Exploring Uncharted Territories of Plant Specialized Metabolism in the Postgenomic Era

Literature Cited

1. 1. 

   Achnine L, Blancaflor EB, Rasmussen S, Dixon RA 2004. Colocalization of l-phenylalanine ammonia-lyase and cinnamate 4-hydroxylase for metabolic channeling in phenylpropanoid biosynthesis. Plant Cell 16:113098–109
   [Google Scholar]
2. 2. 

   Aharoni A, Giri AP, Deuerlein S, Griepink F, de Kogel W-J et al. 2003. Terpenoid metabolism in wild-type and transgenic Arabidopsis plants. Plant Cell 15:122866–84
   [Google Scholar]
3. 3. 

   Balcke GU, Bennewitz S, Bergau N, Athmer B, Henning A et al. 2017. Multi-omics of tomato glandular trichomes reveals distinct features of central carbon metabolism supporting high productivity of specialized metabolites. Plant Cell 29:5960–83
   [Google Scholar]
4. 4. 

   Baldwin IT. 1989. Mechanism of damage-induced alkaloid production in wild tobacco. J. Chem. Ecol. 15:51661–80
   [Google Scholar]
5. 5. 

   Banf M, Zhao K, Rhee SY 2019. METACLUSTER—an R package for context-specific expression analysis of metabolic gene clusters. Bioinformatics 35:173178–80
   [Google Scholar]
6. 6. 

   Ban Z, Qin H, Mitchell AJ, Liu B, Zhang F et al. 2018. Noncatalytic chalcone isomerase-fold proteins in Humulus lupulus are auxiliary components in prenylated flavonoid biosynthesis. PNAS 115:22E5223–32
   [Google Scholar]
7. 7. 

   Bassard J-E, Møller BL, Laursen T 2017. Assembly of dynamic P450-mediated metabolons—order versus chaos. Curr. Mol. Biol. Rep. 3:137–51
   [Google Scholar]
8. 8. 

   Bassard J-E, Richert L, Geerinck J, Renault H, Duval F et al. 2012. Protein-protein and protein-membrane associations in the lignin pathway. Plant Cell 24:114465–82
   [Google Scholar]
9. 9. 

   Battersby AR, Francis RJ, Ruveda EA, Staunton J 1965. Biosynthesis of chelidonine and stylopine. Chem. Commun. 5:89–91
   [Google Scholar]
10. 10. 

    Beaudoin GAW, Facchini PJ. 2014. Benzylisoquinoline alkaloid biosynthesis in opium poppy. Planta 240:119–32
    [Google Scholar]
11. 11. 

    Bohlmann J, Lins T, Martin W, Eilert U 1996. Anthranilate synthase from Ruta graveolens. Duplicated AS alpha genes encode tryptophan-sensitive and tryptophan-insensitive isoenzymes specific to amino acid and alkaloid biosynthesis. Plant Physiol 111:2507–14
    [Google Scholar]
12. 12. 

    Boiteau RM, Hoyt DW, Nicora CD, Kinmonth-Schultz HA, Ward JK, Bingol K 2018. Structure elucidation of unknown metabolites in metabolomics by combined NMR and MS/MS prediction. Metabolites 8:1E8
    [Google Scholar]
13. 13. 

    Bonawitz ND, Chapple C. 2010. The genetics of lignin biosynthesis: connecting genotype to phenotype. Annu. Rev. Genet. 44:337–63
    [Google Scholar]
14. 14. 

    Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C et al. 2009. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324:59351729–32
    [Google Scholar]
15. 15. 

    Brillouet J-M, Romieu C, Schoefs B, Solymosi K, Cheynier V et al. 2013. The tannosome is an organelle forming condensed tannins in the chlorophyllous organs of Tracheophyta. Ann. Bot 112:61003–14
    [Google Scholar]
16. 16. 

    Brillouet J-M, Verdeil J-L, Odoux E, Lartaud M, Grisoni M, Conéjéro G 2014. Phenol homeostasis is ensured in vanilla fruit by storage under solid form in a new chloroplast-derived organelle, the phenyloplast. J. Exp. Bot. 65:92427–35
    [Google Scholar]
17. 17. 

    Brown PD, Tokuhisa JG, Reichelt M, Gershenzon J 2003. Variation of glucosinolate accumulation among different organs and developmental stages of Arabidopsis thaliana. Phytochemistry 62:3471–81
    [Google Scholar]
18. 18. 

    Burbulis IE, Winkel-Shirley B. 1999. Interactions among enzymes of the Arabidopsis flavonoid biosynthetic pathway. PNAS 96:2212929–34
    [Google Scholar]
19. 19. 

    Camacho-Zaragoza JM, Hernández-Chávez G, Moreno-Avitia F, Ramírez-Iñiguez R, Martínez A et al. 2016. Engineering of a microbial coculture of Escherichia coli strains for the biosynthesis of resveratrol. Microb. Cell Fact. 15:1163
    [Google Scholar]
20. 20. 

    Camarero JA. 2017. Cyclotides, a versatile ultrastable micro-protein scaffold for biotechnological applications. Bioorg. Med. Chem. Lett. 27:235089–99
    [Google Scholar]
21. 21. 

    Camm EL, Towers GHN. 1969. Phenylalanine and tyrosine ammonia lyase activity in Sporobolomyces roseus. Phytochemistry 8:81407–13
    [Google Scholar]
22. 22. 

    Caputi L, Franke J, Farrow SC, Chung K, Payne RME et al. 2018. Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle. Science 360:63941235–39
    [Google Scholar]
23. 23. 

    Celedon JM, Yuen MMS, Chiang A, Henderson H, Reid KE, Bohlmann J 2017. Cell-type- and tissue-specific transcriptomes of the white spruce (Picea glauca) bark unmask fine-scale spatial patterns of constitutive and induced conifer defense. Plant J 92:4710–26
    [Google Scholar]
24. 24. 

