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2.A.123 The Sweet; PQ-loop; Saliva; MtN3 (Sweet) Family

The eukaryotic proteins of the SWEET family are found in plants, animals, protozoans, bacteria, etc. They have 7 TMSs in a 3+1+3 repeat arrangement. These proteins appear to catalyze facilitated diffusion (entry or export) of sugars across the plant plasma membrane or the endoplasmic reticulum membrane (Takanaga and Frommer, 2010). Plant sweets fall into four subclades (Chen et al., 2010).  The tomato genome encodes 29 SWEETs. Feng et al. 2015 analyzed the structures, conserved domains, and phylogenetic relationships of these proteins, and also analyzed the transcript levels of SWEET genes in various tissues, organs, and developmental stages in response to exogenous sugar and adverse environmental stress (e.g., high and low temperatures). The phylogeny of SWEETS has been described (Jia et al. 2017). A database (dbSWEET) of SWEET homologues is freely available to the scientific community at (Gupta and Sankararamakrishnan 2018). SWEETs perform diverse physiological functions in plants such as pollen nutrition, nectar secretion, seed filling, phloem loading, and pathogen nutrition (Jeena et al. 2019). Various SWEETS transport various sugars such as sucrose, fructose, glucose, galactose, and mannose (Hu et al. 2019). SWEETS play important roles in sugar efflux, pollen nutrition, nectar secretion, phloem transport, and seed development (Cao et al. 2019). Identification and expression analysis of the SWEET gene family from Poa pratensis under abiotic Stresses has been published (Zhang et al. 2020). The role of SWEET proteins in fruit development and abiotic stress in pomegranate (Punica granatum) has been reviewed (Kumawat et al. 2022). Garlic (Allium sativum L.) has 27 genes encoding clade I-IV SWEET proteins. The promoters of these genes contained hormone- and stress-sensitive elements associated with plant response to phytopathogens (Filyushin et al. 2023). The HuSWEET Family in Pitaya (Hylocereus undatus) has been identified, and key roles of HuSWEET12a and HuSWEET13d in sugar accumulation have been established (Jiang et al. 2023).  Genome-wide identification and expression analysis of the SWEET gene family in annual alfalfa (Medicago polymorpha) has been achieved (Liu et al. 2023).

On average, angiosperm genomes contain approximately 20 SWEET paralogs, most of which serve distinct physiological roles. In Arabidopsis, AtSWEET8 and 13 feed the pollen; SWEET 11 and 12 provide sucrose to MFS-type sucrose transporters for phloem loading; AtSWEET11, 12 and 15 have distinct roles in seed filling; AtSWEET16 and 17 are vacuolar hexose transporters; and SWEET9 is essential for nectar secretion (Eom et al. 2015). The remaining family members await characterization, and could play roles in the gametophyte and elsewhere in the plant. In rice and cassava, and possibly other systems, sucrose transporting SWEETs play central roles in pathogen resistance. Plant sweets participate in diverse physiological processes, including pathogen nutrition, seed filling, nectar secretion, and phloem loading. There are 28 SWEET genes in tea (Camellia sinensis), and several members from the CsSWEET gene family have been localized and characterized (Jiang et al. 2021). Members of this family have been reported to have the MtN3 fold (Ferrada and Superti-Furga 2022). AtSWEET11 and AtSWEET12 transporters function in tandem to modulate sugar flux in plants (Fatima et al. 2023). SWEET proteins are involved in sugar efflux, phloem loading, reproductive development, plant senescence, and stress responses. There are 23 SWEET transporter encoded within the Medicago polymorpha (alfalfa) genome (Liu et al. 2023), and the transcriptional regulation of several have been determined.

