Advances in Metabolic Engineering of Plant Monoterpene Indole Alkaloids

Monoterpene indole alkaloids (MIAs) encompass a diverse family of over 3000 plant natural products with a wide range of medical applications. Further utilizations of these compounds, however, are hampered due to low levels of abundance in their natural sources, causing difficult isolation and complex multi-steps in uneconomical chemical syntheses. Metabolic engineering of MIA biosynthesis in heterologous hosts is attractive, particularly for increasing the yield of natural products of interest and expanding their chemical diversity. Here, we review recent advances and strategies which have been adopted to engineer microbial and plant systems for the purpose of generating MIAs and discuss the current issues and future developments of manufacturing MIAs by synthetic biology approaches.

[1]  L. Caputi,et al.  Single-cell multi-omics in the medicinal plant Catharanthus roseus , 2023, Nature Chemical Biology.

[2]  M. Habib,et al.  Current Status and De Novo Synthesis of Anti-Tumor Alkaloids in Nicotiana , 2023, Metabolites.

[3]  Jiaming Yu,et al.  De novo biosynthesis of a vinblastine precursor in Pichia pastoris. , 2023, Synthetic and systems biotechnology.

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

[5]  L. Caputi,et al.  Engineering the Biosynthesis of Late-Stage Vinblastine Precursors Precondylocarpine Acetate, Catharanthine, Tabersonine in Nicotiana benthamiana , 2022, ACS synthetic biology.

[6]  Jian-Ping Huang,et al.  Bioproduction of monoterpene indole alkaloids in a single cell factory , 2022, Engineering Microbiology.

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

[8]  K. Morey,et al.  Hairy roots: An untapped potential for production of plant products , 2022, Frontiers in Plant Science.

[9]  L. Caputi,et al.  Directed Biosynthesis of New to Nature Alkaloids in a Heterologous Nicotiana benthamiana Expression Host , 2022, Frontiers in Plant Science.

[10]  D. Ro,et al.  Improved protein glycosylation enabled heterologous biosynthesis of monoterpenoid indole alkaloids and their unnatural derivatives in yeast , 2022, bioRxiv.

[11]  Yi Tang,et al.  Engineered Production of Strictosidine and Analogues in Yeast. , 2022, ACS synthetic biology.

[12]  Yimeng Zuo,et al.  Synthetic Biology Toolkit for Marker-Less Integration of Multigene Pathways into Pichia pastoris via CRISPR/Cas9. , 2022, ACS synthetic biology.

[13]  J. Lian,et al.  Construction of ajmalicine and sanguinarine de novo biosynthetic pathways using stable integration sites in yeast , 2022, Biotechnology and bioengineering.

[14]  J. Lian,et al.  De Novo Biosynthesis of Vindoline and Catharanthine in Saccharomyces cerevisiae , 2022, BioDesign Research.

[15]  I. Graham,et al.  Engineering Production of a Novel Diterpene Synthase Precursor in Nicotiana benthamiana , 2021, Frontiers in Plant Science.

[16]  J. Lian,et al.  Efficient production of vindoline from tabersonine by metabolically engineered Saccharomyces cerevisiae , 2021, Communications Biology.

[17]  N. Patron,et al.  Reconstitution of monoterpene indole alkaloid biosynthesis in genome engineered Nicotiana benthamiana , 2021, Communications Biology.

[18]  N. Kulagina,et al.  Enhanced bioproduction of anticancer precursor vindoline by yeast cell factories , 2021, Microbial biotechnology.

[19]  Yongjin J. Zhou,et al.  Recombination machinery engineering facilitates metabolic engineering of the industrial yeast Pichia pastoris , 2021, Nucleic acids research.

[20]  N. Kulagina,et al.  Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories , 2021, Molecules.

[21]  A. McBride,et al.  National Survey on the Effect of Oncology Drug Shortages in Clinical Practice: A Hematology Oncology Pharmacy Association Survey , 2021, JCO oncology practice.

[22]  J. Lian,et al.  Development of synthetic biology tools to engineer Pichia pastoris as a chassis for the production of natural products , 2021, Synthetic and systems biotechnology.

[23]  Abu Montakim Tareq,et al.  Plant-Based Indole Alkaloids: A Comprehensive Overview from a Pharmacological Perspective , 2021, Molecules.

[24]  Aaron Birchfield,et al.  Metabolic engineering and synthetic biology of plant natural products – A minireview , 2020, Current Plant Biology.

[25]  Benjamin R. Lichman,et al.  The evolutionary origins of the cat attractant nepetalactone in catnip , 2020, Science Advances.

[26]  Y. Unguru,et al.  Oncology drug shortages in the USA — business as usual , 2019, Nature Reviews Clinical Oncology.

[27]  Dhruti Amin,et al.  Present status of Catharanthus roseus monoterpenoid indole alkaloids engineering in homo- and hetero-logous systems , 2019, Biotechnology Letters.