    Chae L, Kim T, Nilo-Poyanco R, Rhee SY 2014. Genomic signatures of specialized metabolism in plants. Science 344:6183510–13
    [Google Scholar]
25. 25. 

    Chen WW, Freinkman E, Sabatini DM 2017. Rapid immunopurification of mitochondria for metabolite profiling and absolute quantification of matrix metabolites. Nat. Protoc. 12:102215–31
    [Google Scholar]
26. 26. 

    Chen X, Hagel JM, Chang L, Tucker JE, Shiigi SA et al. 2018. A pathogenesis-related 10 protein catalyzes the final step in thebaine biosynthesis. Nat. Chem. Biol. 14:7738–43Employs an activity-guided approach to identify thebaine synthase and demonstrates that thebaine does not form spontaneously.
    [Google Scholar]
27. 27. 

    Choi YH, van Spronsen J, Dai Y, Verberne M, Hollmann F et al. 2011. Are natural deep eutectic solvents the missing link in understanding cellular metabolism and physiology?. Plant Physiol 156:41701–5
    [Google Scholar]
28. 28. 

    Christ B, Xu C, Xu M, Li F-S, Wada N et al. 2019. Repeated evolution of cytochrome P450–mediated spiroketal steroid biosynthesis in plants. Nat. Commun. 10:13206
    [Google Scholar]
29. 29. 

    Colón AJM, Morgan JA, Dudareva N, Rhodes D 2009. Application of dynamic flux analysis in plant metabolic networks. Plant Metabolic Networks J Schwender 285–305 New York: Springer
    [Google Scholar]
30. 30. 

    Courdavault V, Papon N, Clastre M, Giglioli-Guivarc'h N, St-Pierre B, Burlat V 2014. A look inside an alkaloid multisite plant: the Catharanthus logistics. Curr. Opin. Plant Biol. 19:43–50
    [Google Scholar]
31. 31. 

    Croteau R, Karp F. 1977. Biosynthesis of monoterpenes: partial purification and characterization of 1,8-cineole synthetase from Salvia officinalis. Arch. Biochem. Biophys 179:1257–65
    [Google Scholar]
32. 32. 

    Dai Y, van Spronsen J, Witkamp G-J, Verpoorte R, Choi YH 2013. Natural deep eutectic solvents as new potential media for green technology. Anal. Chim. Acta 766:61–68
    [Google Scholar]
33. 33. 

    Dastmalchi M, Bernards MA, Dhaubhadel S 2016. Twin anchors of the soybean isoflavonoid metabolon: evidence for tethering of the complex to the endoplasmic reticulum by IFS and C4H. Plant J 85:6689–706
    [Google Scholar]
34. 34. 

    Davin LB, Wang H-B, Crowell AL, Bedgar DL, Martin DM et al. 1997. Stereoselective bimolecular phenoxy radical coupling by an auxiliary (dirigent) protein without an active center. Science 275:5298362–66
    [Google Scholar]
35. 35. 

    Deineka VI, Tret'yakov MY, Lapshova MS, Deineka LA 2014. Thiophenes of Tagetes flowers and partial purification of xanthophyll esters. Univers. J. Agric. Res. 2:3101–6
    [Google Scholar]
36. 36. 

    Dell'Agli M, Galli GV, Dal Cero E, Belluti F, Matera R et al. 2008. Potent inhibition of human phosphodiesterase-5 by icariin derivatives. J. Nat. Prod. 71:91513–17
    [Google Scholar]
37. 37. 

    DellaPenna D, Pogson BJ. 2006. Vitamin synthesis in plants: tocopherols and carotenoids. Annu. Rev. Plant Biol. 57:711–38
    [Google Scholar]
38. 38. 

    Disch A, Hemmerlin A, Bach TJ, Rohmer M 1998. Mevalonate-derived isopentenyl diphosphate is the biosynthetic precursor of ubiquinone prenyl side chain in tobacco BY-2 cells. Biochem. J. 331:Part 2615–21
    [Google Scholar]
39. 39. 

    Dong X, Gao Y, Chen W, Wang W, Gong L et al. 2015. Spatiotemporal distribution of phenolamides and the genetics of natural variation of hydroxycinnamoyl spermidine in rice. Mol. Plant 8:1111–21
    [Google Scholar]
40. 40. 

    Dührkop K, Fleischauer M, Ludwig M, Aksenov AA, Melnik AV et al. 2019. SIRIUS 4: a rapid tool for turning tandem mass spectra into metabolite structure information. Nat. Methods 16:4299–302
    [Google Scholar]
41. 41. 

    Duke MV, Paul RN, Elsohly HN, Sturtz G, Duke SO 1994. Localization of artemisinin and artemisitene in foliar tissues of glanded and glandless biotypes of Artemisia annua L. Int. J. Plant Sci. 155:3365–72
    [Google Scholar]
42. 42. 

    el-Basyouni SZ, Chen D, Ibrahim RK, Neish AC, Towers GHN 1964. The biosynthesis of hydroxybenzoic acids in higher plants. Phytochemistry 3:485–92
    [Google Scholar]
43. 43. 

    Fahn A. 1988. Secretory tissues in vascular plants. New Phytol 108:3229–57
    [Google Scholar]
44. 44. 

    Fang C, Luo J. 2019. Metabolic GWAS-based dissection of genetic bases underlying the diversity of plant metabolism. Plant J 97:191–100
    [Google Scholar]
45. 45. 

    Feric M, Vaidya N, Harmon TS, Mitrea DM, Zhu L et al. 2016. Coexisting liquid phases underlie nucleolar subcompartments. Cell 165:71686–97
    [Google Scholar]
46. 46. 

    Ferré S. 2013. Caffeine and substance use disorders. J. Caffeine Res. 3:257–58
    [Google Scholar]
47. 47. 

