# Bacterial extracellular polysaccharide synthesis enzymes
**Bacterial extracellular polysaccharide synthesis enzymes** are enzymes that bacteria use to build polysaccharides outside the cytoplasmic membrane. Bacteria build three kinds of polysaccharide outside the cytoplasmic membrane: capsular polysaccharides that stay attached to the cell surface, O-antigen chains attached to lipopolysaccharide, and exopolysaccharides (EPS) that are mostly secreted into the immediate environment. Capsular polysaccharides and exopolysaccharides afford protection from a wide range of physical, chemical, and biological stresses and support biofilms.[1](https://www.annualreviews.org/content/journals/10.1146/annurev-micro-011420-075607) Four general mechanisms are known for producing these polymers: the Wzx/Wzy-dependent pathway, the ABC transporter-dependent pathway, the synthase-dependent pathway, and extracellular synthesis by a single sucrase protein.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) This article covers the enzymes of the first three pathways and how they differ in mechanism.
| Key fact | Detail |
|---|---|
| Assembly routes | Four mechanisms build bacterial surface and secreted polysaccharides: Wzx/Wzy-dependent, ABC transporter-dependent, synthase-dependent, and single-protein sucrase synthesis.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) |
| Lipid anchor | Wzx/Wzy repeat units are built on an undecaprenol diphosphate (C55) anchor at the inner membrane.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) |
| Initiating enzymes | Two classes of transferase start synthesis by moving sugar-1-phosphate onto undecaprenyl phosphate: PHPT and PNPT; humans have only PNPT-type enzymes.[3](https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/9397/Naismith_2016_COSB_Bacterial_CCBYNCND_Published.pdf?isAllowed=y&sequence=1) |
| ABC-pathway anchor | ABC-dependent capsular polysaccharides carry a conserved reducing-terminal glycolipid of phosphatidylglycerol and a poly-Kdo linker, built by KpsS and KpsC.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) • [4](https://www.nature.com/articles/s41589-024-01664-8) |
| Chain-length control | Wzz produces an organism-specific modal distribution of Wzy-dependent polymer lengths; in the ABC-dependent E. coli O9a system, the coiled-coil ruler WbdD sets length directly.[3](https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/9397/Naismith_2016_COSB_Bacterial_CCBYNCND_Published.pdf?isAllowed=y&sequence=1) |
| Alginate machinery | Alginate polymerization and secretion in *Pseudomonas aeruginosa* use an envelope-spanning complex of at least six subunits (Alg8, Alg44, AlgG, AlgX, AlgK, AlgE).[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) |
| New since 2023 | Transition transferases that prime ABC-dependent capsule polymerization, the previously uncharacterized step II, were identified in 2024.[4](https://www.nature.com/articles/s41589-024-01664-8) |
## The Wzx/Wzy-dependent pathway
The Wzx/Wzy pathway builds polymers from preassembled repeat units. Individual repeating units are linked to an undecaprenol diphosphate anchor (C55) at the inner membrane and assembled there by several glycosyltransferases; the flippase Wzx then translocates each completed unit across the cytoplasmic membrane.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) On the periplasmic face, the Wzy polymerase joins units into a growing chain, and polysaccharide copolymerase (PCP) and OPX family proteins export the polymer through the periplasm and outer membrane.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full)
