De novo progesterone synthesis in plants

The essential roles of progesterone and other C21 steroids in animals are well-documented. Progesterone is an essential hormone for females to maintain a regular menstrual cycle and pregnancy, while also exhibiting anti-inflammatory and antitumor effects. While the biosynthesis pathway of C21 steroids is comprehensively understood in animals, the synthesis mechanisms of progesterone in plants remain unclear. To our best knowledge, this is the first study to elucidate the complete pathway for progesterone biosynthesis in the plant Marsdenia tenacissima, involving the two sterol side chain cleaving cytochrome P450 enzymes (P450scc) Mt108 or Mt150, as well as the Δ5-3β-hydroxysteroid dehydrogenase/Δ5-Δ4 ketosteroid isomerase MtHSD5. This critical discovery paves the way for the sustainable synthesis of steroid hormone drugs using either plants or microbial host cells.

[1]  Yimeng Zuo,et al.  Biosynthesis of catharanthine in engineered Pichia pastoris , 2023, Nature Synthesis.

[2]  J. Franke,et al.  Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants , 2022, Beilstein journal of organic chemistry.

[3]  J. Keasling,et al.  A microbial supply chain for production of the anti-cancer drug vinblastine , 2022, Nature.

[4]  A. Pařízek,et al.  Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine , 2022, International journal of molecular sciences.

[5]  Jiachen Zi,et al.  Rationally engineering santalene synthase to readjust the component ratio of sandalwood oil , 2022, Nature Communications.

[6]  Xueli Zhang,et al.  Metabolic engineering of Saccharomyces cerevisiae for gram-scale diosgenin production. , 2022, Metabolic engineering.

[7]  Xueli Zhang,et al.  De Novo Biosynthesis of the Oleanane-Type Triterpenoids of Tunicosaponins in Yeast. , 2021, ACS synthetic biology.

[8]  Xueli Zhang,et al.  Engineering yeast subcellular compartments for increased production of the lipophilic natural products ginsenosides. , 2021, Metabolic engineering.

[9]  R. Peters,et al.  Expansion within the CYP71D subfamily drives the heterocyclization of tanshinones synthesis in Salvia miltiorrhiza , 2021, Nature Communications.

[10]  S. Kampranis,et al.  Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids , 2020, Proceedings of the National Academy of Sciences.

[11]  C. Smolke,et al.  Biosynthesis of medicinal tropane alkaloids in yeast , 2020, Nature.

[12]  Xueli Zhang,et al.  Elucidation of the complete biosynthetic pathway of the main triterpene glycosylation products of Panax notoginseng using a synthetic biology platform. , 2020, Metabolic engineering.

[13]  J. Y. Lee,et al.  Tailoring the Saccharomyces cerevisiae endoplasmic reticulum for functional assembly of terpene synthesis pathway. , 2019, Metabolic engineering.

[14]  J. Weng,et al.  Repeated evolution of cytochrome P450-mediated spiroketal steroid biosynthesis in plants , 2019, Nature Communications.

[15]  Xueli Zhang,et al.  Identification of a novel cytochrome P450 enzyme that catalyzes the C-2α hydroxylation of pentacyclic triterpenoids and its application in yeast cell factories. , 2019, Metabolic engineering.

[16]  Wen Wang,et al.  Engineering yeast for the production of breviscapine by genomic analysis and synthetic biology approaches , 2018, Nature Communications.

[17]  L. Nielsen,et al.  An Expanded Heterologous GAL Promoter Collection for Diauxie-Inducible Expression in Saccharomyces cerevisiae. , 2018, ACS synthetic biology.

[18]  T. Liu,et al.  De novo biosynthesis of Gastrodin in Escherichia coli. , 2016, Metabolic engineering.

[19]  Q. Guo,et al.  Analysis of the transcriptome of Marsdenia tenacissima discovers putative polyoxypregnane glycoside biosynthetic genes and genetic markers. , 2014, Genomics.

[20]  Xueli Zhang,et al.  Metabolic engineering of Saccharomyces cerevisiae for production of ginsenosides. , 2013, Metabolic engineering.

[21]  J. Keasling,et al.  High-level semi-synthetic production of the potent antimalarial artemisinin , 2013, Nature.

[22]  B. Galán,et al.  Catabolism and biotechnological applications of cholesterol degrading bacteria , 2012, Microbial biotechnology.

[23]  Keith E. J. Tyo,et al.  Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli , 2010, Science.

[24]  D. Ray,et al.  Drug Insight: selective agonists and antagonists of the glucocorticoid receptor , 2008, Nature Clinical Practice Endocrinology &Metabolism.

[25]  W. Kreis,et al.  Molecular cloning and heterologous expression of progesterone 5beta-reductase from Digitalis lanata Ehrh. , 2006, Phytochemistry.

[26]  Denis Pompon,et al.  Total biosynthesis of hydrocortisone from a simple carbon source in yeast , 2003, Nature Biotechnology.

[27]  W. Lennarz,et al.  Protein disulfide isomerase. A multifunctional protein resident in the lumen of the endoplasmic reticulum. , 1992, The Journal of biological chemistry.

[28]  R. Schleimer,et al.  Inhibition of basophil histamine release by anti-inflammatory steroids , 1981, Nature.

[29]  Xueli Zhang,et al.  Production of plant volatile terpenoids (rose oil) by yeast cell factories , 2021 .

[30]  Yu Bo-yang.  Content Determination of Total C_(21) Steroidal Glycosides in Marsdenia tenacissima by Colorimetric Method , 2010 .

[31]  A. A. Akhrem,et al.  Total synthesis of steroids , 1969 .