    Ferrer JL, Jez JM, Bowman ME, Dixon RA, Noel JP 1999. Structure of chalcone synthase and the molecular basis of plant polyketide biosynthesis. Nat. Struct. Biol. 6:8775–84
    [Google Scholar]
48. 48. 

    Field B, Osbourn AE. 2008. Metabolic diversification–independent assembly of operon-like gene clusters in different plants. Science 320:5875543–47
    [Google Scholar]
49. 49. 

    Franke J, Kim J, Hamilton JP, Zhao D, Pham GM et al. 2019. Gene discovery in Gelsemium highlights conserved gene clusters in monoterpene indole alkaloid biosynthesis. ChemBioChem 20:183–87
    [Google Scholar]
50. 50. 

    Frey M, Schullehner K, Dick R, Fiesselmann A, Gierl A 2009. Benzoxazinoid biosynthesis, a model for evolution of secondary metabolic pathways in plants. Phytochemistry 70:15/161645–51
    [Google Scholar]
51. 51. 

    Geu-Flores F, Sherden NH, Courdavault V, Burlat V, Glenn WS et al. 2012. An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis. Nature 492:7427138–42
    [Google Scholar]
52. 52. 

    Gou M, Ran X, Martin DW, Liu C-J 2018. The scaffold proteins of lignin biosynthetic cytochrome P450 enzymes. Nat. Plants 4:5299–310
    [Google Scholar]
53. 53. 

    Gran L. 1973. On the effect of a polypeptide isolated from “Kalata-Kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta Pharmacol. Toxicol. 33:5400–8
    [Google Scholar]
54. 54. 

    Guijas C, Montenegro-Burke JR, Domingo-Almenara X, Palermo A, Warth B et al. 2018. METLIN: a technology platform for identifying knowns and unknowns. Anal. Chem. 90:53156–64
    [Google Scholar]
55. 55. 

    Guirimand G, Guihur A, Poutrain P, Héricourt F, Mahroug S et al. 2011. Spatial organization of the vindoline biosynthetic pathway in Catharanthus roseus. J. Plant Physiol 168:6549–57
    [Google Scholar]
56. 56. 

    Guo Q, Yoshida Y, Major IT, Wang K, Sugimoto K et al. 2018. JAZ repressors of metabolic defense promote growth and reproductive fitness in Arabidopsis. PNAS 115:45E10768–77
    [Google Scholar]
57. 57. 

    Hahlbrock K, Scheel D. 1989. Physiology and molecular biology of phenylpropanoid metabolism. Annu. Rev. Plant Physiol. Plant Mol. Biol. 40:347–69
    [Google Scholar]
58. 58. 

    Haug K, Salek RM, Conesa P, Hastings J, de Matos P et al. 2013. MetaboLights---an open-access general-purpose repository for metabolomics studies and associated meta-data. Nucleic Acids Res 41:D781–86
    [Google Scholar]
59. 59. 

    He X, Sun Y, Zhu R-L 2013. The oil bodies of liverworts: unique and important organelles in land plants. CRC Crit. Rev. Plant Sci. 32:5293–302
    [Google Scholar]
60. 60. 

    Hennel JW, Klinowski J. 2005. Magic-angle spinning: a historical perspective. In New Techniques in Solid-State NMR, ed. J Klinowski, pp. 1--14. Berlin: Springer
    [Google Scholar]
61. 61. 

    Hodgson H, De La Peña R, Stephenson MJ, Thimmappa R, Vincent JL et al. 2019. Identification of key enzymes responsible for protolimonoid biosynthesis in plants: opening the door to azadirachtin production. PNAS 116:3417096–104
    [Google Scholar]
62. 62. 

    Holton RA, Kim HB, Somoza C, Liang F, Biediger RJ et al. 1994. First total synthesis of taxol. 2. Completion of the C and D rings. J. Am. Chem. Soc. 116:41599–600
    [Google Scholar]
63. 63. 

    Holton RA, Somoza C, Kim HB, Liang F, Biediger RJ et al. 1994. First total synthesis of taxol. 1. Functionalization of the B ring. J. Am. Chem. Soc. 116:41597–98
    [Google Scholar]
64. 64. 

    Hsieh K, Huang AHC. 2007. Tapetosomes in Brassica tapetum accumulate endoplasmic reticulum–derived flavonoids and alkanes for delivery to the pollen surface. Plant Cell 19:2582–96
    [Google Scholar]
65. 65. 

    Husebye H, Chadchawan S, Winge P, Thangstad OP, Bones AM 2002. Guard cell– and phloem idioblast–specific expression of thioglucoside glucohydrolase 1 (myrosinase) in Arabidopsis. Plant Physiol 128:41180–88
    [Google Scholar]
66. 66. 

    Hyde CC, Padlan EA, Ahmed SA, Miles EW, Davies DR 1987. Three-dimensional structure of the tryptophan synthase α₂β₂ multienzyme complex from Salmonella typhimurium. J. Biol. Chem 263:3317857–71
    [Google Scholar]
67. 67. 

    Hyman AA, Weber CA, Jülicher F 2014. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30:39–58
    [Google Scholar]
68. 68. 

    Inokuma Y, Yoshioka S, Ariyoshi J, Arai T, Hitora Y et al. 2013. X-ray analysis on the nanogram to microgram scale using porous complexes. Nature 495:7442461–66Introduces the crystalline sponge method, which utilizes a porous metal-organic framework to facilitate small-molecule x-ray crystallography.
    [Google Scholar]
69. 69. 

    Irmer S, Podzun N, Langel D, Heidemann F, Kaltenegger E et al. 2015. New aspect of plant-rhizobia interaction: Alkaloid biosynthesis in Crotalaria depends on nodulation. PNAS 112:134164–69
    [Google Scholar]
70. 70. 

    James WO. 1946. Biosynthesis of the belladonna alkaloids. Nature 159:196–97
    [Google Scholar]
71. 71. 