Initiation uses a family of enzymes that transfer sugar-1-phosphate to undecaprenyl phosphate on the cytoplasmic face of the inner membrane. [Gram-negative bacteria](https://www.edgepedia.org/gram-negative-bacteria) have two broad classes: the polyisoprenyl-phosphate hexose-1-phosphate transferase (PHPT) family and the polyisoprenyl-phosphate N-acetylaminosugar-1-phosphate transferase (PNPT) family. The PNPT class contains 10 or 11 transmembrane helices that together form the active site, while the PHPT class has a cytoplasmic C-terminal soluble domain containing the catalytic machinery; humans have only PNPT-type enzymes.[3](https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/9397/Naismith_2016_COSB_Bacterial_CCBYNCND_Published.pdf?isAllowed=y&sequence=1)
Chain length is not accidental. During Wzy-dependent polymerization, the polysaccharide copolymerase Wzz produces an organism-specific modal distribution of polymer lengths. Using radiolabelled substrates in vitro, researchers monitoring purified *Escherichia coli* O86 Wzy activity found that O-antigen chain-length modality could be restored purely by adding Wzz to the reaction mixture.[3](https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/9397/Naismith_2016_COSB_Bacterial_CCBYNCND_Published.pdf?isAllowed=y&sequence=1) For O-antigen specifically, the finished chain is ligated to lipid A-core oligosaccharide by WaaL.[5](https://cdnsciencepub.com/doi/10.1139/cjm-2014-0595)
## The ABC-transporter-dependent pathway
The ABC-transporter route inverts the Wzx/Wzy logic: polymerization happens entirely in the cytoplasm, and the finished polymer is exported. ABC transporter-dependent capsule assembly proceeds in four steps. First, the Kdo transferase KpsS adds a single β-linked Kdo onto phosphatidylglycerol. Second, KpsC generates poly(Kdo) with alternating β-(2→7)- and β-(2→4)-linkages. Third, serotype-specific capsule polymerases assemble the capsule polymer. Fourth, an ABC transporter complex transports the polymer outside the cell.[4](https://www.nature.com/articles/s41589-024-01664-8) The resulting capsular polysaccharides all carry a conserved glycolipid at the reducing terminus, composed of phosphatidylglycerol and a poly-2-keto-3-deoxyoctulosonic acid (Kdo) linker.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) This glycolipid is believed to be the structural element recognized by the ABC transporter complex.[4](https://www.nature.com/articles/s41589-024-01664-8)
After ATP hydrolysis by the transporter drives polymer transport across the inner membrane, PCP and OPX proteins are needed for secretion through the periplasm and across the outer membrane.[6](https://journals.asm.org/doi/10.1128/spectrum.01290-22) In *E. coli* group 2 capsules, translocation across the periplasm requires the PCP-3 protein KpsE and the OPX protein KpsD, which form an export complex analogous, but perhaps not identical, to Wza-Wzc.[7](https://journals.asm.org/doi/10.1128/mmbr.00024-08) This group 2 system is used by human and animal mucosal pathogens causing urinary tract infections, septicemia, and meningitis, including extraintestinal pathogenic *E. coli*, *Neisseria meningitidis*, *Haemophilus influenzae*, *Campylobacter jejuni*, *Pasteurella multocida*, and *Actinobacillus pleuropneumoniae*.[4](https://www.nature.com/articles/s41589-024-01664-8)
Chain-length control in this pathway works differently. During synthesis of the *E. coli* O9a antigen, a coiled-coil molecular ruler, WbdD, directly controls the length of the polysaccharide formed in the cytoplasm by the polymerase WbdA.[3](https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/9397/Naismith_2016_COSB_Bacterial_CCBYNCND_Published.pdf?isAllowed=y&sequence=1)
## Processive synthases: alginate, curdlan and cellulose-like systems
The synthase-dependent pathway secretes complete polymer strands across the membranes and the cell wall, and is independent of a flippase for translocating repeat units. It is typically used for homopolymers such as curdlan (β-(1-3)-glucose) and bacterial cellulose (β-(1-4)-glucose).[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) This is the mechanistic contrast with Wzy polymerases: instead of a cytoplasmic assembly, flipping and periplasmic polymerization split across separate proteins, a single processive synthase both polymerizes and secretes.
