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Bacterial Carbohydrate Diversity — a Brave New World 1,2 Available online at www.sciencedirect.com ScienceDirect Bacterial carbohydrate diversity — a Brave New World 1,2 Barbara Imperiali Glycans and glycoconjugates feature on the ‘front line’ of (Figure 1a) and among these, the hexoses show extensive bacterial cells, playing critical roles in the mechanical and variation in substitution patterns and the heptoses and chemical stability of the microorganisms, and orchestrating octoses are exclusively prokaryotic. The nonulosonic acids, interactions with the environment and all other living organisms. which are derived biosynthetically from the hexoses, are To negotiate such central tasks, bacterial glycomes also far more varied: there is a single example in man, but incorporate a dizzying array of carbohydrate building blocks dozens have been characterized to date in various bacteria and non-carbohydrate modifications, which create [5]. In addition, a plethora of modifications including alkyl, opportunities for infinite structural variation. This review acyl, amino acyl, phosphoryl, and even nucleoside groups highlights some of the challenges and opportunities for the are often found decorating the carbohydrates [4 ]. Defining chemical biology community in the field of bacterial and cataloging this variety, not to mention understanding glycobiology. its significance, is a Herculean task. Addresses Bacterial carbohydrates may be components of repeating 1 Department of Biology, Massachusetts Institute of Technology, glycopolymers or, more complex glycoconjugates, which Cambridge, MA 02139, United States 2 may reveal elaborate ‘samplers’ of different sugars Department of Chemistry, Massachusetts Institute of Technology, (Figure 1b) [6]. In cells, the glycans commonly include Cambridge, MA 02139, United States cell-surface structures that are essential for the mechanical Corresponding author: Imperiali, Barbara ([email protected]) integrity of bacterial cells and for critical interactions with other bacteria and the hosts with which they coexist [7,8]. The key glycoconjugates in Gram-negative bacteria are Current Opinion in Chemical Biology 2019, 53:1–8 peptidoglycan (PG), lipopolysaccharide (LPS), lipooligosac- This review comes from a themed issue on Mechanistic biology charide (LOS), capsular extracellular polysaccharide (EPS), Edited by Hermen S Overkleeft and David J Vocadlo capsular polysaccharide (CPS), and N-linked and O-linked glycoproteins. In contrast, Gram-positive organisms lack LPS and LOS but instead feature glycosylated lipo techoic acids and wall techoic acids (LTAs and WTAs), which are https://doi.org/10.1016/j.cbpa.2019.04.026 anionic copolymers of glycerol or ribitol phosphate and 1367-5931/ã 2019 Elsevier Ltd. All rights reserved. carbohydrates linked via phosphodiester linkages, conju- gated to either PG (for WTA) or diacyl glycerol (LTA). The Gram-positive mycobacteria show additional glycan varia- tions including arabinogalactan and lipoarabinomannan conjugates, which feature many furanose sugars [9 ]. Introduction This opinion summarizes recent examples of the impor- The human glycome is frequently deemed to be a labyrin- tance of chemical biology approaches for identifying the thine nightmare. Those glycans are based on 10 unique fates of bacterial sugars in pathogen glycoconjugates, monosaccharide building blocks, which can be combined investigating carbohydrate-based interactions, defining into oligomers and polymers with linear and branched the activity of bacterial monosaccharides in eukaryotic structures joined by glycosidic linkages between the vari- signaling, and highlighting the significance of glycan ous hydroxyl groups, with each glycosidic linkage adopting modifications in antibiotic resistance. either a-anomeric or b-anomeric configuration. The struc- tures may additionally be subject to modifications includ- Enlisting metabolic labeling for tracking and ing, for example, sulfation and phosphorylation [1,2]. analyzing bacterial cell-surface glycomes Despite this complexity however, when it comes to com- Metabolic oligosaccharide engineering (MOE) involves parisons of carbohydrate diversity between prokaryotic and delivery of cell-permeable biosynthetic precursors of glycan eukaryotic life forms, prokaryotes win hands down. There constituents into living cells and organisms [10]. MOE are hundreds of unique monosaccharide building blocks reagents are commonly modified with azides or terminal and chemically defined saccharide modifications in the alkynes, which serve as biorthogonal reactivity handles for database of naturally occurring carbohydrates (http:// the introduction of epitope, biotin, or fluorescent tags. MOE csdb.glycoscience.ru/bacterial/) [3,4 ]; the vast majority has proven extremely valuable in research