[28]  Yi Tang,et al.  Engineered mitochondrial production of monoterpenes in Saccharomyces cerevisiae. , 2019, Metabolic engineering.

[29]  Qiyao Wang,et al.  CRISPR–Cas9-mediated genomic multiloci integration in Pichia pastoris , 2019, Microbial Cell Factories.

[30]  C. Smolke,et al.  Engineering a microbial biosynthesis platform for de novo production of tropane alkaloids , 2019, Nature Communications.

[31]  V. Martin,et al.  Engineering Plant Secondary Metabolism in Microbial Systems1[OPEN] , 2019, Plant Physiology.

[32]  O. Safonova,et al.  Completion of the canonical pathway for assembly of anticancer drugs vincristine/vinblastine in Catharanthus roseus , 2018, The Plant journal : for cell and molecular biology.

[33]  Benjamin R. Lichman,et al.  Uncoupled activation and cyclization in catmint reductive terpenoid biosynthesis , 2018, Nature Chemical Biology.

[34]  Vincent Courdavault,et al.  Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle , 2018, Science.

[35]  A. Osbourn,et al.  Engineering terpenoid production through transient expression in Nicotiana benthamiana , 2018, Plant Cell Reports.

[36]  Yanran Li,et al.  Complete biosynthesis of noscapine and halogenated alkaloids in yeast , 2018, Proceedings of the National Academy of Sciences.

[37]  W. Jeong,et al.  A UPLC-ESI-Q-TOF method for rapid and reliable identification and quantification of major indole alkaloids in Catharanthus roseus. , 2018, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[38]  J. Hájíček,et al.  Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine , 2018, Proceedings of the National Academy of Sciences.

[39]  Neil K Garg,et al.  Engineering the biocatalytic selectivity of iridoid production in Saccharomyces cerevisiae. , 2017, Metabolic engineering.

[40]  U. Mortensen,et al.  Synthesis of C‐Glucosylated Octaketide Anthraquinones in Nicotiana benthamiana by Using a Multispecies‐Based Biosynthetic Pathway , 2017, Chembiochem : a European journal of chemical biology.

[41]  S. O’Connor,et al.  A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate , 2017, Nature Communications.

[42]  Anne Osbourn,et al.  A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules , 2017, Metabolic engineering.

[43]  L. Caputi,et al.  Structural investigation of heteroyohimbine alkaloid synthesis reveals active site elements that control stereoselectivity , 2016, Nature Communications.

[44]  S. O’Connor,et al.  Biocatalysts from alkaloid producing plants. , 2016, Current opinion in chemical biology.

[45]  A. Aharoni,et al.  Elucidation of the first committed step in betalain biosynthesis enables the heterologous engineering of betalain pigments in plants. , 2016, The New phytologist.

[46]  V. Martin,et al.  Engineering of a Nepetalactol-Producing Platform Strain of Saccharomyces cerevisiae for the Production of Plant Seco-Iridoids. , 2016, ACS synthetic biology.

[47]  Warren Lau,et al.  Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone , 2015, Science.

[48]  C. Smolke,et al.  Complete biosynthesis of opioids in yeast , 2015, Science.

[49]  Yang Qu,et al.  Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast , 2015, Proceedings of the National Academy of Sciences.

[50]  S. O’Connor,et al.  De novo production of the plant-derived alkaloid strictosidine in yeast , 2015, Proceedings of the National Academy of Sciences.

[51]  Lijie Cui,et al.  Co-overexpression of geraniol-10-hydroxylase and strictosidine synthase improves anti-cancer drug camptothecin accumulation in Ophiorrhiza pumila , 2015, Scientific Reports.

[52]  V. De Luca,et al.  Making iridoids/secoiridoids and monoterpenoid indole alkaloids: progress on pathway elucidation. , 2014, Current opinion in plant biology.

[53]  N. Papon,et al.  A look inside an alkaloid multisite plant: the Catharanthus logistics. , 2014, Current opinion in plant biology.

[54]  V. De Luca,et al.  7-deoxyloganetic acid synthase catalyzes a key 3 step oxidation to form 7-deoxyloganetic acid in Catharanthus roseus iridoid biosynthesis. , 2014, Phytochemistry.

[55]  H. Bouwmeester,et al.  The seco-iridoid pathway from Catharanthus roseus , 2014, Nature Communications.

[56]  V. De Luca,et al.  Virus-induced gene silencing identifies Catharanthus roseus 7-deoxyloganic acid-7-hydroxylase, a step in iridoid and monoterpene indole alkaloid biosynthesis. , 2013, The Plant journal : for cell and molecular biology.

[57]  H. Bouwmeester,et al.  Geraniol hydroxylase and hydroxygeraniol oxidase activities of the CYP76 family of cytochrome P450 enzymes and potential for engineering the early steps of the (seco)iridoid pathway. , 2013, Metabolic engineering.

