{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:48:39Z","timestamp":1790912919964,"version":"4.1.0"},"reference-count":125,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T00:00:00Z","timestamp":1602806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sachsen-Anhalt and EFRE (Europ\u00e4ischer Fonds f\u00fcr regionale Entwicklung)","award":["ZS\/2019\/07\/99749"],"award-info":[{"award-number":["ZS\/2019\/07\/99749"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hypericum perforatum L. commonly known as Saint John\u2019s Wort (SJW), is an important medicinal plant that has been used for more than 2000 years. Although H. perforatum produces several bioactive compounds, its importance is mainly linked to two molecules highly relevant for the pharmaceutical industry: the prenylated phloroglucinol hyperforin and the naphtodianthrone hypericin. The first functions as a natural antidepressant while the second is regarded as a powerful anticancer drug and as a useful compound for the treatment of Alzheimer\u2019s disease. While the antidepressant activity of SJW extracts motivate a multi-billion dollar industry around the world, the scientific interest centers around the biosynthetic pathways of hyperforin and hypericin and their medical applications. Here, we focus on what is known about these processes and evaluate the possibilities of combining state of the art omics, genome editing, and synthetic biology to unlock applications that would be of great value for the pharmaceutical and medical industries.<\/jats:p>","DOI":"10.3390\/genes11101210","type":"journal-article","created":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T05:45:51Z","timestamp":1602913551000},"page":"1210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["The Biochemical and Genetic Basis for the Biosynthesis of Bioactive Compounds in Hypericum perforatum L., One of the Largest Medicinal Crops in Europe"],"prefix":"10.3390","volume":"11","author":[{"given":"Paride","family":"Rizzo","sequence":"first","affiliation":[{"name":"Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), 06466 Gatersleben, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lothar","family":"Altschmied","sequence":"additional","affiliation":[{"name":"Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), 06466 Gatersleben, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4080-8587","authenticated-orcid":false,"given":"Beena M.","family":"Ravindran","sequence":"additional","affiliation":[{"name":"Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), 06466 Gatersleben, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Twan","family":"Rutten","sequence":"additional","affiliation":[{"name":"Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), 06466 Gatersleben, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4865-3938","authenticated-orcid":false,"given":"John C.","family":"D\u2019Auria","sequence":"additional","affiliation":[{"name":"Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), 06466 Gatersleben, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,16]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Taxonomy and Chemotaxonomy of the Genus Hypericum","volume":"5","author":"Crockett","year":"2011","journal-title":"Med. Aromat. Plant Sci. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fpls.2016.01004","article-title":"Neuroprotective activity of hypericum perforatum and its major components","volume":"7","author":"Oliveira","year":"2016","journal-title":"Front. Plant Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Barnes, J., Anderson, L.A., and Phillipson, J.D. (2001). St John\u2019s wort (Hypericum perforatum L.): A Review of its Chemistry, Pharmacology and Clinical properties. J. Pharmacol. Sci., 583\u2013600.","DOI":"10.1211\/0022357011775910"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"M\u00fcller, W.E. St. (2005). John\u2019s Wort and Its Active Principle in Depression and Anxiety, Springer Science & Business Media.","DOI":"10.1007\/b137619"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1055\/s-2007-979342","article-title":"Activity profiles of two hyperforin-containing hypericum extracts in behavioral models","volume":"31","author":"Bhattacharya","year":"1998","journal-title":"Pharmacopsychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0024-3205(98)00299-9","article-title":"Hyperforin as a possible