on the glycobiol- of these are prokaryote-specific. The carbohydrates that ogy of mammalian cells and model organisms. For example, feature in bacterial glycans range from trioses to dodecoses studies with peracetylated derivatives of C-2 acetamido www.sciencedirect.com Current Opinion in Chemical Biology 2019, 53:1–8 2 Mechanistic biology Figure 1 (b) O-antigen O-antigen anchor site repeat (a) ON N P EN T C TRI-TET O PENf P E PENp H PENl HEXf HEXp HEXl HEP Non-sugar modifications OCT X NON E H DEC-DOD Total=722 Current Opinion in Chemical Biology Bacterial carbohydrate diversity. (a) Bacterial carbohydrate distribution based on size. The current BCSDB (http://csdb.glycoscience.ru/bacterial/) includes over 700 unique carbohydrates ranging from trioses to dodecanoses [4 ]. Pentoses and hexoses are further differentiated as furanose ( f), pyranose ( p) and acyclic/ unknown (l). (b) The structure of a lipopolysaccharide (LPS smooth) from Pseudomonas aeruginosa (O12 serotype) exemplifies the diversity of carbohydrates in a single glycoconjugate [6]. An Arap4NP is shown on the Lipid A diglucosamine core for the purpose of illustrating the modification. This carbohydrate is known to be associated with P. aeruginosa, but not specifically documented in the serotype illustrated. Further glycan variation is achieved by carbohydrate modifications for example with amidino (Am), carbamoyl (Ca), phosphatidyl ethanolamine (PEtN), diphosphate (PP) and alanyl (Ala). hexoses, in which the N-acetyl groups are replaced with only nine-carbon sugar in man with the main variation in N-azidoacetyl are useful for labeling eukaryotic N-linked non-human mammals being the N-glycolyl derivative [13]. and O-linked glycoproteins [10]. For these efforts, knowl- MOE in mammalian cells is also enabled by a salvage edge of cellular pathways for conversion of carbohydrate pathway that affords phosphorylation of unmodified hexoses analogs into nucleotide-activated sugars for glycoconjugate to generate precursors for conversion into UDP-sugars [14]. assembly is crucial. Notably, the in-cell conversion of free N- This pathway may not be broadly present bacteria and so acetyl mannosamine into CMP-N-acetylneuraminic acid cannot always be relied upon for MOE. (CMP-NeuNAc), a non-2-ulosonic acid (NulO) [11,12] has been extensively exploited as it is commonly associated Information on the pathways for glycoconjugate biosyn- with mammalian cell-surface glycoproteins. NeuNAc is the thesis in bacteria has led to important avenues for Current Opinion in Chemical Biology 2019, 53:1–8 www.sciencedirect.com Bacterial carbohydrate diversity Imperiali 3 selective MOE in bacterial pathogens. Prokaryote-specific elimination, enolization and reprotonation for epimeriza- NulOs, feature prominently in cell surface-glycoconju- tion or ketoisomerization, and transamination [17]. gates. NulO biosynthesis follows a common logic across domains of life, with the key step involving a three-carbon In bacteria, NulOs play important roles in virulence and extension of a six-carbon sugar intermediate with phos- pathogenicity and may function in carbohydrate mimicry phoenol pyruvate (PEP). For example, CMP-pseudaminic foiling the human immune system [5]. Bacterial NulOs acid (CMP-Pse) [15] and CMP-legionaminic acid (CMP- are common modifications of the capsular polysaccharide Leg) [16] are biosynthesized from UDP-GlcNAc and (CPS) and O-antigen, and are attached to the Fla GDP-GlcNAc, respectively, via the intermediacy of tri- proteins in flagellar appendages that are essential for deoxy-diacetamido-hexoses (Figure 2a). Biochemical motility. Critical to successful MOE is the provision of manipulation of bacterial hexoses, such as those in the cell-permeable precursors, commonly as neutral, per- Pse and Leg pathways, commonly involve site-selective O/N-acetylated derivatives of hexose or hexosamine oxidation of hydroxyl groups (at C3 or C4), which in turn intermediates, which are de-O-acetylated by cellular enables further biochemical manipulation such as esterases and enter into endogenous pathways for Figure 2 (a) (b) UDP-GlcNAc GDP-GlcNAc 1. C4’-oxidation 1. C4’-oxidation, 1 2 3 C5,6-dehydration C5,6-dehydration C5’ epimerization C4’-reduction C4’-reduction (c) KDO-8-P KDO-8-P synthase phosphatase 1.C4’-transamination 1. C4’-transamination Arabinose-5-P 2. C4’-NH2-acetylation 2. C4’-NH2-acetylation CMP-Kdo synthetase CMP-Kdo Nucleotide hydrolase Nucleotide hydrolase/ 2’-epimerase (d) Click chemistry O-antigen and analysis repeat Inner and 1 outer core 3 Lipid A Passive 1. Pse synthase 1. Leg synthase OM NanT 2. CMP-transferase 2. CMP-transferase uptake O-antigen assembly 1 Translocation 3 1. Esterase Ligation with core 2. PEP, Pse synthase LPS transport 3. CMP-transferase CMP-transferase CMP-Pse CMP-Leg CMP-Pse-7-N3
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