Alginate shows how far this design can be elaborated. In *Pseudomonas aeruginosa*, polymerization and secretion are linked via an envelope-spanning multiprotein complex composed of at least six subunits (Alg8, Alg44, AlgG, AlgX, AlgK, AlgE). Alginate is initially synthesized as polymannuronic acid; mannuronan C-5-epimerases convert [mannuronic acid](https://www.edgepedia.org/mannuronic-acid) residues into guluronic acid residues, while other enzymes further modify the polymer, including by acetylation.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) In synthase-dependent systems, periplasmic transport is mediated by a protein scaffold containing [tetratricopeptide repeats](https://www.edgepedia.org/tetratricopeptide-repeat), followed by translocation across the outer membrane through an integral β-barrel porin.[6](https://journals.asm.org/doi/10.1128/spectrum.01290-22) Consistent with this separateness, no schematic crossover between Wzx/Wzy- or ABC-transporter pathway proteins and synthase-dependent pathway proteins has been identified.[6](https://journals.asm.org/doi/10.1128/spectrum.01290-22)
## By the numbers
The quantitative picture from these sources is structural rather than kinetic. Wzx/Wzy-pathway polysaccharides are heteropolymers commonly containing up to four or five types of sugar, xanthan being an example.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) The alginate secretion-polymerization complex has at least six subunits.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full) The ABC-dependent capsule scheme runs in four enzymatic steps.[4](https://www.nature.com/articles/s41589-024-01664-8) The undecaprenyl anchor is C55.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full)
## How it compares with eukaryotic and sibling systems
The shared logic across bacterial and eukaryotic cell-surface glycan synthesis is the lipid-linked carrier: both bacterial Wzx/Wzy systems and eukaryotic [dolichol-pathway glycosyltransferases](https://www.edgepedia.org/dolichol-pathway-glycosyltransferases) build glycans on a polyisoprenol phosphate, and the bacterial initiating enzymes split into PHPT and PNPT classes, of which humans have only the PNPT type.[3](https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/9397/Naismith_2016_COSB_Bacterial_CCBYNCND_Published.pdf?isAllowed=y&sequence=1) The synthase-dependent pathway, meanwhile, shares its single-enzyme logic with hyaluronic acid synthesis, which is catalyzed by a single hyaluronan synthase performing both polymerization and secretion using glucuronic acid and GlcNAc precursors.[2](https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full)
## Recent developments
The clearest recent advance is the 2024 identification of transition transferases that prime capsule polymerization. This addressed step II of the ABC-dependent pathway, which had been uncharacterized and comprised the synthesis of the region connecting the glycolipid and the capsule polymer.[4](https://www.nature.com/articles/s41589-024-01664-8)
## References
1. Assembly of Bacterial Capsular Polysaccharides and Exopolysaccharides | Annual Reviews — https://www.annualreviews.org/content/journals/10.1146/annurev-micro-011420-075607
2. Bacterial exopolysaccharides: biosynthesis pathways and engineering strategies — https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00496/full
3. Bacterial polysaccharide synthesis and export (Naismith, Current Opinion in Structural Biology) — https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/9397/Naismith_2016_COSB_Bacterial_CCBYNCND_Published.pdf?isAllowed=y&sequence=1
4. Transition transferases prime bacterial capsule polymerization | Nature Chemical Biology — https://www.nature.com/articles/s41589-024-01664-8
5. Synthesis of bacterial polysaccharides via the Wzx/Wzy-dependent pathway — https://cdnsciencepub.com/doi/10.1139/cjm-2014-0595
6. Bacterial Outer Membrane Polysaccharide Export (OPX) Proteins Occupy Three Structural Classes with Selective β-Barrel Porin Requirements for Polymer Secretion — https://journals.asm.org/doi/10.1128/spectrum.01290-22
7. Pivotal Roles of the Outer Membrane Polysaccharide Export and Polysaccharide Copolymerase Protein Families in Export of Extracellular Polysaccharides in Gram-Negative Bacteria — https://journals.asm.org/doi/10.1128/mmbr.00024-08
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Enzyme classes and activities › Glycosyltransferases and glyco-enzyme activities › Dolichol-linked and polysaccharide-synthesizing enzymes › Bacterial extracellular polysaccharide synthesis enzymes*
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