antidepressant component of Hypericum extracts","volume":"63","author":"Chatterjee","year":"1998","journal-title":"Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1055\/s-2007-979345","article-title":"Pharmacodynamic effects of two different hypericum extracts in healthy volunteers measured by quantitative EEG","volume":"31","author":"Schellenberg","year":"1998","journal-title":"Pharmacopsychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1055\/s-2007-979343","article-title":"Effects of a methanolic extract and a hyperforin-enriched CO2 extract of St. John\u2019s Wort (Hypericum perforatum) on intracerebral field potentials in the freely moving rat (Tele-Stereo-EEG)","volume":"31","author":"Dimpfel","year":"1998","journal-title":"Pharmacopsychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Benzie, I.F.F., and Wachtel-Galor, S. (2011). Herbal Medicine Biomolecular and Clinical Aspects, CRC Press. [2nd ed.].","DOI":"10.1201\/b10787"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.2174\/15672050113106660171","article-title":"Reduced Alzheimer\u2019s disease pathology by St. John\u2019s Wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice","volume":"10","author":"Hofrichter","year":"2013","journal-title":"Curr. Alzheimer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00262-011-1184-2","article-title":"Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin","volume":"61","author":"Garg","year":"2012","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1111\/j.1742-4658.2008.06576.x","article-title":"Octaketide-producing type III polyketide synthase from Hypericum perforatum is expressed in dark glands accumulating hypericins","volume":"275","author":"Karppinen","year":"2008","journal-title":"FEBS J."},{"key":"ref_13","first-page":"1","article-title":"Comparative transcriptome reconstruction of four hypericum species focused on Hypericin biosynthesis","volume":"7","author":"Klein","year":"2016","journal-title":"Front. Plant Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1111\/pbi.13141","article-title":"Discovery of key regulators of dark gland development and hypericin biosynthesis in St. John\u2019s Wort (Hypericum perforatum)","volume":"17","author":"Rizzo","year":"2019","journal-title":"Plant Biotechnol. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1211\/jpp.57.12.0015","article-title":"Quantitative analysis of the major constituents of St John\u2019s wort with HPLC-ESI-MS","volume":"57","author":"Chandrasekera","year":"2005","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fpls.2018.01973","article-title":"John\u2019s Wort (Hypericum perforatum) Products \u2013 How Variable Is the Primary Material?","volume":"9","author":"Scotti","year":"2019","journal-title":"Front. Plant Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1055\/s-2007-979533","article-title":"Biologically active and other chemical constituents of the herb of Hypericum perforation L.","volume":"30","author":"Nahrstedt","year":"1997","journal-title":"Pharmacopsychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1055\/s-2007-979346","article-title":"John\u2019s Wort in mild to moderate depression: The relevance of hyperforin for the clinical efficacy","volume":"31","author":"Laakmann","year":"1998","journal-title":"Pharmacopsychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s00213-002-1229-5","article-title":"Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extracts","volume":"164","author":"Cervo","year":"2002","journal-title":"Psychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Obata, H. (2017). Analgesic mechanisms of antidepressants for neuropathic pain. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112483"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1055\/s-2001-15512","article-title":"Hyperforin\u2014Antidepressant activity by a novel mechanism of action","volume":"34","author":"Singer","year":"2001","journal-title":"Pharmacopsychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1111\/j.1476-5381.1969.tb08506.x","article-title":"Sodium-dependent accumulation of 5-hydroxytryptamine by rat blood platelets","volume":"37","author":"Sneddon","year":"1969","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0005-2736(70)90074-X","article-title":"Effects of sodium and potassium on kinetics of 5-hydroxytryptamine and norepinephrine transport by rabbit synaptosomes","volume":"219","author":"Bogdanski","year":"1970","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1001\/jama.285.15.1978","article-title":"Effectiveness of St. John\u2019s Wort in major depression: A randomized controlled trial","volume":"285","author":"Shelton","year":"2001","journal-title":"J. Am. Med. Assoc."