    Jeon JE, Kim J-G, Fischer CR, Mehta N, Dufour-Schroif C et al. 2020. A pathogen-responsive gene cluster for highly modified fatty acids in tomato. Cell 180:1176–87
    [Google Scholar]
72. 72. 

    Jin M, Fuller GG, Han T, Yao Y, Alessi AF et al. 2017. Glycolytic enzymes coalesce in G bodies under hypoxic stress. Cell Rep 20:4895–908
    [Google Scholar]
73. 73. 

    Jones CG, Martynowycz MW, Hattne J, Fulton TJ, Stoltz BM et al. 2018. The cryoEM method microED as a powerful tool for small molecule structure determination. ACS Cent. Sci. 4:111587–92
    [Google Scholar]
74. 74. 

    Jørgensen K, Bak S, Busk PK, Sørensen C, Olsen CE et al. 2005. Cassava plants with a depleted cyanogenic glucoside content in leaves and tubers. Distribution of cyanogenic glucosides, their site of synthesis and transport, and blockage of the biosynthesis by RNA interference technology. Plant Physiol 139:1363–74
    [Google Scholar]
75. 75. 

    Jørgensen K, Rasmussen AV, Morant M, Nielsen AH, Bjarnholt N et al. 2005. Metabolon formation and metabolic channeling in the biosynthesis of plant natural products. Curr. Opin. Plant Biol. 8:3280–91
    [Google Scholar]
76. 76. 

    Kappers IF, Aharoni A, van Herpen TWJM, Luckerhoff LLP, Dicke M, Bouwmeester HJ 2005. Genetic engineering of terpenoid metabolism attracts bodyguards to Arabidopsis. Science 309:57432070–72
    [Google Scholar]
77. 77. 

    Kautsar SA, Suarez Duran HG, Blin K, Osbourn A, Medema MH 2017. plantiSMASH: automated identification, annotation and expression analysis of plant biosynthetic gene clusters. Nucleic Acids Res 45:W155–63
    [Google Scholar]
78. 78. 

    Kenrick P, Crane PR. 1997. The origin and early evolution of plants on land. Nature 389:33–39
    [Google Scholar]
79. 79. 

    Kersten RD, Lee S, Fujita D, Pluskal T, Kram S et al. 2017. A red algal bourbonane sesquiterpene synthase defined by microgram-scale NMR-coupled crystalline sponge X-ray diffraction analysis. J. Am. Chem. Soc. 139:4616838–44
    [Google Scholar]
80. 80. 

    Kersten RD, Weng J-K. 2018. Gene-guided discovery and engineering of branched cyclic peptides in plants. PNAS 115:46E10961–69Describes a genome-mining-based approach to identify novel lyciumin peptides in numerous plant lineages.
    [Google Scholar]
81. 81. 

    Keun HC, Beckonert O, Griffin JL, Richter C, Moskau D et al. 2002. Cryogenic probe ¹³C NMR spectroscopy of urine for metabonomic studies. Anal. Chem. 74:4588–93
    [Google Scholar]
82. 82. 

    Keymer A, Pimprikar P, Wewer V, Huber C, Brands M et al. 2017. Lipid transfer from plants to arbuscular mycorrhiza fungi. eLife 6:e29107
    [Google Scholar]
83. 83. 

    King AJ, Brown GD, Gilday AD, Larson TR, Graham IA 2014. Production of bioactive diterpenoids in the Euphorbiaceae depends on evolutionarily conserved gene clusters. Plant Cell 26:83286–98
    [Google Scholar]
84. 84. 

    Kita T, Imai S, Sawada H, Kumagai H, Seto H 2008. The biosynthetic pathway of curcuminoid in turmeric (Curcuma longa) as revealed by ¹³C-labeled precursors. Biosci. Biotechnol. Biochem. 72:71789–98
    [Google Scholar]
85. 85. 

    Koehbach J, Attah AF, Berger A, Hellinger R, Kutchan TM et al. 2013. Cyclotide discovery in Gentianales revisited—identification and characterization of cyclic cystine-knot peptides and their phylogenetic distribution in Rubiaceae plants. Pept. Sci. 100:5438–52
    [Google Scholar]
86. 86. 

    Köksal M, Jin Y, Coates RM, Croteau R, Christianson DW 2010. Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis. Nature 469:116–20
    [Google Scholar]
87. 87. 

    Kreuzaler F, Hahlbrock K. 1975. Enzymic synthesis of an aromatic ring from acetate units: partial purification and some properties of flavanone synthase from cell-suspension cultures of Petroselinum hortense. Eur. J. Biochem 56:1205–13
    [Google Scholar]
88. 88. 

    Kroll K, Holland CK, Starks CM, Jez JM 2017. Evolution of allosteric regulation in chorismate mutases from early plants. Biochem. J. 474:223705–17
    [Google Scholar]
89. 89. 

    Kusari S, Lamshöft M, Kusari P, Gottfried S, Zühlke S et al. 2014. Endophytes are hidden producers of maytansine in Putterlickia roots. J. Nat. Prod. 77:122577–84
    [Google Scholar]
90. 90. 

    Lallemand B, Erhardt M, Heitz T, Legrand M 2013. Sporopollenin biosynthetic enzymes interact and constitute a metabolon localized to the endoplasmic reticulum of tapetum cells. Plant Physiol 162:2616–25
    [Google Scholar]
91. 91. 

    Lange BM, Fischedick JT, Lange MF, Srividya N, Šamec D, Poirier BC 2017. Integrative approaches for the identification and localization of specialized metabolites in Tripterygium roots. Plant Physiol 173:1456–69
    [Google Scholar]
92. 92. 

    Laursen T, Borch J, Knudsen C, Bavishi K, Torta F et al. 2016. Characterization of a dynamic metabolon producing the defense compound dhurrin in sorghum. Science 354:6314890–93Utilizes styrene maleic acid polymer to isolate and characterize the dhurrin metabolon from sorghum.
    [Google Scholar]
93. 93. 

    Lau W, Sattely ES. 2015. Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone. Science 349:62531224–28
    [Google Scholar]
94. 94. 

    Lee SC, Knowles TJ, Postis VLG, Jamshad M, Parslow RA et al. 2016. A method for detergent-free isolation of membrane proteins in their local lipid environment. Nat. Protoc. 11:71149–62
    [Google Scholar]
95. 95. 

    Li B, Bhandari DR, Janfelt C, Römpp A, Spengler B 2014. Natural products in Glycyrrhiza glabra (licorice) rhizome imaged at the cellular level by atmospheric pressure matrix-assisted laser desorption/ionization tandem mass spectrometry imaging. Plant J 80:1161–71
    [Google Scholar]
96. 96. 

    Li F-S, Phyo P, Jacobowitz J, Hong M, Weng J-K 2019. The molecular structure of plant sporopollenin. Nat. Plants 5:141–46
    [Google Scholar]
97. 97. 

    Li F-S, Weng J-K. 2017. Demystifying traditional herbal medicine with modern approach. Nat. Plants 3:17109
    [Google Scholar]
98. 98. 

    Li H, Ban Z, Qin H, Ma L, King AJ, Wang G 2015. A heteromeric membrane-bound prenyltransferase complex from hop catalyzes three sequential aromatic prenylations in the bitter acid pathway. Plant Physiol 167:3650–59
    [Google Scholar]
99. 99. 

    Li J, Schuman MC, Halitschke R, Li X, Guo H et al. 2018. The decoration of specialized metabolites influences stylar development. eLife 7:e38611
    [Google Scholar]
100. 100. 

     Li M, Kildegaard KR, Chen Y, Rodriguez A, Borodina I, Nielsen J 2015. De novo production of resveratrol from glucose or ethanol by engineered Saccharomyces cerevisiae. Metab. Eng 32:1–11
     [Google Scholar]
101. 101. 

     Li-Beisson Y, Shorrosh B, Beisson F, Andersson MX, Arondel V et al. 2010. Acyl-lipid metabolism. Arabidopsis Book 8:e0133
     [Google Scholar]
102. 102. 

     Lin X, Hezari M, Koepp AE, Floss HG, Croteau R 1996. Mechanism of taxadiene synthase, a diterpene cyclase that catalyzes the first step of taxol biosynthesis in Pacific yew. Biochemistry 35:92968–77
     [Google Scholar]
103. 103. 

     Lorenzo Tejedor M, Mizuno H, Tsuyama N, Harada T, Masujima T 2012. In situ molecular analysis of plant tissues by live single-cell mass spectrometry. Anal. Chem. 84:125221–28
     [Google Scholar]
104. 104. 

     Luo X, Reiter MA, d'Espaux L, Wong J, Denby CM et al. 2019. Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. Nature 567:7746123–26
     [Google Scholar]
105. 105. 

     Lu R, Martin-Hernandez AM, Peart JR, Malcuit I, Baulcombe DC 2003. Virus-induced gene silencing in plants. Methods 30:4296–303
     [Google Scholar]
106. 106. 

     Lu Y, Stegemann S, Agrawal S, Karcher D, Ruf S, Bock R 2017. Horizontal transfer of a synthetic metabolic pathway between plant species. Curr. Biol. 27:193034–41.e3
     [Google Scholar]
107. 107. 

     Matsuda Y, Mitsuhashi T, Lee S, Hoshino M, Mori T et al. 2016. Astellifadiene: structure determination by NMR spectroscopy and crystalline sponge method, and elucidation of its biosynthesis. Angew. Chem. Int. Ed. Engl. 55:195785–88
     [Google Scholar]
108. 108. 

     Mayor S. 2011. Tree that provides paclitaxel is put on list of endangered species. BMJ 343:d7411
     [Google Scholar]
109. 109. 

     Mizuno H, Tsuyama N, Harada T, Masujima T 2008. Live single-cell video mass spectrometry for cellular and subcellular molecular detection and cell classification. J. Mass Spectrom. 43:121692–700
     [Google Scholar]
110. 110. 

     Moore BM, Wang P, Fan P, Leong B, Schenck CA et al. 2019. Robust predictions of specialized metabolism genes through machine learning. PNAS 116:62344–53
     [Google Scholar]
111. 111. 

     Newman DJ, Cragg GM, Snader KM 2000. The influence of natural products upon drug discovery (antiquity to late 1999). Nat. Prod. Rep. 17:215–234
     [Google Scholar]
112. 112. 

     Nguyen KNT, Nguyen GKT, Nguyen PQT, Ang KH, Dedon PC, Tam JP 2016. Immunostimulating and Gram-negative-specific antibacterial cyclotides from the butterfly pea (Clitoria ternatea). FEBS J 283:112067–90
     [Google Scholar]
113. 113. 

     Nicolaou KC, Yang Z, Liu JJ, Ueno H, Nantermet PG et al. 1994. Total synthesis of taxol. Nature 367:6464630–34
     [Google Scholar]
114. 114. 

     Ning J, Moghe GD, Leong B, Kim J, Ofner I et al. 2015. A feedback-insensitive isopropylmalate synthase affects acylsugar composition in cultivated and wild tomato. Plant Physiol 169:31821–35
     [Google Scholar]
115. 115. 

     Nintemann SJ, Hunziker P, Andersen TG, Schulz A, Burow M, Halkier BA 2018. Localization of the glucosinolate biosynthetic enzymes reveals distinct spatial patterns for the biosynthesis of indole and aliphatic glucosinolates. Physiol. Plant 163:2138–54
     [Google Scholar]
116. 116. 

