Catalytic divergence of O-methyltransferases shapes the chemo-diversity of polymethoxylated bibenzyls in Dendrobium catenatum.
Dendrobium catenatum
O‐methyltransferase
biosynthetic network
chemical synthesis
polymethoxylated bibenzyl
Journal
The Plant journal : for cell and molecular biology
ISSN: 1365-313X
Titre abrégé: Plant J
Pays: England
ID NLM: 9207397
Informations de publication
Date de publication:
30 Aug 2024
30 Aug 2024
Historique:
revised:
12
07
2024
received:
20
02
2024
accepted:
23
07
2024
medline:
31
8
2024
pubmed:
31
8
2024
entrez:
30
8
2024
Statut:
aheadofprint
Résumé
Erianin, crepidatin, and chrysotobibenzyl are typical medicinal polymethoxylated bibenzyls (PMBs) that are commercially produced in Dendrobium species. PMBs' chemo-diversity is mediated by the manifold combinations of O-methylation and hydroxylation in a definite order, which remains unsolved. To unequivocally elucidate the methylation mechanism of PMBs, 15 possible intermediates in the biosynthetic pathway of PMBs were chemically synthesized. DcOMT1-5 were highly expressed in tissues where PMBs were biosynthesized, and their expression patterns were well-correlated with the accumulation profiles of PMBs. Moreover, cell-free orthogonal tests based on the synthesized intermediates further confirmed that DcOMT1-5 exhibited distinct substrate preferences and displayed hydroxyl-group regiospecificity during the sequential methylation process. The stepwise methylation of PMBs was discovered from SAM to dihydro-piceatannol (P) in the following order: P → 3-MeP → 4-OH-3-MeP → 4-OH-3,5-diMeP → 3,3'(4'),5-triMeP → 3,4,4',5-tetraMeP (erianin) or 3,3',4,5-tetraMeP (crepidatin) → 3,3',4,4',5-pentaMeP (chrysotobibenzyl). Furthermore, the regioselectivities of DcOMTs were investigated by ligand docking analyses which corresponded precisely with the catalytic activities. In summary, the findings shed light on the sequential catalytic mechanisms of PMB biosynthesis and provide a comprehensive PMB biosynthetic network in D. catenatum. The knowledge gained from this study may also contribute to the development of plant-based medicinal applications and the production of high-value PMBs.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Natural Science Foundation of China
ID : 82173703
Organisme : National Natural Science Foundation of China
ID : 82293682
Organisme : National Key Research and Development Program of China
ID : 2019YFA0905700
Informations de copyright
© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.
Références
Adejobi, O.I., Guan, J., Yang, L., Hu, J.‐M., Yu, A., Muraguri, S. et al. (2021) Transcriptomic analyses shed light on critical genes associated with Bibenzyl biosynthesis in Dendrobium officinale. Plants, 10, 633.
Austin, M.B. & Noel, J.P. (2003) The chalcone synthase superfamily of type III polyketide synthases. Natural Product Reports, 20, 79–110.
Berim, A. & Gang, D.R. (2016) Methoxylated flavones: occurrence, importance, biosynthesis. Phytochemistry Reviews, 15, 363–390.
Bhummaphan, N., Pongrakhananon, V., Sritularak, B. & Chanvorachote, P. (2018) Cancer stem cell‐suppressing activity of Chrysotoxine, a Bibenzyl from dendrobium pulchellum. Journal of Pharmacology and Experimental Therapeutics, 364, 332–346.
Boddington, K.F., Soubeyrand, E., Van Gelder, K., Casaretto, J.A., Perrin, C., Forrester, T.J.B. et al. (2021) Bibenzyl synthesis in Cannabis sativa L. The Plant Journal, 109, 693–707.
Brandt, W., Manke, K. & Vogt, T. (2015) A catalytic triad‐‐Lys‐Asn‐asp‐‐is essential for the catalysis of the methyl transfer in plant cation‐dependent O‐methyltransferases. Phytochemistry, 113, 130–139.
Chen, C., Chen, H., Zhang, Y., Thomas, H.R., Frank, M.H., He, Y. et al. (2020) TBtools: an integrative toolkit developed for interactive analyses of big biological data. Molecular Plant, 13, 1194–1202.
Chen, P., Wu, Q., Feng, J., Yan, L., Sun, Y., Liu, S. et al. (2020) Erianin, a novel dibenzyl compound in dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin‐dependent ferroptosis. Signal Transduction and Targeted Therapy, 5, 51.
Chizzali, C. & Beerhues, L. (2012) Phytoalexins of the pyrinae: biphenyls and dibenzofurans. Beilstein Journal of Organic Chemistry, 8, 613–620.
Chong, J., Poutaraud, A. & Hugueney, P. (2009) Metabolism and roles of stilbenes in plants. Plant Science, 177, 143–155.
Cui, M.Y., Lu, A.R., Li, J.X., Liu, J., Fang, Y.M., Pei, T.L. et al. (2022) Two types of O‐methyltransferase are involved in biosynthesis of anticancer methoxylated 4′‐deoxyflavones in Scutellaria baicalensis Georgi. Plant Biotechnology Journal, 20, 129–142.
Fliegmann, J., Schroder, G., Schanz, S., Britsch, L. & Schroder, J. (1992) Molecular analysis of chalcone and dihydropinosylvin synthase from scots pine (Pinus sylvestris), and differential regulation of these and related enzyme activities in stressed plants. Plant Molecular Biology, 18, 489–503.
Gould, K.S. & Lister, C. (2006) Flavonoid functions in plants. Flavonoids: Chemistry, biochemistry and applications, pp. 397–441.
He, L., Su, Q., Bai, L., Li, M., Liu, J., Liu, X. et al. (2020) Recent research progress on natural small molecule bibenzyls and its derivatives in dendrobium species. European Journal of Medicinal Chemistry, 204, 112530.
Huang, J.‐M., Huang, F.‐I. & Yang, C.‐R. (2019) Moscatilin ameliorates tau phosphorylation and cognitive deficits in Alzheimer's disease models. Journal of Natural Products, 82, 1979–1988.
Joshi, C.P. & Chiang, V.L. (1998) Conserved sequence motifs in plant S‐adenosyl‐L‐methionine‐dependent methyltransferases. Plant Molecular Biology, 37, 663–674.
Khalil, M.N., Beuerle, T., Müller, A., Ernst, L., Bhavanam, V.B., Liu, B. et al. (2013) Biosynthesis of the biphenyl phytoalexin aucuparin in Sorbus aucuparia cell cultures treated with Venturia inaequalis. Phytochemistry, 96, 101–109.
Khalil, M.N., Brandt, W., Beuerle, T., Reckwell, D., Groeneveld, J., Hansch, R. et al. (2015) O‐methyltransferases involved in biphenyl and dibenzofuran biosynthesis. The Plant Journal, 83, 263–276.
Kim, B.‐G., Sung, S.H., Chong, Y., Lim, Y. & Ahn, J.‐H. (2010) Plant flavonoid O‐methyltransferases: substrate specificity and application. Journal Of Plant Biology, 53, 321–329.
Koeduka, T., Hatada, M., Suzuki, H., Suzuki, S. & Matsui, K. (2019) Molecular cloning and functional characterization of an O‐methyltransferase catalyzing 4′‐O‐methylation of resveratrol in Acorus calamus. Journal of Bioscience and Bioengineering, 127, 539–543.
Koirala, N., Thuan, N.H., Ghimire, G.P., Thang, D.V. & Sohng, J.K. (2016) Methylation of flavonoids: chemical structures, bioactivities, progress and perspectives for biotechnological production. Enzyme and Microbial Technology, 86, 103–116.
Kopycki, J.G., Rauh, D., Chumanevich, A.A., Neumann, P., Vogt, T. & Stubbs, M.T. (2008) Biochemical and structural analysis of substrate promiscuity in plant Mg2+‐dependent O‐methyltransferases. Journal of Molecular Biology, 378, 154–164.
Lau, W. & Sattely, E.S. (2015) Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone. Science, 349(6253), 1224–1228.
Lee, E., Han, A.‐R., Nam, B., Kim, Y.‐R., Jin, C.H., Kim, J.‐B. et al. (2020) Moscatilin induces apoptosis in human head and neck squamous cell carcinoma cells via JNK signaling pathway. Molecules, 25, 901.
Li, Y.‐P., Wang, Y.‐J. & Chen, L.‐L. (2016) Antioxidant bibenzyls, phenanthrenes, and fluorenones from Dendrobium chrysanthum. Chemistry of Natural Compounds, 52, 90–92.
Liao, Z., Liu, X., Zheng, J., Zhao, C., Wang, D., Xu, Y. et al. (2023) A multifunctional true caffeoyl coenzyme a O‐methyltransferase enzyme participates in the biosynthesis of polymethoxylated flavones in citrus. Plant Physiology, 192, 2049–2066.
Liu, C.J., Deavours, B.E., Richard, S.B., Ferrer, J.L., Blount, J.W., Huhman, D. et al. (2006) Structural basis for dual functionality of isoflavonoid O‐methyltransferases in the evolution of plant defense responses. The Plant Cell, 18, 3656–3669.
