Fungal sugars boost vaccine protection.

In this issue of Cell, Borriello et al. show that soluble fungal mannans elicit potent innate immune responses within skin-draining lymph nodes. These can be exploited for effective development of adaptive immune responses against viral glycoproteins, thus enhancing vaccine immunogenicity and protection.

Beyond gut instincts: Microbe survival depends on sugars and butyrate.

The factors and mechanisms that shape the composition and function of closely related members in a complex microbial community are largely unknown. The study by Park and colleagues reveals that the fitness of various Bacteroidales species and strains in the gut microbiome is regulated by butyrate in a glycan-dependent manner.

Some Like It Sweet: Dendritic Cells Add Sugar to Their T(ea).

In this issue of Cell, Liu et al. present FucoID, a glycosyltransferase-mediated tagging platform, to biochemically label and capture antigen-specific T cells. With this technology, the authors isolate and characterize tumor-specific CD8+ and CD4+ T cells in murine tumor models. FucoID shows promise as a tool to enhance the understanding of anti-tumor immune responses.

Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum.

Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.

Surface Sugars Get Cells in Shape.

Cell membranes can adopt a variety of shapes and curvatures, yet our understanding of the factors involved remains limited. In this issue of Cell, Shurer et al. (2019) demonstrate that the glycocalyx can regulate cell shape from the outside in.

Sex Differences in Intestinal Carbohydrate Metabolism Promote Food Intake and Sperm Maturation.

Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signaling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this male-biased intestinal metabolic state in controlling food intake and sperm production through gut-derived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, revealing that metabolic communication across organs is physiologically important. The instructive role of citrate in inter-organ communication might be significant in more biological contexts than previously recognized.

A case of too much sugar: Lung DCs flummoxed by flu.

Diabetes is known to increase susceptibility to respiratory infections, but the underlying basis remains elusive. In a recent study in Nature, Nobs et al. showed that hyperglycemia impinges on the histone acetylation landscape to impair the ability of lung dendritic cells to prime adaptive immunity.

Sugar Turns Bacteria Sweet: A Peace Offering in the Gut.

Following an infection, a subset of individuals can remain disease free despite harboring a pathogen for a prolonged period. In this issue of Cell, Sanchez et al. demonstrate that a metabolically favorable host response can drive an otherwise lethal bacterial pathogen to abandon virulence and become a commensal microorganism.

Evolution of the diagnostic value of "the sugar of the blood": hitting the sweet spot to identify alterations in glucose dynamics.

In this paper, we provide an overview of the evolution of the definition of hyperglycemia during the past century and the alterations in glucose dynamics that cause fasting and postprandial hyperglycemia. We discuss how extensive mechanistic, physiological research into the factors and pathways that regulate the appearance of glucose in the circulation and its uptake and metabolism by tissues and organs has contributed knowledge that has advanced our understanding of different types of hyperglycemia, namely prediabetes and diabetes and their subtypes (impaired fasting plasma glucose, impaired glucose tolerance, combined impaired fasting plasma glucose, impaired glucose tolerance, type 1 diabetes, type 2 diabetes, gestational diabetes mellitus), their relationships with medical complications, and how to prevent and treat hyperglycemia.

Direct radical functionalization of native sugars.

Naturally occurring (native) sugars and carbohydrates contain numerous hydroxyl groups of similar reactivity1,2. Chemists, therefore, rely typically on laborious, multi-step protecting-group strategies3 to convert these renewable feedstocks into reagents (glycosyl donors) to make glycans. The direct transformation of native sugars to complex saccharides remains a notable challenge. Here we describe a photoinduced approach to achieve site- and stereoselective chemical glycosylation from widely available native sugar building blocks, which through homolytic (one-electron) chemistry bypasses unnecessary hydroxyl group masking and manipulation. This process is reminiscent of nature in its regiocontrolled generation of a transient glycosyl donor, followed by radical-based cross-coupling with electrophiles on activation with light. Through selective anomeric functionalization of mono- and oligosaccharides, this protecting-group-free 'cap and glycosylate' approach offers straightforward access to a wide array of metabolically robust glycosyl compounds. Owing to its biocompatibility, the method was extended to the direct post-translational glycosylation of proteins.

The molecular basis of sugar detection by an insect taste receptor.

