Polysialic acid: three-dimensional structure, biosynthesis and function

doi:10.1016/S0959-440X(98)80144-9

Current Opinion in Structural Biology

Volume 8, Issue 5, October 1998, Pages 558-564

https://doi.org/10.1016/S0959-440X(98)80144-9 Get rights and content

Abstract

Polysialic acid is a unique cell surface polysaccharide found in the capsule of neuroinvasive bacteria and as a highly regulated post-translational modification of the neural cell adhesion molecule. Recent progress has been achieved in research on both the physicochemical properties of polysialic acid and the biosynthetic pathways leading to polysialic acid expression in bacteria and mammals.

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Polysialic acid (PSA) is a straight-chain homoglycan linked by N-acetylneuraminic acid monomers via α-2, 8- or α-2, 9-glycosidic bonds. As a negatively charged non-glycosaminoglycan, PSA has the remarkable characteristics of non-immunogenicity and biodegradation. Although different in class, PSA is similar to poly(ethylene glycol), and was originally used to increase the stability of the delivery system in circulation to prolong the half-life. As research continues, PSA's application potential in the pharmaceutical field becomes increasingly prominent. It can be used as a biomaterial for protein polysialylation and tissue engineering, and it can be used alone or with other materials to develop multifunctional drug delivery systems. In this article, the results of the bioproduction and biofunction of PSA are introduced, the common strategies for chemical modification of PSA are summarized, and the application progress of PSA-based drug delivery systems is reviewed.
Bioencapsulation of proteins in therapeutics
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The methionine dependence is a well known phenomenon in metabolism of cancer cells. Methionine γ-lyase (EC 4.4.1.11, MGL) catalyzes the γ-elimination reaction of L-methionine and thus could effectively inhibit the growth of malignant cells. Recently we have demonstrated that the mutant form of the enzyme C115H MGL can be used as a component of the pharmacological pair enzyme/S-(allyl/alkyl)-L-cysteine sulfoxides to yield thiosulfinates in situ. Thiosulfinates were shown to be toxic to various cancer cell lines. Therefore the application of the enzyme in enzyme pro-drug therapy may be promising. The conjugates of MGL and C115H MGL with polysialic acid were obtained and their kinetic and pharmacokinetic parameters were determined. The formation of polysialic shell around the enzyme was confirmed by atomic force microscopy. The half-life of conjugated enzymes increased 3–6 times compared to the native enzyme. The cytotoxic effect of conjugated MGL against methionine dependent cancer cell lines was increased two times compared to the values for the native enzymes. The anticancer efficiency of thiosulfinates produced by pharmacological pair C115H MGL/S-(allyl/alkyl)-L-cysteine sulfoxides was demonstrated in vitro. The results indicate that the conjugates of MGL with polysialic acid could be new antitumor drugs.
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The coats of bacteria contain an astounding variety of sugars within polysaccharides, peptidoglycans and/or lipopolysaccharides (LPS) that comprise an outer O-antigenic polysaccharide. These glycoconjugates are essential for maintenance of the bacterial cell wall, their functions and interactions with hosts and the environment, and represent major virulence factors. Very few of the enzymes that synthesize bacterial polysaccharides have been biochemically characterized. Several distinct mechanisms have been identified by which O-antigens are assembled. In the ATP-binding cassette (ABC) transporter-dependent pathway, a polysaccharide is assembled in the cytoplasm on a lipid carrier, and is then transported to the periplasm for processing and completion of the polymer and transfer to lipid A. In the polymerase pathway, repeating units are assembled on a lipid carrier in the cytoplasm and then translocated to the periplasm where units are polymerized and then transferred to the outer core oligosaccharide of LPS. LPS is transported to the outer membrane by a complex transporter system. Other polysaccharides or oligosaccharides are assembled on lipid carriers by similar pathways or by stepwise addition of sugar residues. This article describes structures, functions and the biosyntheses of polysaccharides and protein-bound oligosaccharides with a focus on O antigens. A comparison of glycosyltransferases serves to highlight their mechanisms of action and how they can serve as tools to synthesize polysaccharides for functional studies of bacteria and for the preparation of vaccines.
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Citation Excerpt :
Therefore, extraction of Neu5Ac from natural raw materials struggles to meet the demand for industrial-scale production of Neu5Ac. PolySia is a special polymer of sugar with some roles in different species (from microorganisms to man) (Colley et al., 2014; Muhlenhoff et al., 1998). It is attached to glycoproteins and functions in various biological processes (Angel Ferrero and Rodriguez Aparicio, 2010; Colley et al., 2014; Lin et al., 2016).
Sialic acids (Sias) are negatively charged functional monosaccharides present in a wide variety of natural sources (plants, animals and microorganisms). Sias play an important role in many life processes, which are widely applied in the medical and food industries as intestinal antibacterials, antivirals, anti-oxidative agents, food ingredients, and detoxification agents. Most Sias are composed of N-acetylneuraminic acid (Neu5Ac, >99%), and Sia is its most commonly used name. In this article, we review Sias in terms of their structures, applications, determination methods, metabolism, and production strategies. In particular, we summarise and compare different production strategies, including extraction from natural sources, chemical synthesis, polymer decomposition, enzymatic synthesis, whole-cell catalysis, and de novo biosynthesis via microorganism fermentation. We also discuss research on their physiological functions and applications, barriers to efficient production, and strategies for overcoming these challenges. We focus on efficient de novo biosynthesis strategies for Neu5Ac via microbial fermentation using novel synthetic biology tools and methods that may be applied in future. This work provides a comprehensive overview of recent advances on Sias, and addresses future challenges regarding their functions, applications, and production.
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Polysialic acid (PSA), an acidic polysaccharide usually exists as a double-chain structure on cell adhesion molecules in vertebrates. The available PSA produced from Escherichia coli fermentation, however, is monochain PSA. In this work, a biomimetic biantenna type PSA (biPSA) was synthesized in vitro under mild conditions, and the terminal nonreducing ends of sialic acid residue were retained. The structure of biPSA was characterized through infrared spectroscopy, and NMR, and the double-chain structure of biPSA was confirmed by the doubled molecular weight and particle size of biPSA. Analysis through circular dichroism, isothermal titration calorimetry, and thermostability experiments revealed that the obtained biPSA was more stable in aqueous solution than PSA, especially after complexation with Ca²⁺, which increased the variation in enthalpy and entropy. However, the addition of Cu²⁺ had a negligible effect on configuration of PSA and biPSA. The addition of Ca²⁺ promoted cell proliferation in a culture of microglia BV-2 cells with biPSA in medium. By contrast, the addition of Cu²⁺ had toxic effects. Supplementation with biPSA can maintain cell viability for a longer period than supplementation with monochain PSA. This work indicates that biPSA is a potential substitute for monochain PSA in practical applications.