     Nour-Eldin HH, Andersen TG, Burow M, Madsen SR, Jørgensen ME et al. 2012. NRT/PTR transporters are essential for translocation of glucosinolate defence compounds to seeds. Nature 488:7412531–34
     [Google Scholar]
117. 117. 

     O'Connor SE. 2015. Engineering of secondary metabolism. Annu. Rev. Genet. 49:71–94
     [Google Scholar]
118. 118. 

     Olsson V, Joos L, Zhu S, Gevaert K, Butenko MA, De Smet I 2019. Look closely, the beautiful may be small: precursor-derived peptides in plants. Annu. Rev. Plant Biol. 70:153–86
     [Google Scholar]
119. 119. 

     Onoyovwe A, Hagel JM, Chen X, Khan MF, Schriemer DC, Facchini PJ 2013. Morphine biosynthesis in opium poppy involves two cell types: sieve elements and laticifers. Plant Cell 25:104110–22Uses an immunolabeling approach to resolve ambiguities regarding the localization of morphine biosynthesis across multiple cell types.
     [Google Scholar]
120. 120. 

     Ott A, Schnable JC, Yeh C-T, Wu L, Liu C et al. 2018. Linked read technology for assembling large complex and polyploid genomes. BMC Genom 19:1651
     [Google Scholar]
121. 121. 

     Pan Q, Mustafa NR, Tang K, Choi YH, Verpoorte R 2016. Monoterpenoid indole alkaloids biosynthesis and its regulation in Catharanthus roseus: a literature review from genes to metabolites. Phytochem. Rev. 15:221–50
     [Google Scholar]
122. 122. 

     Pateraki I, Andersen-Ranberg J, Hamberger B, Heskes AM, Martens HJ et al. 2014. Manoyl oxide (13R), the biosynthetic precursor of forskolin, is synthesized in specialized root cork cells in Coleus forskohlii. Plant Physiol 164:31222–36
     [Google Scholar]
123. 123. 

     Phillipson JD. 2001. Phytochemistry and medicinal plants. Phytochemistry 56:3237–43
     [Google Scholar]
124. 124. 

     Pluskal T, Torrens-Spence MP, Fallon TR, De Abreu A, Shi CH, Weng J-K 2019. The biosynthetic origin of psychoactive kavalactones in kava. Nat. Plants 5:8867–78
     [Google Scholar]
125. 125. 

     Plys AJ, Kingston RE. 2018. Dynamic condensates activate transcription. Science 361:6400329–30
     [Google Scholar]
126. 126. 

     Porto WF, Miranda VJ, Pinto MFS, Dohms SM, Franco OL 2016. High-performance computational analysis and peptide screening from databases of cyclotides from Poaceae. Biopolymers 106:1109–18
     [Google Scholar]
127. 127. 

     Qu Y, Safonova O, De Luca V 2019. Completion of the canonical pathway for assembly of anticancer drugs vincristine/vinblastine in Catharanthus roseus. Plant J 97:2257–66
     [Google Scholar]
128. 128. 

     Quinn CM, Wang M, Polenova T 2018. NMR of macromolecular assemblies and machines at 1 GHz and beyond: new transformative opportunities for molecular structural biology. Methods Mol. Biol. 1688:1–35
     [Google Scholar]
129. 129. 

     Rahman A, Hallgrímsdóttir I, Eisen M, Pachter L 2018. Association mapping from sequencing reads using k-mers. eLife 7:e32920
     [Google Scholar]
130. 130. 

     Rajniak J, Barco B, Clay NK, Sattely ES 2015. A new cyanogenic metabolite in Arabidopsis required for inducible pathogen defence. Nature 525:7569376–79
     [Google Scholar]
131. 131. 

     Ralph J, Bunzel M, Marita JM, Hatfield RD, Lu F et al. 2004. Peroxidase-dependent cross-linking reactions of p-hydroxycinnamates in plant cell walls. Phytochem. Rev. 3:179–96
     [Google Scholar]
132. 132. 

     Recktenwald J, Shawky R, Puk O, Pfennig F, Keller U et al. 2002. Nonribosomal biosynthesis of vancomycin-type antibiotics: a heptapeptide backbone and eight peptide synthetase modules. Microbiology 148:Part 41105–18
     [Google Scholar]
133. 133. 

     Reed J, Stephenson MJ, Miettinen K, Brouwer B, Leveau A et al. 2017. A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. Metab. Eng. 42:185–93
     [Google Scholar]
134. 134. 

     Rehm FBH, Jackson MA, De Geyter E, Yap K, Gilding EK et al. 2019. Papain-like cysteine proteases prepare plant cyclic peptide precursors for cyclization. PNAS 116:167831–36
     [Google Scholar]
135. 135. 

     Rhoads A, Au KF. 2015. PacBio sequencing and its applications. Genom. Proteom. Bioinform. 13:5278–89
     [Google Scholar]
136. 136. 

     Riback JA, Katanski CD, Kear-Scott JL, Pilipenko EV, Rojek AE et al. 2017. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168:61028–40.e19
     [Google Scholar]
137. 137. 

     Ro D-K, Paradise EM, Ouellet M, Fisher KJ, Newman KL et al. 2006. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:7086940–43
     [Google Scholar]
138. 138. 

     Rodriguez E, Aregullin M, Nishida T, Uehara S, Wrangham R et al. 1985. Thiarubrine A, a bioactive constituent of Aspilia (Asteraceae) consumed by wild chimpanzees. Experientia 41:3419–20
     [Google Scholar]
139. 139. 

     Rohmer M. 1999. The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat. Prod. Rep. 16:5565–74
     [Google Scholar]
140. 140. 

     Saether O, Craik DJ, Campbell ID, Sletten K, Juul J, Norman DG 1995. Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry 34:134147–58
     [Google Scholar]
141. 141. 