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"(2002). Hypericum Depression Trial Study Group Effects of Hypericum perforatum (St John\u2019s Wort) in Major Depressive Disorder. J. Am. Med. Assoc., 287, 1807\u20131814.","DOI":"10.1001\/jama.287.14.1807"},{"key":"ref_26","first-page":"1","article-title":"St John\u2019s wort for major depression (Review)","volume":"4","author":"Linde","year":"2008","journal-title":"Wiley Cochrane Collab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/S0140-6736(99)00214-7","article-title":"Antibacterial activity of hyperforin from St John\u2019s wort, against multiresistant Staphylococcus aureus and gram-positive bacteria","volume":"353","author":"Schempp","year":"1999","journal-title":"Lancet"},{"key":"ref_28","first-page":"5","article-title":"Melanoma targeting with the loco-regional chemotherapeutic, Melphalan: From cell death to immunotherapeutic efficacy","volume":"4","author":"Garg","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0065-2571(99)00021-7","article-title":"Apoptotic and anti-apoptotic signaling pathways induced by photodynamic therapy with hypericin","volume":"40","author":"Agostinis","year":"2000","journal-title":"Adv. Enzyme Regul."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S1357-2725(01)00126-1","article-title":"Hypericin in cancer treatment: More light on the way","volume":"34","author":"Agostinis","year":"2002","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1007\/s10495-010-0479-7","article-title":"Photodynamic therapy: Illuminating the road from cell death towards anti-tumour immunity","volume":"15","author":"Garg","year":"2010","journal-title":"Apoptosis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e631","DOI":"10.1038\/cddis.2013.156","article-title":"V Many faces of DAMPs in cancer therapy","volume":"4","author":"Krysko","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2019.01272","article-title":"Antiviral activity against infectious bronchitis virus and bioactive components of Hypericum perforatum L.","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1089\/aid.1992.8.1929","article-title":"Inactivation of the Human Immunodeficiency Virus by Hypericin: Evidence for Photochemical Alterations of p24 and a Block in Uncoating","volume":"8","author":"Degar","year":"1992","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0166-3542(93)90006-5","article-title":"The importance of light in the anti-HIV effect of hypericin","volume":"20","author":"Hudson","year":"1993","journal-title":"Antiviral Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0166-3542(90)90015-Y","article-title":"Virucidal activity of hypericin against enveloped and non-enveloped DNA and RNA viruses","volume":"13","author":"Tang","year":"1990","journal-title":"Antiviral Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1562\/0031-8655(2000)0710188SFEOEV2.0.CO2","article-title":"Strategies for Evaluation of Enveloped Virus Inactivation in Red Cell Concentrates Using Hypericin","volume":"71","author":"Prince","year":"2000","journal-title":"Photochem. Photobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.phymed.2017.08.009","article-title":"Hypericin inhibits hepatitis C virus replication via deacetylation and down-regulation of heme oxygenase-1","volume":"46","author":"Shih","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"110052","DOI":"10.1016\/j.msec.2019.110052","article-title":"Hypericin-loaded graphene oxide protects ducks against a novel duck reovirus","volume":"105","author":"Du","year":"2019","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1534\/g3.119.200997","article-title":"Full-length transcriptome sequencing and the discovery of new transcripts in the unfertilized eggs of Zebrafish (Danio rerio)","volume":"9","author":"Mehjabin","year":"2019","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1073\/pnas.90.1.158","article-title":"Photodynamic inactivation of infectivity of human immunodeficiency virus and other enveloped viruses using hypericin and rose bengal: Inhibition of fusion and syncytia formation (vesicular stomatitis virus\/influenza virus\/Sendai virus\/hemolysis)","volume":"90","author":"Lenard","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3288","DOI":"10.1016\/j.febslet.2008.08.039","article-title":"In vitro perturbation of aggregation processes in \u03b2-amyloid peptides: A spectroscopic study","volume":"582","author":"Sgarbossa","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1007\/s00249-010-0607-x","article-title":"Effects of hypericin on the structure and aggregation properties of \u03b2-amyloid peptides","volume":"39","author":"Bramanti","year":"2010","journal-title":"Eur. Biophys. J."