Sugar efflux transporters are essential for the maintenance of animal blood glucose levels, plant nectar production, and plant seed and pollen development. Chen et al. (2010) reviewed evidence for a new class of sugar transporters, named SWEETs. At least six out of seventeen Arabidopsis, two out of over twenty rice and two out of seven homologues in Caenorhabditis elegans, and the single copy human protein, mediate glucose transport. Arabidopsis SWEET8 is essential for pollen viability, and the rice homologues SWEET11 and SWEET14 are specifically exploited by bacterial pathogens for virulence by means of direct binding of a bacterial effector to the SWEET promoter. Bacterial symbionts and fungal and bacterial pathogens induce the expression of different SWEET genes, indicating that the sugar efflux function of SWEET transporters is targeted by pathogens and symbionts for nutritional gain. The metazoan homologues may be involved in sugar efflux from intestinal, liver, epididymis and mammary cells.

Plants transport fixed carbon predominantly as sucrose, which is produced in mesophyll cells and imported into phloem cells for translocation throughout the plant. It had not been known how sucrose migrates from sites of synthesis in the mesophyll to the phloem, or which cells mediate efflux into the apoplasm as a prerequisite for phloem loading by the SUT sucrose-H+ (proton) cotransporters. Using optical sucrose sensors, Chen et al. (2012) identified a subfamily of SWEET sucrose efflux transporters. AtSWEET11 and 12 localize to the plasma membrane of the phloem. Mutant plants carrying insertions in AtSWEET11 and 12 are defective in phloem loading, thus revealing a two-step mechanism of SWEET-mediated export from parenchyma cells feeding H+-coupled import into the sieve element-companion cell complex. Restriction of intercellular transport to the interface of adjacent phloem cells may be an effective mechanism to limit the availability of photosynthetic carbon in the leaf apoplasm in order to prevent pathogen infections.

Many bacterial homologues (semisweets) have only 3 TMSs and are half sized, but they nevertheless are members of the MtN3 family with a single 3 TMS repeat unit per polypeptide chain. Other bacterial homologues have 7 TMSs as do most eukaryotic proteins in this family. The SWEET family is large and diverse. These semisweet proteins probably all function as dimeric carriers. The prokaryotic members of this family have been studied and reviewed (Jia et al. 2018).  Conservation patterns of known residues in the selectivity-filter have been used to predict the substrate preference of plant SWEETs and some clusters of metazoans and bacteria. Some residues at the gating and substrate-binding regions, pore-facing positions and at the helix-helix interface are conserved across all taxonomic groups. Conservation of polar/charged residues at specific pore-facing positions, helix-helix interface and in loops seems to be unique for plant SWEETs (Gupta and Sankararamakrishnan 2024).

Arabidopsis SWEETs homo- and heterooligomerize. Xuan et al., (2013) examined mutant SWEET variants for negative dominance to test if oligomerization is necessary for function. Mutation of the conserved Y57 or G58 residues in SWEET1 led to loss of activity. Coexpression of the defective mutants with functional A. thaliana SWEET1 inhibited glucose transport, indicating that homooligomerization is necessary for function. Collectively, these data imply that the basic unit of SWEETs, is a 3-TMS unit and that a functional transporter contains at least four such domains. The radish (Rs)SWEET genes play vital roles in reproductive organ development (Liu et al. 2023).

Plant SWEETs play crucial roles in cellular sugar efflux processes: phloem loading, pollen nutrition and nectar secretion. Bacterial SemiSWEETs often consist of a triple-helix bundle and form semi-symmetrical, parallel dimers, thereby generating the translocation pathway. Two SemiSWEET isoforms have been crystallized, one in an apparently open state and one in an occluded state, indicating that SemiSWEETs and SWEETs are transporters that undergo rocking-type movements during the transport cycle (Xu et al., 2014). In SemiSWEETs and SWEETs, two triple-helix bundles are arranged in a parallel configuration to produce the 6- and (3 + 1 + 3) -transmembrane-helix pores, respectively. Given the similarity of SemiSWEETs and SWEETs to PQ-loop amino acid transporters and to mitochondrial pyruvate carriers (MPCs), the structures characterized by Xu et al., 2014 may also be relevant to other transporters in the TOG superfamily (Yee et al. 2013). Characterization and expression profiling of the 30 SWEET proteins (8 with one repeat unit, 21 with two, and 1 with 4) in cabbage (Brassica oleracea) revealed their roles in chilling and clubroot disease responses.