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Polysialic acid: three-dimensional structure, biosynthesis and function

Abstract

Int Rev Cytol

J Biol Chem

J Biol Chem

Int J Infect Dis

J Immunol

Glycobiology

J Biochem

J Biol Chem

EMBO J

J Biol Chem

J Biol Chem

Brain Res Mol Brain Res

J Neurochem

Glycobiology

Curr Opin Cell Biol

Neurosci Res

J Neurosci Res

J Neurochem

Br J Cancer

Cancer Res

Int J Cancer

Mol Cell Neurosci

J Biol Chem

Functional and biosynthetic aspects of sialic acid diversity

Indian J Biochem Biophys

Comparison of the conformation of the epitope of α(2→8) polysialic acid with its reduced and N-acyl derivatives

Biochemistry

Antibodies to polysialic acid and its N-propyl derivative: binding properties and interaction with human embryonal brain glycopeptides

J Infect Dis

Cleavage of the polysialosyl units of brain glycoproteins by a bacteriophage endosialidase. Involvement of a long oligosaccharide segment in molecular interactions of polysialic acid

J Biol Chem

N-propionylated group B meningococcal polysaccharide mimics a unique bactericidal capsular epitope in group B Neisseria meningitidis

J Exp Med

Coating the surface: a model for expression of capsular polysialic acid in Escherichia coli K1

Mol Microbiol

Dynamics of the murine humoral immune response to Neisseria meningitis group B capsular polysaccharide

Infect Immun

Complement factor C3 deposition and serum resistance in isogenic capsule and lipooligosaccharide sialic acid mutants of serogroup B Neisseria meningitidis

Infect Immun

Recognition and control of neisserial infection by antibody and complement

Trends Microbiol