     Sainsbury F, Thuenemann EC, Lomonossoff GP 2009. pEAQ: versatile expression vectors for easy and quick transient expression of heterologous proteins in plants. Plant Biotechnol. J. 7:7682–93
     [Google Scholar]
142. 142. 

     Salim V, Yu F, Altarejos J, De Luca V 2013. Virus-induced gene silencing identifies Catharanthus roseus 7-deoxyloganic acid–7-hydroxylase, a step in iridoid and monoterpene indole alkaloid biosynthesis. Plant J 76:5754–65
     [Google Scholar]
143. 143. 

     Samanani N, Alcantara J, Bourgault R 2006. The role of phloem sieve elements and laticifers in the biosynthesis and accumulation of alkaloids in opium poppy. Plant J 47:4547–63
     [Google Scholar]
144. 144. 

     Sapir-Mir M, Mett A, Belausov E, Tal-Meshulam S, Frydman A et al. 2008. Peroxisomal localization of Arabidopsis isopentenyl diphosphate isomerases suggests that part of the plant isoprenoid mevalonic acid pathway is compartmentalized to peroxisomes. Plant Physiol 148:31219–28
     [Google Scholar]
145. 145. 

     Schenck CA, Chen S, Siehl DL, Maeda HA 2015. Non-plastidic, tyrosine-insensitive prephenate dehydrogenases from legumes. Nat. Chem. Biol. 11:152–57Describes a secondary, cytosolic pathway for the biosynthesis of prephenate, which likely enables the diversification of tyrosine-derived specialized metabolites.
     [Google Scholar]
146. 146. 

     Schläpfer P, Zhang P, Wang C, Kim T, Banf M et al. 2017. Genome-wide prediction of metabolic enzymes, pathways, and gene clusters in plants. Plant Physiol 173:42041–59
     [Google Scholar]
147. 147. 

     Shin Y, Brangwynne CP. 2017. Liquid phase condensation in cell physiology and disease. Science 357:6357eaaf4382
     [Google Scholar]
148. 148. 

     Shirley AM, McMichael CM, Chapple C 2001. The sng2 mutant of Arabidopsis is defective in the gene encoding the serine carboxypeptidase-like protein sinapoylglucose:choline sinapoyltransferase. Plant J 28:183–94
     [Google Scholar]
149. 149. 

     Shulse CN, Cole BJ, Ciobanu D, Lin J, Yoshinaga Y et al. 2019. High-throughput single-cell transcriptome profiling of plant cell types. Cell Rep 27:72241–47.e4Describes one of the first applications of single-cell RNA-seq in plants.
     [Google Scholar]
150. 150. 

     Singatulina AS, Hamon L, Sukhanova MV, Desforges B, Joshi V et al. 2019. PARP-1 activation directs FUS to DNA damage sites to form PARG-reversible compartments enriched in damaged DNA. Cell Rep 27:61809–21.e5
     [Google Scholar]
151. 151. 

     Sønderby IE, Geu-Flores F, Halkier BA 2010. Biosynthesis of glucosinolates—gene discovery and beyond. Trends Plant Sci 15:5283–90
     [Google Scholar]
152. 152. 

     Srinivasan P, Smolke CD. 2019. Engineering a microbial biosynthesis platform for de novo production of tropane alkaloids. Nat. Commun. 10:3634
     [Google Scholar]
153. 153. 

     Stegemann S, Bock R. 2009. Exchange of genetic material between cells in plant tissue grafts. Science 324:5927649–51
     [Google Scholar]
154. 154. 

     Strauch RC, Svedin E, Dilkes B, Chapple C, Li X 2015. Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana. PNAS 112:3711726–31
     [Google Scholar]
155. 155. 

     Suzuki M, Xiang T, Ohyama K, Seki H, Saito K et al. 2006. Lanosterol synthase in dicotyledonous plants. Plant Cell Physiol 47:5565–71
     [Google Scholar]
156. 156. 

     Takahashi K, Kozuka T, Anegawa A, Nagatani A, Mimura T 2015. Development and application of a high-resolution imaging mass spectrometer for the study of plant tissues. Plant Cell Physiol 56:71329–38
     [Google Scholar]
157. 157. 

     Tholl D, Lee S. 2011. Terpene specialized metabolism in Arabidopsis thaliana. Arabidopsis Book 9:e0143
     [Google Scholar]
158. 158. 

     Tivendale ND, Davidson SE, Davies NW, Smith JA, Dalmais M et al. 2012. Biosynthesis of the halogenated auxin, 4-chloroindole-3-acetic acid. Plant Physiol 159:31055–63
     [Google Scholar]
159. 159. 

     Tohge T, de Souza LP, Fernie AR 2017. Current understanding of the pathways of flavonoid biosynthesis in model and crop plants. J. Exp. Bot. 68:154013–28
     [Google Scholar]
160. 160. 

     Tomita M, Okamoto Y, Kikuchi T, Osaki K, Nishikawa M et al. 1971. Studies on the alkaloids of menispermaceous plants. CCLIX. Alkaloids of Menispermum dauricum DC. (Suppl. 7). Structures of acutumine and acutumidine, chlorine-containing alkaloids with a novel skeleton. Chem. Pharm. Bull. 19:4770–91
     [Google Scholar]
161. 161. 

     Töpfer N, Fuchs L-M, Aharoni A 2017. The PhytoClust tool for metabolic gene clusters discovery in plant genomes. Nucleic Acids Res 45:127049–63
     [Google Scholar]
162. 162. 

     Torrens-Spence MP, Fallon TR, Weng JK 2016. A workflow for studying specialized metabolism in nonmodel eukaryotic organisms. Methods Enzymol 576:69–97
     [Google Scholar]
163. 163. 

     Torrens-Spence MP, Liu P, Ding H, Harich K, Gillaspy G, Li J 2013. Biochemical evaluation of the decarboxylation and decarboxylation-deamination activities of plant aromatic amino acid decarboxylases. J. Biol. Chem. 288:42376–87
     [Google Scholar]
164. 164. 