Latorraca et al. 2017; captured the translocationprocess by crystallography and unguided molecular dynamics simulations, providing an atomic-level description of alternating access transport. Simulations of a SWEET-family transporter initiated from an outward-open, glucose-bound structure  spontaneously adopts occluded and inward-open conformations matching crystal structures. Mutagenesis experiments validated simulation predictions suggesting that state transitions are driven by favorable interactions formed upon closure of extracellular and intracellular 'gates' and by an unfavorable transmembrane helix configuration when both gates are closed. This mechanism leads to tight allosteric coupling between gates, preventing them from opening simultaneously. The substrate appears to take a 'free ride' across the membrane without causing major structural rearrangements in the transporter.

Plant SWEET sugar transporters play roles in phloem transport, nectar secretion, pollen nutrition, stress tolerance, and plant-pathogen interactions (Gao et al. 2017). Fify nine family members have been identified in wheat.  Phylogenetic relationships, numbers of TMSs, gene structures, and motifs showed that TaSWEETs have 3-7 TMSs fall into four clades with 10 different types of motifs. Examination of the expression patterns of 18 SWEET genes revealed that a few are tissue-specific while most are ubiquitously expressed. Using a stem rust-susceptible cultivar, 'Little Club' (LC) the expression of five SWEETs tested induced following inoculation (Gao et al. 2017). Sugar is transported via SWEETS and semi-SWEETS from the extracellular side (via an outward-open state) to the intracellular side (inward-open state) through an intermediate occluded state with both extracellular and intracellular gates closed (Bera and Klauda 2018).

SWEET transporters play roles in phloem loading, seed and fruit development, pollen development, and stress response in plants. Longan (Dimocarpus longan), a subtropic fruit tree with high economic value, is sensitive to cold. A total of 20 longan SWEET (DlSWEET) genes were identified, and their phylogenetic relationships, gene structures, cis-acting elements, and tissue-specific expression patterns were systematically analyzed (Fang et al. 2022). This family is divided into four clades. Gene structure and motif analyses indicated that the majority of DlSWEETs in each clade share similar exon-intron organization and conserved motifs. Tissue-specific gene expression suggested diverse possible functions for DlSWEET genes. DlSWEET1 responds to cold stress, and the overexpression of DlSWEET1 improved cold tolerance in transgenic Arabidopsis, suggesting that DlSWEET1 might play a positive role in D. longan's responses to cold stress (Fang et al. 2022).

The SWEET family is a member of the TOG superfamily, which is believed to have arisen via the pathway:

2 TMSs --> 4 TMSs --> 8 TMSs --> 7 TMSs --> 3 + 3 TMSs (Shlykov et al. 2012; Yee et al. 2013).

The generalized reation catalyzed by known proteins of this family is:

sugars (in) ⇌ sugars (out)

References associated with 2.A.123 family:

Bera, I. and J.B. Klauda. (2018). Structural Events in a Bacterial Uniporter Leading to Translocation of Glucose to the Cytosol. J. Mol. Biol. 430: 3337-3352. 29913162
Cao, Y., W. Liu, Q. Zhao, H. Long, Z. Li, M. Liu, X. Zhou, and L. Zhang. (2019). Integrative analysis reveals evolutionary patterns and potential functions of SWEET transporters in Euphorbiaceae. Int J Biol Macromol 139: 1-11. 31323266
Chen, L.Q., B.H. Hou, S. Lalonde, H. Takanaga, M.L. Hartung, X.Q. Qu, W.J. Guo, J.G. Kim, W. Underwood, B. Chaudhuri, D. Chermak, G. Antony, F.F. White, S.C. Somerville, M.B. Mudgett, and W.B. Frommer. (2010). Sugar transporters for intercellular exchange and nutrition of pathogens. Nature 468: 527-532. 21107422
Chen, L.Q., X.Q. Qu, B.H. Hou, D. Sosso, S. Osorio, A.R. Fernie, and W.B. Frommer. (2012). Sucrose efflux mediated by SWEET proteins as a key step for phloem transport. Science 335: 207-211. 22157085
Chu, Z., B. Fu, H. Yang, C. Xu, Z. Li, A. Sanchez, Y.J. Park, J.L. Bennetzen, Q. Zhang, and S. Wang. (2006). Targeting xa13, a recessive gene for bacterial blight resistance in rice. Theor Appl Genet 112: 455-461. 16328230
Eom, J.S., L.Q. Chen, D. Sosso, B.T. Julius, I.W. Lin, X.Q. Qu, D.M. Braun, and W.B. Frommer. (2015). SWEETs, transporters for intracellular and intercellular sugar translocation. Curr. Opin. Plant Biol. 25: 53-62. 25988582
Fang, T., Y. Rao, M. Wang, Y. Li, Y. Liu, P. Xiong, and L. Zeng. (2022). Characterization of the Gene Family in Longan () and the Role of in Cold Tolerance. Int J Mol Sci 23:. 36012186
Fatima, U., D. Balasubramaniam, W.A. Khan, M. Kandpal, J. Vadassery, A. Arockiasamy, and M. Senthil-Kumar. (2023). AtSWEET11 and AtSWEET12 transporters function in tandem to modulate sugar flux in plants. Plant Direct 7: e481. 36911252
Feng CY., Han JX., Han XX. and Jiang J. (2015). Genome-wide identification, phylogeny, and expression analysis of the SWEET gene family in tomato. Gene. 573(2):261-72. 26190159
Ferrada, E. and G. Superti-Furga. (2022). A structure and evolutionary-based classification of solute carriers. iScience 25: 105096. 36164651
Filyushin, M.A., O.K. Anisimova, A.V. Shchennikova, and E.Z. Kochieva. (2023). Genome-Wide Identification, Expression, and Response to Infection of the Gene Family in Garlic ( L.). Int J Mol Sci 24:. 37108694
Gao, Y., Z.Y. Wang, V. Kumar, X.F. Xu, P. Yuan, X.F. Zhu, T.Y. Li, B.L. Jia, and Y.H. Xuan. (2017). Genome-wide identification of the SWEET gene family in wheat. Gene. [Epub: Ahead of Print] 29155326
Ge, Y.X., G.C. Angenent, P.E. Wittich, J. Peters, J. Franken, M. Busscher, L.M. Zhang, E. Dahlhaus, M.M. Kater, G.J. Wullems, and T. Creemers-Molenaar. (2000). NEC1, a novel gene, highly expressed in nectary tissue of Petunia hybrida. Plant J. 24: 725-734. 11135107
Guan, Y.F., X.Y. Huang, J. Zhu, J.F. Gao, H.X. Zhang, and Z.N. Yang. (2008). RUPTURED POLLEN GRAIN1, a member of the MtN3/saliva gene family, is crucial for exine pattern formation and cell integrity of microspores in Arabidopsis. Plant Physiol. 147: 852-863. 18434608
Gupta, A. and R. Sankararamakrishnan. (2018). dbSWEET: An Integrated Resource for SWEET Superfamily to Understand, Analyze and Predict the Function of Sugar Transporters in Prokaryotes and Eukaryotes. J. Mol. Biol. [Epub: Ahead of Print] 29665371