Liu, Y., Li, X., Sui, S., Tang, J., Chen, D., Kang, Y. et al. (2023) Structural diversification of bioactive bibenzyls through modular co‐culture leading to the discovery of a novel neuroprotective agent. Acta Pharmaceutica Sinica B, 13, 1771–1785.
Louie, G.V., Bowman, M.E., Tu, Y., Mouradov, A., Spangenberg, G. & Noel, J.P. (2010) Structure‐function analyses of a caffeic acid O‐methyltransferase from perennial ryegrass reveal the molecular basis for substrate preference. The Plant Cell, 22, 4114–4127.
Mori, T., Shimokawa, Y., Matsui, T., Kinjo, K., Kato, R., Noguchi, H. et al. (2013) Cloning and structure‐function analyses of quinolone‐ and acridone‐producing novel type III polyketide synthases from Citrus microcarpa. Journal of Biological Chemistry, 288, 28845–28858.
Nandy, S. & Dey, A. (2020) Bibenzyls and bisbybenzyls of bryophytic origin as promising source of novel therapeutics: pharmacology, synthesis and structure‐activity. DARU Journal of Pharmaceutical Sciences, 28, 701–734.
Paasela, T., Lim, K.J., Pietiäinen, M. & Teeri, T.H. (2017) The O‐methyltransferase PMT2 mediates methylation of pinosylvin in scots pine. New Phytologist, 214, 1537–1550.
Petpiroon, N., Bhummaphan, N., Tungsukruthai, S., Pinkhien, T., Maiuthed, A., Sritularak, B. et al. (2019) Chrysotobibenzyl inhibition of lung cancer cell migration through Caveolin‐1‐dependent mediation of the integrin switch and the sensitization of lung cancer cells to cisplatin‐mediated apoptosis. Phytomedicine, 58, 152888.
Peyret, H. & Lomonossoff, G.P. (2013) The pEAQ vector series: the easy and quick way to produce recombinant proteins in plants. Plant Molecular Biology, 83, 51–58.
Pompon, D., Louerat, B., Bronine, A. & Urban, P. (1996) Yeast expression of animal and plant P450s in optimized redox environments. Methods in Enzymology, 272, 51–64.
Preisig‐Muller, R., Gnau, P. & Kindl, H. (1995) The inducible 9, 10‐dihydrophenanthrene pathway: characterization and expression of bibenzyl synthase and S‐adenosylhomocysteine hydrolase. Archives of Biochemistry and Biophysics, 317, 201–207.
Qiao, Q., Du, Y. & Xie, L. (2022) Research advances of erianin: source, production, biological activities and pharmacological properties. Pharmacological Research—Modern Chinese Medicine, 2, 100059.
Sale, S., Tunstall, R.G., Ruparelia, K.C., Potter, G.A., Steward, W.P. & Gescher, A.J. (2005) Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′‐tetramethoxystilbene (DMU‐212) on adenoma development in the Apc(min+) mouse and cyclooxygenase‐2 in human‐derived colon cancer cells. International Journal of Cancer, 115, 194–201.
Sale, S., Verschoyle, R.D., Boocock, D., Jones, D.J.L., Wilsher, N., Ruparelia, K.C. et al. (2004) Pharmacokinetics in mice and growth‐inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′‐tetramethoxystilbene. British Journal of Cancer, 90, 736–744.
Schmidlin, L., Poutaraud, A., Claudel, P., Mestre, P., Prado, E., Santos‐Rosa, M. et al. (2008) A stress‐inducible resveratrol O‐methyltransferase involved in the biosynthesis of pterostilbene in grapevine. Plant Physiology, 148, 1630–1639.
Sheng, Y., Chen, Y., Zeng, Z., Wu, W., Wang, J., Ma, Y. et al. (2021) Identification of pyruvate carboxylase as the cellular target of natural bibenzyls with potent anticancer activity against hepatocellular carcinoma via metabolic reprogramming. Journal of Medicinal Chemistry, 65, 460–484.
Sircar, D., Gaid, M.M., Chizzali, C., Reckwell, D., Kaufholdt, D., Beuerle, T. et al. (2015) Biphenyl 4‐hydroxylases involved in aucuparin biosynthesis in rowan and apple are cytochrome P450 736A proteins. Plant Physiology, 168, 428–442.
Song, J.‐X., Shaw, P.‐C., Sze, C.‐W., Tong, Y., Yao, X.‐S., Ng, T.‐B. et al. (2010) Chrysotoxine, a novel bibenzyl compound, inhibits 6‐hydroxydopamine induced apoptosis in SH‐SY5Y cells via mitochondria protection and NF‐κB modulation. Neurochemistry International, 57, 676–689.