},{"key":"ref_44","first-page":"7","article-title":"Inhibitors of \u03b2-amyloid aggregation: Still an issue of structure and function?","volume":"1","author":"Talaga","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/nsmb1345","article-title":"Evidence of fibril-like \u03b2-sheet structures in a neurotoxic amyloid intermediate of Alzheimer\u2019s \u03b2-amyloid","volume":"14","author":"Chimon","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5032","DOI":"10.1021\/jf049571r","article-title":"Antioxidant activity of a flavonoid-rich extract of Hypericum perforatum L. in vitro","volume":"52","author":"Zou","year":"2004","journal-title":"J. Agric. Food Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/BF03033510","article-title":"Quercetin, kaempferol and biapigenin from hypericum perforatum are neuroprotective against excitotoxic insults","volume":"13","author":"Silva","year":"2008","journal-title":"Neurotox. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1093\/aob\/mcm057","article-title":"Hyperforin accumulates in the translucent glands of Hypericum perforatum","volume":"99","author":"Soelberg","year":"2007","journal-title":"Ann. Bot."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1006\/anbo.2001.1514","article-title":"Translucent Glands and Secretory Canals in Hypericum perforatum L. (Hypericaceae): Morphological, Anatomical and Histochemical Studies During the Course of Ontogenesis","volume":"88","author":"Ciccarelli","year":"2001","journal-title":"Ann. Bot."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1093\/aob\/mcl169","article-title":"Plant-environment interactions: Accumulation of hypericin in dark glands of Hypericum perforatum","volume":"98","author":"Zobayed","year":"2006","journal-title":"Ann. Bot."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1078\/0367-2530-00019","article-title":"Ultrastructural studies on the developing secretory nodules of Hypericum perforatum","volume":"197","author":"Onelli","year":"2002","journal-title":"Flora"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sot\u00e1k, M., Czerankov\u00e1, O., Klein, D., Nigutov\u00e1, K., Altschmied, L., Li, L., Adarsch, J., Wurtele, E.S., and Cellarova, E. (2016). Differentially Expressed Genes in Hypericin-Containing Hypericum perforatum Leaf Tissues as Revealed by De Novo Assembly of RNA-Seq. Plant Mol. Biol. Rep., 1027\u20131041.","DOI":"10.1007\/s11105-016-0982-2"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Stracke, R., Werber, M., and Weisshaar, B. (2001). The R2R3-MYBgene family in Arabidopsis thaliana. Cell Signal. Gene Regul., 447\u2013456.","DOI":"10.1016\/S1369-5266(00)00199-0"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.plantsci.2004.06.014","article-title":"Arabidopsis MYB68 in development and responses to environmental cues","volume":"167","author":"Feng","year":"2004","journal-title":"Plant Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1105\/tpc.105.038745","article-title":"Blind homologous R2R3 Myb genes control the pattern of lateral meristem initiation in Arabidopsis","volume":"18","author":"Schmitz","year":"2006","journal-title":"Plant Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1007\/s10529-013-1451-8","article-title":"Chimeric repressor analysis identifies MYB87 as a possible regulator of morphogenesis via cell wall organization and remodeling in Arabidopsis","volume":"36","author":"Fujiwara","year":"2014","journal-title":"Biotechnol. Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12099","DOI":"10.1073\/pnas.1515576112","article-title":"MYB36 regulates the transition from proliferation to differentiation in the Arabidopsis root","volume":"112","author":"Liberman","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3008","DOI":"10.1105\/tpc.109.068742","article-title":"MOSAIC FLORAL ORGANS1, an AGL6-Like MADS Box Gene, Regulates Floral Organ Identity and Meristem Fate in Rice","volume":"21","author":"Ohmori","year":"2009","journal-title":"Plant Cell"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Viaene, T., Vekemans, D., Becker, A., Melzer, S., and Geuten, K. (2010). Expression divergence of the AGL6 MADS domain transcription factor lineage after a core eudicot duplication suggests functional diversification. BMC Plant Biol., 10.","DOI":"10.1186\/1471-2229-10-148"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.tplants.2015.06.007","article-title":"Flavonoid transport mechanisms: How to go, and with whom","volume":"20","author":"Zhao","year":"2015","journal-title":"Trends Plant Sci."},{"key":"ref_61","unstructured":"Buchner, A. (1830). Buchner\u2019s Report. Pharmacie, 217."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1515\/bchm2.1911.73.5.371","article-title":"\u00dcber das Hypericin (Hypericumrot)","volume":"73","year":"1911","journal-title":"Zeitschrift f\u00fcr Physiol. Chemie"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1002\/cber.19570901027","article-title":"Totalsynthese des Hypericins","volume":"37","author":"Brockmann","year":"1957","journal-title":"Chem. Ber."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jlac.19425530102","article-title":"\u00dcber das Hypericin, den photodynamischen Farbstoff des Johanniskrautes (Hypericum perforatum). Justus Liebigs Annalen der Chemie","volume":"553","author":"Brockmann","year":"1942","journal-title":"Justus Liebigs Ann. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/cber.19510840915","article-title":"Die Konstitution des Hypericins","volume":"84","author":"Brockmann","year":"1951","journal-title":"Chem. Ber."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1002\/(SICI)1521-3773(19991102)38:21<3116::AID-ANIE3116>3.0.CO;2-S","article-title":"From the Photosensitizer Hypericin to the Photoreceptor Stentorin- The Chemistry of Phenanthroperylene Quinones","volume":"38","author":"Falk","year":"1999","journal-title":"Angew. Chemie"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Agarwal, P., and Agarwal, P.K. (2014). Pathogenesis related-10 proteins are small, structurally similar but with diverse role in stress signaling. Mol. Biol. Rep., 599\u2013611.","DOI":"10.1007\/s11033-013-2897-4"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"32413","DOI":"10.1074\/jbc.M301681200","article-title":"Molecular and biochemical characterization of an enzyme responsible for the formation of hypericin in St. John\u2019s wort (Hypericum perforatum L.)","volume":"278","author":"Bais","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/BF00629065","article-title":"Zur Biosynthese des Hypericins","volume":"40","author":"Brockmann","year":"1953","journal-title":"Naturwissenschaften"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1021\/np50060a035","article-title":"Pigments of Fungi, Part 8. Bianthroquinones from Democybe austroveneta","volume":"51","author":"Gill","year":"1988","journal-title":"J. Nat. Prod."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Kosuth, J., Katkovcinova, Z., Olexova, P., and Cellarova, E. (2007). Expression of the hyp-1 gene in early stages of development of Hypericum perforatum L.. Plant Cell Rep., 211\u2013217.","DOI":"10.1007\/s00299-006-0240-4"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jsb.2009.10.008","article-title":"Crystal structure of Hyp-1, a St. John\u2019s wort protein implicated in the biosynthesis of hypericin","volume":"169","author":"Michalska","year":"2010","journal-title":"J. Struct. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Kosuth, J., Smelcerovic, A., Borsch, T., Zuehlke, S., Karppinen, K., Spiteller, M., Hohtola, A., and Cell\u00e1rov\u00e1, E. (2011). The hyp-1 gene is not a limiting factor for hypericin biosynthesis in the genus Hypericum. Funct. Plant Biol., 35\u201343.","DOI":"10.1071\/FP10144"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s11240-013-0316-0","article-title":"Stress-induced expression and structure of the putative gene hyp-1 for hypericin biosynthesis","volume":"114","author":"Kosuth","year":"2013","journal-title":"Plant Cell Tissue Org. Cult."