Gupta, A. and R. Sankararamakrishnan. (2024). Substrate selectivity and unique sequence signatures in SWEET/semiSWEET homologs of four taxonomic groups: Sequence analysis and phylogenetic studies. Proteins. [Epub: Ahead of Print] 38243636
Hamada, M., S. Wada, K. Kobayashi, and N. Satoh. (2005). Ci-Rga, a gene encoding an MtN3/saliva family transmembrane protein, is essential for tissue differentiation during embryogenesis of the ascidian Ciona intestinalis. Differentiation 73: 364-376. 16219040
Hamada, M., S. Wada, K. Kobayashi, and N. Satoh. (2007). Novel genes involved in Ciona intestinalis embryogenesis: characterization of gene knockdown embryos. Dev Dyn 236: 1820-1831. 17557306
Hao, L., X. Shi, S. Qin, J. Dong, H. Shi, Y. Wang, and Y. Zhang. (2023). Genome-wide identification, characterization and transcriptional profile of the SWEET gene family in Dendrobium officinale. BMC Genomics 24: 378. 37415124
Hu, B., H. Wu, W. Huang, J. Song, Y. Zhou, and Y. Lin. (2019). Gene Family in : Genome-Wide Identification, Expression and Substrate Specificity Analysis. Plants (Basel) 8:. 31505820
Jeena, G.S., S. Kumar, and R.K. Shukla. (2019). Structure, evolution and diverse physiological roles of SWEET sugar transporters in plants. Plant Mol. Biol. 100: 351-365. 31030374
Jia, B., L. Hao, Y.H. Xuan, and C.O. Jeon. (2018). New Insight Into the Diversity of SemiSWEET Sugar Transporters and the Homologs in Prokaryotes. Front Genet 9: 180. 29872447
Jia, B., X.F. Zhu, Z.J. Pu, Y.X. Duan, L.J. Hao, J. Zhang, L.Q. Chen, C.O. Jeon, and Y.H. Xuan. (2017). Integrative View of the Diversity and Evolution of SWEET and SemiSWEET Sugar Transporters. Front Plant Sci 8: 2178. 29326750
Jiang, L., C. Song, X. Zhu, and J. Yang. (2021). SWEET Transporters and the Potential Functions of These Sequences in Tea (). Front Genet 12: 655843. 33868386
Jiang, R., L. Wu, J. Zeng, K. Shah, R. Zhang, G. Hu, Y. Qin, and Z. Zhang. (2023). Identification of Family in Pitaya () and Key Roles of and in Sugar Accumulation. Int J Mol Sci 24:. 37629062
Kanno, Y., T. Oikawa, Y. Chiba, Y. Ishimaru, T. Shimizu, N. Sano, T. Koshiba, Y. Kamiya, M. Ueda, and M. Seo. (2016). AtSWEET13 and AtSWEET14 regulate gibberellin-mediated physiological processes. Nat Commun 7: 13245. 27782132
Kuanyshev, N., A. Deewan, S.S. Jagtap, J. Liu, B. Selvam, L.Q. Chen, D. Shukla, C.V. Rao, and Y.S. Jin. (2021). Identification and analysis of sugar transporters capable of co-transporting glucose and xylose simultaneously. Biotechnol J e2100238. [Epub: Ahead of Print] 34418308
Kumawat, S., Y. Sharma, S. Vats, S. Sudhakaran, S. Sharma, R. Mandlik, G. Raturi, V. Kumar, N. Rana, A. Kumar, H. Sonah, and R. Deshmukh. (2022). Understanding the role of SWEET genes in fruit development and abiotic stress in pomegranate (Punica granatum L.). Mol Biol Rep 49: 1329-1339. 34855106
Latorraca, N.R., N.M. Fastman, A.J. Venkatakrishnan, W.B. Frommer, R.O. Dror, and L. Feng. (2017). Mechanism of Substrate Translocation in an Alternating Access Transporter. Cell 169: 96-107.e12. 28340354
Lee, Y., T. Nishizawa, K. Yamashita, R. Ishitani, and O. Nureki. (2015). Structural basis for the facilitative diffusion mechanism by SemiSWEET transporter. Nat Commun 6: 6112. 25598322