Tamura, K., Stecher, G. & Kumar, S. (2021) MEGA11: molecular evolutionary genetics analysis version 11. Molecular Biology and Evolution, 38, 3022–3027.
Tan, Y., Yang, J., Jiang, Y., Sun, S., Wei, X., Wang, R. et al. (2022) Identification and characterization of two Isatis indigotica O‐methyltransferases methylating C‐glycosylflavonoids. Horticulture Research, 9, uhac140.
Teixeira da Silva, J.A., Cardoso, J.C., Dobránszki, J. & Zeng, S. (2015) Dendrobium micropropagation: a review. Plant Cell Reports, 34, 671–704.
Teka, T., Zhang, L., Ge, X., Li, Y., Han, L. & Yan, X. (2022) Stilbenes: source plants, chemistry, biosynthesis, pharmacology, application and problems related to their clinical application a comprehensive review. Phytochemistry, 197, 113128.
Truan, G., Cullin, C., Reisdorf, P., Urban, P. & Pompon, D. (1993) Enhanced in vivo monooxygenase activities of mammalian P450s in engineered yeast cells producing high levels of NADPH‐P450 reductase and human cytochrome b5. Gene, 125, 49–55.
Vidgren, J., Svensson, L.A. & Liljas, A. (1994) Crystal structure of catechol O‐methyltransferase. Nature, 368, 354–358.
Walker, A.M., Sattler, S.A., Regner, M., Jones, J.P., Ralph, J., Vermerris, W. et al. (2016) The structure and catalytic mechanism of Sorghum bicolor caffeoyl‐CoA O‐methyltransferase. Plant Physiology, 172, 78–92.
Wang, J., Liao, N., Liu, G., Li, Y., Xu, F. & Shi, J. (2023) Diversity and regioselectivity of O‐methyltransferases catalyzing the formation of O‐methylated flavonoids. Critical Reviews in Biotechnology, 44, 1203–1225.
Wang, P., Jia, X., Lu, B., Huang, H., Liu, J., Liu, X. et al. (2023) Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2. Signal Transduction and Targeted Therapy, 8, 96.
Wils, C.R., Brandt, W., Manke, K. & Vogt, T. (2013) A single amino acid determines position specificity of an Arabidopsis thaliana CCoAOMT‐like O‐methyltransferase. FEBS Letters, 587, 683–689.
Yu, C.‐L., Weng, M.‐S., Chen, W.‐C., Chien, K.‐T., Chi, C.‐W., Chung, C.‐H. et al. (2021) Moscatilin inhibits metastatic behavior of human hepatocellular carcinoma cells: a crucial role of uPA suppression via Akt/NF‐κB‐dependent pathway. International Journal of Molecular Sciences, 22, 2930.
Zhai, D., Lv, X., Chen, J., Peng, M. & Cai, J. (2022) Recent research progress on natural stilbenes in dendrobium species. Molecules, 27, 7233.
Zhang, C., Liu, S.‐J., Yang, L., Yuan, M.‐Y., Li, J.‐Y., Hou, B. et al. (2017) Sesquiterpene amino ether and cytotoxic phenols from dendrobium wardianum Warner. Fitoterapia, 122, 76–79.
Zhang, G.Q., Xu, Q., Bian, C., Tsai, W.C., Yeh, C.M., Liu, K.W. et al. (2016) The Dendrobium catenatum Lindl. genome sequence provides insights into polysaccharide synthase, floral development and adaptive evolution. Scientific Reports, 6, 19029.
Zhang, X., Xu, J.‐K., Wang, J., Wang, N.‐L., Kurihara, H., Kitanaka, S. et al. (2007) Bioactive bibenzyl derivatives and fluorenones from Dendrobium nobile. Journal of Natural Products, 70, 24–28.
Zhou, J.‐M., Lee, E., Kanapathy‐Sinnaiaha, F., Park, Y., Kornblatt, J.A., Lim, Y. et al. (2010) Structure‐function relationships of wheat flavone O‐methyltransferase: homology modeling and site‐directed mutagenesis. BMC Plant Biology, 10, 156.
Zubieta, C., He, X.Z., Dixon, R.A. & Noel, J.P. (2001) Structures of two natural product methyltransferases reveal the basis for substrate specificity in plant O‐methyltransferases. Nature Structural Biology, 8, 271–279.
Zubieta, C., Kota, P., Ferrer, J.L., Dixon, R.A. & Noel, J.P. (2002) Structural basis for the modulation of lignin monomer methylation by caffeic acid/5‐hydroxyferulic acid 3/5‐O‐methyltransferase. Plant Cell, 14, 1265–1277.