Soluble sugars serve five main purposes in multicellular organisms: as sources of carbon skeletons, osmolytes, signals, and transient energy storage and as transport molecules. Most sugars are derived from photosynthetic organisms, particularly plants. In multicellular organisms, some cells specialize in providing sugars to other cells (e.g., intestinal and liver cells in animals, photosynthetic cells in plants), whereas others depend completely on an external supply (e.g., brain cells, roots and seeds). This cellular exchange of sugars requires transport proteins to mediate uptake or release from cells or subcellular compartments. Thus, not surprisingly, sugar transport is critical for plants, animals, and humans. At present, three classes of eukaryotic sugar transporters have been characterized, namely the glucose transporters (GLUTs), sodium-glucose symporters (SGLTs), and SWEETs. This review presents the history and state of the art of sugar transporter research, covering genetics, biochemistry, and physiology-from their identification and characterization to their structure, function, and physiology. In humans, understanding sugar transport has therapeutic importance (e.g., addressing diabetes or limiting access of cancer cells to sugars), and in plants, these transporters are critical for crop yield and pathogen susceptibility.

Eukaryotes rely on efficient distribution of energy and carbon skeletons between organs in the form of sugars. Glucose in animals and sucrose in plants serve as dominant distribution forms. Cellular sugar uptake and release require vesicular and/or plasma membrane transport proteins. Humans and plants use related proteins from three superfamilies for sugar translocation: the major facilitator superfamily (MFS), the sodium solute symporter Family (SSF; only animal kingdom), and SWEETs1-5. SWEETs carry mono- and disaccharides6 across vacuolar or plasma membranes. Plant SWEETs play key roles in sugar translocation between compartments, cells, and organs, notably in nectar secretion7, phloem loading for long distance translocation8, pollen nutrition9, and seed filling10. Plant SWEETs cause pathogen susceptibility by sugar leakage from infected cells3,11,12. The vacuolar AtSWEET2 sequesters sugars in root vacuoles; loss-of-function increases susceptibility to Pythium infection13. Here we show that its orthologue, the vacuolar glucose transporter OsSWEET2b from rice, consists of an asymmetrical pair of triple-helix-bundles (THBs), connected by an inversion linker helix (TM4) to create the translocation pathway. Structural and biochemical analyses show OsSWEET2b in an apparent inward (cytosolic) open state forming homomeric trimers. TM4 tightly interacts with the first THB within a protomer and mediates key contacts among protomers. Structure-guided mutagenesis of the close paralogue SWEET1 from Arabidopsis identified key residues in substrate translocation and protomer crosstalk. Insights into the structure-function relationship of SWEETs is valuable for understanding the transport mechanism of eukaryotic SWEETs and may be useful for engineering sugar flux.

SemiSWEETs and SWEETs are mono- and disaccharide transporters present from Archaea to higher plants and humans1-3. SWEETs play crucial roles in cellular sugar efflux processes, i.e. phloem loading4, pollen nutrition5 and nectar secretion6. Their bacterial homologs, SemiSWEETs, are among the smallest known transporters1,3. Here we show SemiSWEET, consisting of a triple-helix-bundle (THB), forms a symmetric parallel dimer to create the translocation pathway. Two SemiSWEET isoforms were crystallized in apparent open and occluded states, indicating that SemiSWEETs/SWEETs are transporters that undergo rocking-type movements during the transport cycle. The topology of THB is similar to the basic building block in MFS transporters (GLUTs, SUTs), indicating that they may have evolved from an ancestral THB into a parallel configuration to produce 6/6+1 transmembrane-helix pores for SemiSWEETs/SWEETs, and an antiparallel configuration of 2×2 THBs to generate 12 transmembrane-helix pores for MFS transporters. Given the similarity of SemiSWEETs/SWEETs to PQ-loop amino acid transporters and mitochondrial MPC organic acid transporters, the structures characterized here may also be relevant for other MtN3 clan transporters7-9.