title: Regulation of Anticancer Styrylpyrone Biosynthesis in the Medicinal Mushroom Inonotus obliquus Requires Thioredoxin Mediated Transnitrosylation of S-nitrosoglutathione Reductase.
abstract: The medicinal macrofungus Inonotus obliquus widely utilized as folk medicine in Russia and Baltic countries is a source of phenylpropanoid-derived styrylpyrone polyphenols that can inhibit tumor proliferation. Insights into the regulatory machinery that controls I. obliquus styrylpyrone polyphenol biosynthesis will enable strategies to increase the production of these molecules. Here we show that Thioredoxin (Trx) mediated transnitrosylation of S-nitrosoglutathione reductase (GSNOR) underpins the regulation of styrylpyrone production, driven by nitric oxide (NO) synthesis triggered by P. morii coculture. NO accumulation results in the S-nitrosylation of PAL and 4CL required for the synthesis of precursor phenylpropanoids and styrylpyrone synthase (SPS), integral to the production of styrylpyrone, inhibiting their activities. These enzymes are targeted for denitrosylation by Trx proteins, which restore their activity. Further, this Trx S-nitrosothiol (SNO) reductase activity was potentiated following S-nitrosylation of Trx proteins at a non-catalytic cysteine (Cys) residue. Intriguingly, this process was counterbalanced by Trx denitrosylation, mediated by Trx-dependent transnitrosylation of GSNOR. Thus, unprecedented interplay between Trx and GSNOR oxidoreductases regulates the biosynthesis of styrylpyrone polyphenols in I. obliquus.
authors.affiliation: Laboratory for Biotechnology of Medicinal Plants, School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Laboratory for Biotechnology of Medicinal Plants, School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China.
authors.forename: Meihong
authors.initials: M
authors.lastname: He
authors.affiliation: Laboratory for Biotechnology of Medicinal Plants, School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China.
authors.forename: Jianing
authors.initials: J
authors.lastname: Ding
authors.affiliation: Laboratory for Biotechnology of Medicinal Plants, School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xi
authors.affiliation: Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.|Jiangsu Normal University - Edinburgh University, Centre for Biotechnology of Medicinal and Food Plants, Jiangsu Normal University, Xuzhou 221116, China.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Loake
authors.affiliation: Laboratory for Biotechnology of Medicinal Plants, School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China.
authors.forename: Weifa
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000363:Agaricales / Q000201:enzymology*; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D055162:Biocatalysis; D002853:Chromatography, Liquid; D018920:Coculture Techniques; D008954:Models, Biological; D015538:Nitrosation; D000073039:Nitrosative Stress; D010084:Oxidation-Reduction; D059808:Polyphenols / Q000378:metabolism; D011485:Protein Binding; D011753:Pyrones / Q000138:chemical synthesis*; D053719:Tandem Mass Spectrometry; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D059808:Polyphenols; D011753:Pyrones; D013879:Thioredoxins; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent