy and SanSyn) by multiscale simulations. F441 of SanSyn is found as a key residue restricting the conformational dynamics of the intermediates, and thereby the direct deprotonation by the general base T298 dominantly produce α-santalene. The subsequent mutagenesis of this plastic residue leads to generation of a mutant enzyme SanSyn^F441V which can produce both α- and β-santalenes. Through metabolic engineering efforts, the santalene/santalol titer reaches 704.2 mg/L and the component ratio well matches the ISO 3518:2002 standard. This study represents a paradigm of constructing biotechnological platforms of PEOs with desirable component ratios by the combination of metabolic and enzymatic engineering.

SUBMITTER: Zha W

PROVIDER: S-EPMC9076924 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Rationally engineering santalene synthase to readjust the component ratio of sandalwood oil.

Zha Wenlong W Zhang Fan F Shao Jiaqi J Ma Xingmei X Zhu Jianxun J Sun Pinghua P Wu Ruibo R Zi Jiachen J

Nature communications 20220506 1

Plant essential oils (PEOs) are widely used in cosmetic and nutraceutical industries. The component ratios of PEOs determine their qualities. Controlling the component ratios is challenging in construction of PEO biotechnological platforms. Here, we explore the catalytic reaction pathways of both product-promiscuous and product-specific santalene synthases (i.e., SaSSy and SanSyn) by multiscale simulations. F441 of SanSyn is found as a key residue restricting the conformational dynamics of the i ...[more]

PMID: 35523896

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Project description:Background: Frankincense (Ru Xiang) and sandalwood (Tan Xiang) are ingredients used in traditional Chinese medicine, and have been recognized as cancer preventive and therapeutic agents. Hydrodistillation of frankincense gum resins and sandalwood heartwood to prepare essential oils is a method to extract biologically active ingredients from these plant-derived products. This study was designed to differentiate frankincense (Boswellia carterii) and sandalwood (Santalum album) induced anti-proliferative and pro-apoptotic activities in cultured human bladder cancer cells. Methods: Frankincense and sandalwood essential oils-mediated cytotoxicity was studied in established human bladder cancer J82 cells and immortalized normal human bladder urothelial UROtsa cells using a colorimetric assay. Essential oils-activated gene expression and pathway activation in human bladder cancer J82 cells were identified using high density microarray and bioinformatics techniques. Results: Human bladder cancer cells were more sensitive to immortalized normal bladder cells with suppressed viability following frankincense essential oil exposure. In contrast, both cancerous and normal bladder cells responded to sandalwood essential with similar levels of cytotoxicity. Based on microarray and bioinformatics analyses, genes responsible for suppressing biological processes and apoptosis were induced in J82 cells by both essential oils. Although both frankincense and sandalwood essential oils activated common ontologies and canonical pathways leading to suppressed J82 cell viability and apoptosis, each essential oil had unique property on these cells. For example, heat shock proteins and histone core were ongologies regulated by frankincense essential oil, whereas transcription regulation and G-protein couple receptor were ontologies unique to sandalwood essential oil treatment. In addition, NRF-2 mediated oxidative stress was implicated as the primary cause of frankincense essential oil-induced J82 cell death; in contrast, DNA damage and cell cycle arrest might be attributed to sandalwood essential oil-mediated cytotoxicity. Conclusion: Based on cell biology and comprehensive gene expression analysis, our results provide a preliminary, yet focused characterization of genetic responses to frankincense and sandalwood essential oils with respect to their proposed anti-neoplastic properties. Modern biomedical technologies are powerful tools to study biological responses following treatments with traditional Chinese medicine, which always consist of complex chemical constituents.

Project description:BackgroundFrankincense (Boswellia carterii, known as Ru Xiang in Chinese) and sandalwood (Santalum album, known as Tan Xiang in Chinese) are cancer preventive and therapeutic agents in Chinese medicine. Their biologically active ingredients are usually extracted from frankincense by hydrodistillation and sandalwood by distillation. This study aims to investigate the anti-proliferative and pro-apoptotic activities of frankincense and sandalwood essential oils in cultured human bladder cancer cells.MethodsThe effects of frankincense (1,400-600 dilutions) (v/v) and sandalwood (16,000-7,000 dilutions) (v/v) essential oils on cell viability were studied in established human bladder cancer J82 cells and immortalized normal human bladder urothelial UROtsa cells using a colorimetric XTT cell viability assay. Genes that responded to essential oil treatments in human bladder cancer J82 cells were identified using the Illumina Expression BeadChip platform and analyzed for enriched functions and pathways. The chemical compositions of the essential oils were determined by gas chromatography-mass spectrometry.ResultsHuman bladder cancer J82 cells were more sensitive to the pro-apoptotic effects of frankincense essential oil than the immortalized normal bladder UROtsa cells. In contrast, sandalwood essential oil exhibited a similar potency in suppressing the viability of both J82 and UROtsa cells. Although frankincense and sandalwood essential oils activated common pathways such as inflammatory interleukins (IL-6 signaling), each essential oil had a unique molecular action on the bladder cancer cells. Heat shock proteins and histone core proteins were activated by frankincense essential oil, whereas negative regulation of protein kinase activity and G protein-coupled receptors were activated by sandalwood essential oil treatment.ConclusionThe effects of frankincense and sandalwood essential oils on J82 cells and UROtsa cells involved different mechanisms leading to cancer cell death. While frankincense essential oil elicited selective cancer cell death via NRF-2-mediated oxidative stress, sandalwood essential oil induced non-selective cell death via DNA damage and cell cycle arrest.

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Rationally engineering santalene synthase to readjust the component ratio of sandalwood oil.

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Rationally engineering santalene synthase to readjust the component ratio of sandalwood oil.

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