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fpls.2016.00526","article-title":"Molecular Cloning and Expression Analysis of hyp-1 Type PR-10 Family Genes in Hypericum perforatum","volume":"7","author":"Karppinen","year":"2016","journal-title":"Front. Plant Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fpls.2016.00668","article-title":"Crystal Structure of Hyp-1, a Hypericum perforatum PR-10 Protein, in Complex with Melatonin","volume":"7","author":"Sliwiak","year":"2016","journal-title":"Front. Plant Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"23684","DOI":"10.1074\/jbc.M202065200","article-title":"The Major Birch Allergen, Bet v 1, Shows Affinity for a Broad Spectrum of Physiological Ligands","volume":"277","author":"Mogensen","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1105\/tpc.110.077958","article-title":"Norcoclaurine Synthase Is a Member of the Pathogenesis-Related 10\/Bet v1 Protein Family","volume":"22","author":"Lee","year":"2010","journal-title":"Plant Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.jplph.2007.04.008","article-title":"Molecular cloning and tissue-specific expression of two cDNAs encoding polyketide synthases from Hypericum perforatum","volume":"165","author":"Karppinen","year":"2008","journal-title":"J. Plant Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4779","DOI":"10.1007\/s00216-015-8682-6","article-title":"Spatial chemo-profiling of hypericin and related phytochemicals in Hypericum species using MALDI-HRMS imaging","volume":"407","author":"Kusari","year":"2015","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/ppl.12422","article-title":"Interspecific variation in localization of hypericins and phloroglucinols in the genus Hypericum as revealed by desorption electrospray ionization mass spectrometry imaging","volume":"157","author":"Janfelt","year":"2016","journal-title":"Physiol. Plant."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"12709","DOI":"10.1021\/ja053945v","article-title":"Engineered Biosynthesis of Plant Polyketides: Chain Length Control in an Octaketide-Producing Plant Type III Polyketide Synthase","volume":"127","author":"Abe","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1111\/j.1742-4658.2009.06971.x","article-title":"Novel type III polyketide synthases from Aloe arborescens","volume":"276","author":"Mizuuchi","year":"2009","journal-title":"FEBS J."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"12811","DOI":"10.1073\/pnas.1200330109","article-title":"Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides","volume":"109","author":"Gagne","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7689","DOI":"10.1007\/s00216-018-1384-0","article-title":"Phenotyping the genus Hypericum by secondary metabolite profiling: Emodin vs. skyrin, two possible key intermediates in hypericin biosynthesis","volume":"410","author":"Idkowiak","year":"2018","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1016\/S0040-4039(00)75241-5","article-title":"The structure of hyperforin","volume":"16","author":"Bystrov","year":"1975","journal-title":"Tetrahedron Lett."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/S0040-4039(00)87088-4","article-title":"The relative stereochemistry of hyperforin\u2014An antibiotic from L","volume":"23","author":"Brondz","year":"1982","journal-title":"Tetrahedron Lett."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4786","DOI":"10.1021\/jm0209782","article-title":"Biosynthesis of hyperforin in Hypericum perforatum","volume":"45","author":"Adam","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1055\/s-2006-961483","article-title":"Analysis and Stability of Hyperici Oleum","volume":"58","author":"Maisenbacher","year":"1992","journal-title":"Planta Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1055\/s-2007-979339","article-title":"Hyperforin, Possibly the Major Non-Nitrogenous Secondary Metabolite of Hypericum perforatum L.","volume":"31","author":"Erdelmeier","year":"1998","journal-title":"Pharmacopsychiatry"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1021\/np9903752","article-title":"Hyperforin Analogues from St. John\u2019s Wort (Hypericum perforatum)","volume":"63","author":"Verotta","year":"2000","journal-title":"J. Nat. Prod."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1021\/np000362k","article-title":"Three New Hyperforin Analogues from Hypericum perforatum","volume":"64","author":"Hu","year":"2001","journal-title":"J. Nat. Prod."