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Candidate Enzymes for Saffron Crocin Biosynthesis Are Localized in Multiple Cellular Compartments

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Candidate Enzymes for Saffron Crocin Biosynthesis Are Localized in Multiple Cellular Compartments Candidate enzymes for saffron crocin biosynthesis are localized in multiple cellular compartments Item Type Article Authors Demurtas, Olivia Costantina; Frusciante, Sarah; Ferrante, Paola; Diretto, Gianfranco; Azad, Noraddin Hosseinpour; Pietrella, Marco; Aprea, Giuseppe; Taddei, Anna Rita; Romano, Elena; Mi, Jianing; Al-Babili, Salim; Frigerio, Lorenzo; Giuliano, Giovanni Citation Demurtas OC, Frusciante S, Ferrante P, Diretto G, Azad NH, et al. (2018) Candidate enzymes for saffron crocin biosynthesis are localized in multiple cellular compartments. Plant Physiology: pp.01815.2017. Available: http://dx.doi.org/10.1104/pp.17.01815. Eprint version Post-print DOI 10.1104/pp.17.01815 Publisher American Society of Plant Biologists (ASPB) Journal Plant Physiology Rights Archived with thanks to Plant Physiology Download date 28/09/2021 10:07:42 Link to Item http://hdl.handle.net/10754/628006 Plant Physiology Preview. Published on May 29, 2018, as DOI:10.1104/pp.17.01815 1 Short title: Compartmentation of saffron crocin biosynthesis 2 3 Corresponding author: Giovanni Giuliano, ENEA, Italian National Agency for New 4 Technologies, Energy and Sustainable Economic Development, Casaccia Research Centre, Via 5 Anguillarese n° 301, 00123 Rome, Italy; Phone: +390630483192, E-mail: 6 [email protected] 7 8 Candidate enzymes for saffron crocin biosynthesis are localized in multiple cellular 9 compartments 10 11 Olivia Costantina Demurtas1, Sarah Frusciante1, Paola Ferrante1, Gianfranco Diretto1, Noraddin 12 Hosseinpour Azad2, Marco Pietrella1,3, Giuseppe Aprea1, Anna Rita Taddei4, Elena Romano5, 13 Jianing Mi6, Salim Al-Babili6, Lorenzo Frigerio7, Giovanni Giuliano1* 14 15 1Italian National Agency for New Technologies, Energy and Sustainable Economic 16 Development (ENEA), Casaccia Res. Ctr., 00123, Rome, Italy 17 2Department of Medicinal plant and plant production, University of Mohaghegh Ardabili, 18 Ardabil, Iran 19 3Council for Agricultural Research and Economics (CREA), Research Center for Olive, Citrus 20 and Tree Fruit, 47121 Forlì, Italy 21 4Center of Large Equipment-section of Electron Microscopy, University of Tuscia, Largo 22 dell’Università, snc, Viterbo, Italy 23 5Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica Snc, 24 00133 Rome, Italy. 25 6King Abdullah University of Science and Technology (KAUST), Biological and 26 Environmental Sciences and Engineering Division, The Bioactives Lab, Thuwal 23955-6900, 27 Kingdom of Saudi Arabia 28 7School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom 29 30 One-sentence summary: Carotenoid cleavage dioxygenase 2 and candidate aldehyde 31 dehydrogenase and UDP-glycosyltransferase enzymes involved in saffron crocin biosynthesis 32 are localized in the chromoplast, the endoplasmic reticulum, and the cytoplasm. 33 34 Footnotes: 1 Downloaded from on June 3, 2018 - Published by www.plantphysiol.org Copyright © 2018 American Society of Plant Biologists. All rights reserved. Copyright 2018 by the American Society of Plant Biologists 35 Author contributions: O.C.D., S.F., P.F., G.D., N.H.A., A.R.T., E.R., J.M., S.A-B., and L.F. 36 produced data. O.C.D., M.P., G.A., S.A-B., L.F., and G.G. analyzed data. G.G. coordinated the 37 study. O.C.D. and G.G. wrote the manuscript. All authors reviewed the results and approved the 38 final version of the manuscript. 39 40 Funding: This work was supported by the European Union [From discovery to products: A 41 next generation pipeline for the sustainable generation of high-value plant products, FP7 42 Contract 613153], by baseline funding given to S. A-B. from King Abdullah University of 43 Science and Technology (KAUST) and benefited from the networking activities within the 44 European Cooperation in Science and Technology Action CA15136 (EUROCAROTEN). 45 46 *Corresponding author email: [email protected] 47 48 2 Downloaded from on June 3, 2018 - Published by www.plantphysiol.org Copyright © 2018 American Society of Plant Biologists. All rights reserved. 49 Abstract 50 51 Saffron is the dried stigmas of Crocus sativus and is the most expensive spice in the world. Its 52 red color is due to crocins, which are apocarotenoid glycosides that accumulate in the vacuole to 53 a level up to 10% of the stigma dry weight. Previously, we characterized the first dedicated 54 enzyme in the crocin biosynthetic pathway, carotenoid cleavage dioxygenase 2 (CsCCD2), 55 which cleaves zeaxanthin to yield crocetin dialdehyde. In this work, we identified six putative 56 aldehyde dehydrogenase (ALDH) genes expressed in C. sativus stigmas. Heterologous 57 expression in E. coli showed that only one of corresponding proteins (CsALDH3I1) was able to 58 convert crocetin dialdehyde into the crocin precursor crocetin. CsALDH3I1 carries a C-terminal 59 hydrophobic domain, similar to that of the Neurospora membrane-associated apocarotenoid 60 dehydrogenase YLO-1. We also characterized the UDP-glycosyltransferase CsUGT74AD1, 61 which converts crocetin to crocins 1 and 2’. In vitro assays revealed high specificity of 62 CsALDH3I1 for crocetin dialdehyde and long-chain apocarotenals, and of CsUGT74AD1 for 63 crocetin. Following extract fractionation, CsCCD2, CsALDH3I1, and CsUGT74AD1 were 64 found in the insoluble fraction, suggesting their association with membranes or large insoluble 65 complexes. Analysis of protein localization in both C. sativus stigmas and following transgene 66 expression in Nicotiana benthamiana leaves revealed that CsCCD2, CsALDH3I, and 67 CsUGT74AD1 were respectively localized to the plastids, the endoplasmic reticulum (ER), and 68 the cytoplasm in association with cytoskeletal-like structures. Based on these findings and 69 current literature, we propose that the ER and cytoplasm function as “transit centers” for 70 metabolites whose biosynthesis starts in the plastid and are accumulated in the vacuole. 71 72 3 Downloaded from on June 3, 2018 - Published by www.plantphysiol.org Copyright © 2018 American Society of Plant Biologists. All rights reserved. 73 Introduction 74 One gram of dried saffron is composed of the stigmas of approximately 150 Crocus sativus 75 flowers, picked by hand. This makes saffron the most expensive spice in the world, with prices 76 ranging from 2 to 10 EUR/gram. The main organoleptic properties of the stigmas are due to the 77 accumulation of three apocarotenoid classes: crocins (composed of different glucosyl- and 78 gentiobiosyl-esters of crocetin), picrocrocin, and safranal (Tarantilis et al., 1995), conferring to 79 saffron, respectively, its red color, bitter taste, and pungent aroma. Crocins make up to 10% of 80 stigma dry weight and, by virtue of their glycosylation, are water-soluble. They have 81 applications as textile colorants and histochemical stains (Bathaie et al., 2014), antioxidants 82 (Alavizadeh and Hosseinzadeh, 2014), and in the prevention of age-related macular 83 degeneration (Bisti et al., 2014). Due to their complex structure and abundance of chiral centers, 84 crocins cannot be synthesized chemically, and there is a strong industrial interest in their 85 biotechnological production. 86 87 In C. sativus stigmas, crocin biosynthesis starts with symmetric oxidative cleavage of the C7,C8 88 and C7’,C8’ double bonds in zeaxanthin, which is catalyzed by the enzyme carotenoid cleavage 89 dioxygenase 2 (CsCCD2) producing crocetin dialdehyde (Fig. 1; Frusciante et al., 2014). Like 90 many aldehydes, crocetin dialdehyde is highly reactive and is converted into the diacid crocetin 91 by yet unidentified aldehyde dehydrogenase (ALDH) enzymes. ALDHs are NAD(P)+- 92 dependent oxidoreductases that generally contribute to different processes, such as cytoplasmic 93 male sterility, plant defense, and abiotic stress response (Kirch et al., 2004). The final step of 94 crocin biosynthesis involves glycosylation of crocetin. This reaction is usually catalyzed by 95 uridine diphosphate glycosyl transferase (UGTs) that mediate the glycosylation of secondary 96 metabolites, xenobiotics, and hormones (Wang, 2009). In Gardenia jasminoides, two crocetin 97 UGTs have been characterized (Nagatoshi et al., 2012): UGT75L6 is responsible for the 98 primary glycosylation of crocetin, producing crocetin monoglucosyl and diglucosyl esters, 99 whereas UGT94E5 is responsible for the secondary glycosylation of the glucose groups, leading 100 to the formation of one or two gentiobiose groups (Fig. 1). Contrasting data have been reported 101 on crocin formation in saffron: a crocetin UGT purified from C. sativus stigmas has been shown 102 to catalyze only primary glycosylation (Cote et al., 2001) whereas a cloned UGT (UGTCs2) has 103 been reported to mediate both types of glycosylation (Moraga et al., 2004). 104 105 The crocin biosynthetic pathway encompasses multiple subcellular compartments: the initial 106 precursor, zeaxanthin, is localized in plastids whereas the final products, crocins, accumulate in 107 vacuoles (Bouvier et al., 2003; Gomez-Gomez et al., 2017), like many other plant glycosylated 4 Downloaded from on June 3, 2018 - Published by www.plantphysiol.org Copyright © 2018 American Society of Plant Biologists. All rights reserved. 108 metabolites (Martinoia et al., 2007). We have identified the carotenoid cleavage dioxygenase 109 responsible for the first dedicated step in C. sativus carotenoid biosynthesis, CsCCD2. It has 110 been shown that CsCCD2, the enzyme that catalyzes the cleavage of zeaxanthin in crocin 111 biosynthesis (Frusciante et al., 2014),
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