Animals crave sugars because of their energy potential and the pleasurable sensation of tasting sweetness. Yet all sugars are not metabolically equivalent, requiring mechanisms to detect and differentiate between chemically similar sweet substances. Insects use a family of ionotropic gustatory receptors to discriminate sugars1, each of which is selectively activated by specific sweet molecules2-6. Here, to gain insight into the molecular basis of sugar selectivity, we determined structures of Gr9, a gustatory receptor from the silkworm Bombyx mori (BmGr9), in the absence and presence of its sole activating ligand, D-fructose. These structures, along with structure-guided mutagenesis and functional assays, illustrate how D-fructose is enveloped by a ligand-binding pocket that precisely matches the overall shape and pattern of chemical groups in D-fructose. However, our computational docking and experimental binding assays revealed that other sugars also bind BmGr9, yet they are unable to activate the receptor. We determined the structure of BmGr9 in complex with one such non-activating sugar, L-sorbose. Although both sugars bind a similar position, only D-fructose is capable of engaging a bridge of two conserved aromatic residues that connects the pocket to the pore helix, inducing a conformational change that allows the ion-conducting pore to open. Thus, chemical specificity does not depend solely on the selectivity of the ligand-binding pocket, but it is an emergent property arising from a combination of receptor-ligand interactions and allosteric coupling. Our results support a model whereby coarse receptor tuning is derived from the size and chemical characteristics of the pocket, whereas fine-tuning of receptor activation is achieved through the selective engagement of an allosteric pathway that regulates ion conduction.

Sugar defeats the Hippo: Glycogen regulation of the Hippo pathway in liver.

Liver glycogen is famous for glucose storage, but new work by Liu et al. (2021) now reveals that it's been hiding a few secrets and can directly promote liver enlargement and tumorigenesis by sequestering the tumor-suppressive Hippo signaling pathway.

Sweet Temptation: From Sugar Metabolism to Gene Regulation.

In a recent issue of Nature, Zhang et al. (2019) describe an additional histone post-translational modification, named histone lactylation. Following increased lactate production as a consequence of M1 polarization, histone lactylation regulates the induction of an M2-like phenotype in late stages of M1 macrophage activation to promote wound healing.

Sugar Fix Keeps RIPK3 at Bay.

Immunometabolism is emerging as an important modulator of immune responses. In this issue of Immunity, Li et al. (2019) examine the link between lipopolysaccharide (LPS)-induced glucose metabolism and innate immune signaling and identify how ß-N-acetylglucosamine (O-GlcNAc) modification of the RIPK3 RHIM domain limits inflammation and necroptosis.

Site-selective, stereocontrolled glycosylation of minimally protected sugars.

The identification of general and efficient methods for the construction of oligosaccharides stands as one of the great challenges for the field of synthetic chemistry1,2. Selective glycosylation of unprotected sugars and other polyhydroxylated nucleophiles is a particularly significant goal, requiring not only control over the stereochemistry of the forming bond but also differentiation between similarly reactive nucleophilic sites in stereochemically complex contexts3,4. Chemists have generally relied on multi-step protecting-group strategies to achieve site control in glycosylations, but practical inefficiencies arise directly from the application of such approaches5-7. Here we describe a strategy for small-molecule-catalyst-controlled, highly stereo- and site-selective glycosylations of unprotected or minimally protected mono- and disaccharides using precisely designed bis-thiourea small-molecule catalysts. Stereo- and site-selective galactosylations and mannosylations of a wide assortment of polyfunctional nucleophiles is thereby achieved. Kinetic and computational studies provide evidence that site-selectivity arises from stabilizing C-H/π interactions between the catalyst and the nucleophile, analogous to those documented in sugar-binding proteins. This work demonstrates that highly selective glycosylation reactions can be achieved through control of stabilizing non-covalent interactions, a potentially general strategy for selective functionalization of carbohydrates.

Gut-brain circuits for fat preference.

The perception of fat evokes strong appetitive and consummatory responses1. Here we show that fat stimuli can induce behavioural attraction even in the absence of a functional taste system2,3. We demonstrate that fat acts after ingestion via the gut-brain axis to drive preference for fat. Using single-cell data, we identified the vagal neurons responding to intestinal delivery of fat, and showed that genetic silencing of this gut-to-brain circuit abolished the development of fat preference. Next, we compared the gut-to-brain pathways driving preference for fat versus sugar4, and uncovered two parallel systems, one functioning as a general sensor of essential nutrients, responding to intestinal stimulation with sugar, fat and amino acids, whereas the other is activated only by fat stimuli. Finally, we engineered mice lacking candidate receptors to detect the presence of intestinal fat, and validated their role as the mediators of gut-to-brain fat-evoked responses. Together, these findings reveal distinct cells and receptors that use the gut-brain axis as a fundamental conduit for the development of fat preference.

Teixobactin kills bacteria by a two-pronged attack on the cell envelope.

Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1-3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a ß-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.