     Torrens-Spence MP, Pluskal T, Li F-S, Carballo V, Weng J-K 2018. Complete pathway elucidation and heterologous reconstitution of Rhodiola salidroside biosynthesis. Mol. Plant. 11:1205–17
     [Google Scholar]
165. 165. 

     Tu Y. 2016. Nobel lecture: Artemisinin—a gift from traditional Chinese medicine to the world. Angew. Chem. Int. Ed. Engl. 55:3510210–26
     [Google Scholar]
166. 166. 

     Tzin V, Malitsky S, Zvi MMB, Bedair M, Sumner L et al. 2012. Expression of a bacterial feedback-insensitive 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase of the shikimate pathway in Arabidopsis elucidates potential metabolic bottlenecks between primary and secondary metabolism. New Phytol 194:2430–39
     [Google Scholar]
167. 167. 

     Vanholme R, Sundin L, Seetso KC, Kim H, Liu X et al. 2019. COSY catalyses trans–cis isomerization and lactonization in the biosynthesis of coumarins. Nat. Plants 5:101066–75
     [Google Scholar]
168. 168. 

     Wall ME, Wani MC. 1995. 13th Bruce F. Cain Memorial Award Lecture: Camptothecin and taxol: discovery to clinic. Cancer Res 55:4753–60
     [Google Scholar]
169. 169. 

     Wang C, Liwei M, Park J-B, Jeong S-H, Wei G et al. 2018. Microbial platform for terpenoid production: Escherichia coli and yeast. Front. Microbiol. 9:2460
     [Google Scholar]
170. 170. 

     Wang M, Carver JJ, Phelan VV, Sanchez LM, Garg N et al. 2016. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat. Biotechnol. 34:8828–37
     [Google Scholar]
171. 171. 

     Wang P, Guo L, Jaini R, Klempien A, McCoy RM et al. 2018. A ¹³C isotope labeling method for the measurement of lignin metabolic flux in Arabidopsis stems. Plant Methods 14:51
     [Google Scholar]
172. 172. 

     Wang T, Park YB, Caporini MA, Rosay M, Zhong L et al. 2013. Sensitivity-enhanced solid-state NMR detection of expansin's target in plant cell walls. PNAS 110:4116444–49
     [Google Scholar]
173. 173. 

     Weidmann J, Craik DJ. 2016. Discovery, structure, function, and applications of cyclotides: circular proteins from plants. J. Exp. Bot. 67:164801–12
     [Google Scholar]
174. 174. 

     Weng J-K. 2014. The evolutionary paths towards complexity: a metabolic perspective. New Phytol 201:41141–49
     [Google Scholar]
175. 175. 

     Williams MC, Molyneux RJ. 1987. Occurrence, concentration, and toxicity of pyrrolizidine alkaloids in Crotalaria seeds. Weed Sci 35:4476–81
     [Google Scholar]
176. 176. 

     Wink M. 2013. Evolution of secondary metabolites in legumes (Fabaceae). S. Afr. J. Bot. 89:164–75
     [Google Scholar]
177. 177. 

     Wu S, Schalk M, Clark A, Miles RB, Coates R, Chappell J 2006. Redirection of cytosolic or plastidic isoprenoid precursors elevates terpene production in plants. Nat. Biotechnol. 24:111441–47
     [Google Scholar]
178. 178. 

     Xu M, Wilderman PR, Peters RJ 2007. Following evolution's lead to a single residue switch for diterpene synthase product outcome. PNAS 104:187397–401
     [Google Scholar]
179. 179. 

     Xu R, Fazio GC, Matsuda SPT 2004. On the origins of triterpenoid skeletal diversity. Phytochemistry 65:3261–91
     [Google Scholar]
180. 180. 

     Yahara S, Shigeyama C, Nohara T, Okuda H, Wakamatsu K, Yasuhara T 1989. Structures of anti-ace and -renin peptides from Lycii radicis cortex. Tetrahedron Lett 30:446041–42
     [Google Scholar]
181. 181. 

     Yamamoto K, Takahashi K, Mizuno H, Anegawa A, Ishizaki K et al. 2016. Cell-specific localization of alkaloids in Catharanthus roseus stem tissue measured with imaging MS and single-cell MS. PNAS 113:143891–96
     [Google Scholar]
182. 182. 

     Yanofsky C, Rachmeler M. 1958. The exclusion of free indole as an intermediate in the biosynthesis of tryptophan in Neurospora crassa. Biochim. Biophys. Acta 28:3640–41
     [Google Scholar]
183. 183. 

     Yonekura-Sakakibara K, Tanaka Y, Fukuchi-Mizutani M, Fujiwara H, Fukui Y et al. 2000. Molecular and biochemical characterization of a novel hydroxycinnamoyl-CoA: anthocyanin 3-O-glucoside-6″-O-acyltransferase from Perilla frutescens. Plant Cell Physiol 41:4495–502
     [Google Scholar]
184. 184. 

     Yu BW, Meng LH, Chen JY, Zhou TX, Cheng KF et al. 2001. Cytotoxic oxoisoaporphine alkaloids from Menispermum dauricum. J. Nat. Prod 64:7968–70
     [Google Scholar]
185. 185. 

     Zhang W, Liu H, Li X, Liu D, Dong X-T et al. 2017. Production of naringenin from d-xylose with co-culture of E. coli and S. cerevisiae. Eng. Life Sci 17:91021–29
     [Google Scholar]
186. 186. 

     Zhao EM, Suek N, Wilson MZ, Dine E, Pannucci NL et al. 2019. Light-based control of metabolic flux through assembly of synthetic organelles. Nat. Chem. Biol. 15:6589–97Introduces light-switchable phase separation of metabolic pathways, highlighting the utility of biological condensates in bioengineering.
     [Google Scholar]