[58]  F. Geu-Flores,et al.  A Pair of Tabersonine 16-Hydroxylases Initiates the Synthesis of Vindoline in an Organ-Dependent Manner in Catharanthus roseus1[C][W] , 2013, Plant Physiology.

[59]  K. Terasaka,et al.  A 7-Deoxyloganetic Acid Glucosyltransferase Contributes a Key Step in Secologanin Biosynthesis in Madagascar Periwinkle[C][W][OPEN] , 2013, Plant Cell.

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

[61]  S. O’Connor,et al.  Recent progress in the metabolic engineering of alkaloids in plant systems. , 2013, Current opinion in biotechnology.

[62]  Vincent Courdavault,et al.  An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis , 2012, Nature.

[63]  Jay D. Keasling,et al.  Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin , 2012, Proceedings of the National Academy of Sciences.

[64]  S. O’Connor,et al.  Homolog of tocopherol C methyltransferases catalyzes N methylation in anticancer alkaloid biosynthesis , 2010, Proceedings of the National Academy of Sciences.

[65]  V. Courdavault,et al.  Strictosidine activation in Apocynaceae: towards a "nuclear time bomb"? , 2010, BMC Plant Biology.

[66]  S. O’Connor,et al.  Metabolic reprogramming of periwinkle plant culture. , 2009, Nature chemical biology.

[67]  L. Szabó.  Rigorous Biogenetic Network for a Group of Indole Alkaloids Derived from Strictosidine† , 2008, Molecules.

[68]  V. De Luca,et al.  The Leaf Epidermome of Catharanthus roseus Reveals Its Biochemical Specialization[W][OA] , 2008, The Plant Cell Online.

[69]  J. Memelink,et al.  Molecular Cloning and Characterization of a Vacuolar Class III Peroxidase Involved in the Metabolism of Anticancer Alkaloids in Catharanthus roseus1[C] , 2007, Plant Physiology.

[70]  Won-Seok Kim,et al.  Application of carborundum abrasion for investigating the leaf epidermis: molecular cloning of Catharanthus roseus 16-hydroxytabersonine-16-O-methyltransferase. , 2007, The Plant journal : for cell and molecular biology.

[71]  M. Riekkola,et al.  A simplified procedure for indole alkaloid extraction from Catharanthus roseus combined with a semi-synthetic production process for vinblastine. , 2007, Molecules.

[72]  S. O’Connor,et al.  Chemistry and biology of monoterpene indole alkaloid biosynthesis. , 2006, Natural product reports.

[73]  R. Verpoorte,et al.  The Catharanthus alkaloids: pharmacognosy and biotechnology. , 2004, Current medicinal chemistry.

[74]  J. Memelink,et al.  Geraniol 10‐hydroxylase1, a cytochrome P450 enzyme involved in terpenoid indole alkaloid biosynthesis , 2001, FEBS letters.

[75]  J. Memelink,et al.  Biotransformation of tryptamine and secologanin into plant terpenoid indole alkaloids by transgenic yeast , 2001, Applied Microbiology and Biotechnology.

[76]  S. Irmler,et al.  Indole alkaloid biosynthesis in Catharanthus roseus: new enzyme activities and identification of cytochrome P450 CYP72A1 as secologanin synthase. , 2000, The Plant journal : for cell and molecular biology.

[77]  J. Memelink,et al.  Molecular Cloning and Analysis of Strictosidine β-d-Glucosidase, an Enzyme in Terpenoid Indole Alkaloid Biosynthesis in Catharanthus roseus * , 2000, The Journal of Biological Chemistry.

[78]  N. Hampp,et al.  The cDNA clone for strictosidine synthase from Rauvolfia serpentina DNA sequence determination and expression in Escherichia coli , 1988, FEBS letters.

[79]  V. Luca,et al.  Acetyl Coenzyme A: Deacetylvindoline O-Acetyltransferase, A Novel Enzyme from Catharanthus , 1985 .

[80]  H. Bouwmeester,et al.  Monoterpene biosynthesis potential of plant subcellular compartments. , 2016, The New phytologist.

[81]  J. Memelink,et al.  Characterization of the plastidial geraniol synthase from Madagascar periwinkle which initiates the monoterpenoid branch of the alkaloid pathway in internal phloem associated parenchyma. , 2013, Phytochemistry.

[82]  V. De Luca,et al.  Discovery and functional analysis of monoterpenoid indole alkaloid pathways in plants. , 2012, Methods in enzymology.

[83]  V. De Luca,et al.  Purification, characterization, and kinetic analysis of a 2-oxoglutarate-dependent dioxygenase involved in vindoline biosynthesis from Catharanthus roseus. , 1993, The Journal of biological chemistry.