Liu, N., Z. Wei, X. Min, L. Yang, Y. Zhang, J. Li, and Y. Yang. (2023). Genome-Wide Identification and Expression Analysis of the Gene Family in Annual Alfalfa (). Plants (Basel) 12:. 37653865
Liu, T., Q. Cui, Q. Ban, L. Zhou, Y. Yuan, A. Zhang, Q. Wang, and C. Wang. (2023). Identification and expression analysis of the SWEET genes in radish reveal their potential functions in reproductive organ development. Mol Biol Rep. [Epub: Ahead of Print] 37501046
Shlykov, M.A., W.H. Zheng, J.S. Chen, and M.H. Saier, Jr. (2012). Bioinformatic characterization of the 4-Toluene Sulfonate Uptake Permease (TSUP) family of transmembrane proteins. Biochim. Biophys. Acta. 1818: 703-717. 22192777
Takanaga, H. and W.B. Frommer. (2010). Facilitative plasma membrane transporters function during ER transit. FASEB J. 24: 2849-2858. 20354141
Tao, Y., L.S. Cheung, S. Li, J.S. Eom, L.Q. Chen, Y. Xu, K. Perry, W.B. Frommer, and L. Feng. (2015). Structure of a eukaryotic SWEET transporter in a homotrimeric complex. Nature 527: 259-263. 26479032
Wang, L., L. Yao, X. Hao, N. Li, W. Qian, C. Yue, C. Ding, J. Zeng, Y. Yang, and X. Wang. (2018). Tea plant SWEET transporters: expression profiling, sugar transport, and the involvement of CsSWEET16 in modifying cold tolerance in Arabidopsis. Plant Mol. Biol. 96: 577-592. 29616437
Wu, Z., K.M. Soliman, J.J. Bolton, S. Saha, and J.N. Jenkins. (2008). Identification of differentially expressed genes associated with cotton fiber development in a chromosomal substitution line (CS-B22sh). Funct Integr Genomics 8: 165-174. 18043952
Xie, H., D. Wang, Y. Qin, A. Ma, J. Fu, Y. Qin, G. Hu, and J. Zhao. (2019). Genome-wide identification and expression analysis of SWEET gene family in Litchi chinensis reveal the involvement of LcSWEET2a/3b in early seed development. BMC Plant Biol 19: 499. 31726992
Xu Y., Tao Y., Cheung LS., Fan C., Chen LQ., Xu S., Perry K., Frommer WB. and Feng L. (2014). Structures of bacterial homologues of SWEET transporters in two distinct conformations. Nature. 515(7527):448-52. 25186729
Xuan, Y.H., Y.B. Hu, L.Q. Chen, D. Sosso, D.C. Ducat, B.H. Hou, and W.B. Frommer. (2013). Functional role of oligomerization for bacterial and plant SWEET sugar transporter family. Proc. Natl. Acad. Sci. USA 110: E3685-3694. 24027245
Yang, B., A. Sugio, and F.F. White. (2006). Os8N3 is a host disease-susceptibility gene for bacterial blight of rice. Proc. Natl. Acad. Sci. USA 103: 10503-10508. 16798873
Yee, D.C., M.A. Shlykov, A. Västermark, V.S. Reddy, S. Arora, E.I. Sun, and M.H. Saier, Jr. (2013). The transporter-opsin-G protein-coupled receptor (TOG) superfamily. FEBS J. 280: 5780-5800. 23981446
Zhang, G., S.S. Liu, X.J. Yang, Y. Chen, L.L. Liu, and S.X. Guo. (2016). [Molecular cloning and characterization of a novel DoSWEET1 gene from Dendrobium officinale]. Yao Xue Xue Bao 51: 991-997. 29883078
Zhang, R., K. Niu, and H. Ma. (2020). Identification and Expression Analysis of the Gene Family from Under Abiotic Stresses. DNA Cell Biol 39: 1606-1620. 32749870
Zhu, L.Q., Z.K. Bao, W.W. Hu, J. Lin, Q. Yang, and Q.H. Yu. (2015). Cloning and functional analysis of goat SWEET1. Genet Mol Res 14: 17124-17133. 26681059