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.jpba.2004.10.034","article-title":"Liquid chromatography\u2013mass spectrometry studies of St. John\u2019s wort methanol extraction: Active constituents and their transformation","volume":"37","author":"Liu","year":"2005","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Brahmachari, G. (2018). Biosynthetic and Total Synthetic Approaches for (+)-Hyperforin. Discovery and Development of Neuroprotective Agents from Natural Products, Elsevier.","DOI":"10.1016\/B978-0-12-809593-5.00012-4"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.phytochem.2003.11.003","article-title":"Detection of hypericins in the \u2018red glands\u2019 of Hypericum elodes by ESI-MS\/MS","volume":"65","author":"Piovan","year":"2004","journal-title":"Phytochemistry"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1055\/s-2006-960798","article-title":"Quantitative Phytochemical Analyses of Six Hypericum Species Growing in Slovenia","volume":"65","author":"Umek","year":"1999","journal-title":"Planta Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1055\/s-2000-9779","article-title":"Quantitative Changes of Dianthrones, Hyperforin and Flavonoids Content in the Flower Ontogenesis of Hypericum perforatum","volume":"66","year":"2000","journal-title":"Planta Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1055\/s-2006-961463","article-title":"Adhyperforin: A Homologue of Hyperforin from Hypericum perforatum","volume":"58","author":"Maisenbacher","year":"1992","journal-title":"Planta Med."},{"key":"ref_99","unstructured":"Grigson, G. (1958). The Englishman\u2019s Flora. The Englishman\u2019s Flora, Harper-Collins."},{"key":"ref_100","first-page":"510","article-title":"Antibiotic hyperforin from Hypericum perforatum L.","volume":"16","author":"Gurevich","year":"1971","journal-title":"Antibiotiki"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"263","DOI":"10.3891\/acta.chem.scand.37a-0263","article-title":"The Absolute Configuration of Hyperforin, an Antibiotic from Hypericum perforatum L., Based on the Crystal Structure Determination of its p-Bromobenzoate Ester","volume":"37a","author":"Brondz","year":"1983","journal-title":"Acta Chem. Scand."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s12934-016-0549-9","article-title":"Biosynthesis of phlorisovalerophenone and 4-hydroxy-6-isobutyl-2-pyrone in Escherichia coli from glucose","volume":"15","author":"Zhou","year":"2016","journal-title":"Microb. Cell Fact."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.phytochem.2007.01.001","article-title":"Biosynthesis of hyperforin and adhyperforin from amino acid precursors in shoot cultures of Hypericum perforatum","volume":"68","author":"Karppinen","year":"2007","journal-title":"Phytochemistry"},{"key":"ref_104","first-page":"188","article-title":"Production of secondary metabolites using plant cell cultures","volume":"Volume 132","author":"Stahl","year":"2007","journal-title":"Food Biotechnology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1042\/bst0280785","article-title":"Sterols and Isoprenoids","volume":"28","author":"Lichtenthaler","year":"2000","journal-title":"Biochem. Soc. Trans."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1046\/j.1432-1327.1999.00444.x","article-title":"Phlorisovalerophenone synthase, a novel polyketide synthase from hop (Humulus lupulus L.) cones","volume":"262","author":"Paniego","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.phytochem.2004.11.003","article-title":"Biosynthesis of the hyperforin skeleton in Hypericum calycinum cell cultures","volume":"66","author":"Klingauf","year":"2005","journal-title":"Phytochemistry"},{"key":"ref_108","unstructured":"Hillwig, M.L. (2008). Understanding the Biological Activity of Hypericum Species through Metabolomics Studies. [Ph.D. Thesis, Iowa State University]."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.1073\/pnas.082590499","article-title":"Expanding the biosynthetic repertoire of plant type III polyketide synthases by altering starter molecule specificity","volume":"99","author":"Jez","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1039\/b909988n","article-title":"Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases","volume":"27","author":"Abe","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_111","first-page":"163","article-title":"Bifunctional activities of Valerophenone synthase in hop (Humulus lupulus L.)","volume":"59","author":"Okada","year":"2001","journal-title":"J. Am. Soc. Brew. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Clark, S.M., Vaitheeswaran, V., Ambrose, S.J., Purves, R.W., and Page, J.E. (2013). Transcriptome analysis of bitter acid biosynthesis and precursor pathways in hop (Humulus lupulus). BMC Plant Biol., 13.","DOI":"10.1186\/1471-2229-13-12"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.phytochem.2004.10.020","article-title":"The first prenylation step in hyperforin biosynthesis","volume":"66","author":"Boubakir","year":"2005","journal-title":"Phytochemistry"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1016\/S0031-9422(98)00179-4","article-title":"In-vitro prenylation of aromatic intermediates in the biosynthesis of bitter acids in Humulus lupulus","volume":"49","author":"Zuurbier","year":"1998","journal-title":"Phytochemistry"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1016\/j.febslet.2009.05.024","article-title":"Characterization of olivetol synthase, a polyketide synthase putatively involved in cannabinoid biosynthetic pathway","volume":"583","author":"Taura","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1016\/j.phytochem.2006.08.017","article-title":"Hyperforin","volume":"67","author":"Beerhues","year":"2006","journal-title":"Phytochemistry"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1021\/np070669k","article-title":"An Endophytic Fungus from Hypericum perforatum that Produces Hypericin","volume":"71","author":"Kusari","year":"2008","journal-title":"J. Nat. Prod."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Zubek, S., Mielcarek, S., and Turnau, K. (2012). Hypericin and pseudohypericin concentrations of a valuable medicinal plant Hypericum perforatum L. are enhanced by arbuscular mycorrhizal fungi. Mycorrhiza, 149\u2013156.","DOI":"10.1007\/s00572-011-0391-1"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s00572-016-0756-6","article-title":"Arbuscular mycorrhizal fungi altered the hypericin, pseudohypericin, and hyperforin content in flowers of Hypericum perforatum grown under contrasting P availability in a highly organic substrate","volume":"27","author":"Lazzara","year":"2017","journal-title":"Mycorrhiza"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"109","DOI":"10.17221\/2725-PPS","article-title":"Enhanced Hypericin Production in Hypericum perforatum and Hypericum pruinatum in Response to Inoculation with Two Fungal Pathogens","volume":"41","author":"Cirak","year":"2004","journal-title":"Plant Prot. Sci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/S0040-4039(02)02693-X","article-title":"Synthesis of the core bicyclic system of hyperforin and nemorosone","volume":"44","author":"Kraus","year":"2003","journal-title":"Tetrahedron Lett."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3519","DOI":"10.1016\/j.tetlet.2009.03.041","article-title":"Synthetic studies towards the phloroglucin natural product hyperforin: Construction of the fully prenylated bicyclic core","volume":"50","author":"Mehta","year":"2009","journal-title":"Tetrahedron Lett."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1002\/anie.201207984","article-title":"An Alternative Isovaleryl CoA Biosynthetic Pathway Involving a Previously Unknown 3-Methylglutaconyl CoA Decarboxylase","volume":"52","author":"Li","year":"2013","journal-title":"Angew. Chemie Int. Ed."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fpls.2016.00879","article-title":"A perspective on hypericum perforatum genetic transformation","volume":"7","author":"Hou","year":"2016","journal-title":"Front. Plant Sci."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.indcrop.2017.11.032","article-title":"Development of enhanced hypericin yielding transgenic plants and somaclones: High throughput direct organogenesis from leaf and callus explants of Hypericum perforatum","volume":"111","author":"Khan","year":"2018","journal-title":"Ind. Crops Prod."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/10\/1210\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:22:28Z","timestamp":1760178148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/10\/1210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,16]]},"references-count":125,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["genes11101210"],"URL":"https:\/\/doi.org\/10.3390\/genes11101210","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,16]]}}}