Discovery of Glycerol Phosphate Modification on Streptococcal Rhamnose Polysaccharides Using Multidimensional NMR Spectroscopy

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Discovery of Glycerol Phosphate Modification on Streptococcal Rhamnose Polysaccharides Using Multidimensional NMR Spectroscopy

Rebecca J. Edgar 1 , Vincent P. van Hensbergen 3 , Alessandro Ruda 2 , Andrew G. Turner 4 , Pan Deng 5 , Yoann Le Breton 6 , Najib M. El-Sayed 6 , Ashton T. Belew 6 , Kevin S. McIver 6 , Alastair G. McEwan 4 , Andrew J. Morris 5 , Gérard Lambeau 8 , Mark J. Walker 4 , Jeffrey S. Rush 1 , Konstantin V. Korotkov 1 , Göran Widmalm 2 , Nina M. van Sorge 3 , Natalia Korotkova 1

1 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, USA, 2 Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden, 3 University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands, 4 Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia, 5 Division of Cardiovascular Medicine and the Gill Heart Institute, University of Kentucky, Lexington, USA, 6 Department of Cell Biology & Molecular Genetics and Maryland Pathogen Research Institute, University of Maryland, College Park, USA, 7 Center for Bioinformatics and Computational Biology, University of Maryland, College Park, USA, 8 Université Côte d’Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne Sophia Antipolis, France

Gram-positive bacteria have their cell wall composed by an intricated network of peptidoglycan layers to which different families of glycopolymers are covalently grafted, the most common of which are teichoic acid-based copolymers. These polyanionic structures confer the bacterial cell wall strong rigidity by attracting cations such as magnesium and sodium, but they are also involved in many other critical functions – inter alia, metal ion homeostasis, cell division, antibiotic resistance, phage-mediated horizontal gene transfer. [1]

Certain species, such as Streptococcus Pyogenes and Streptococcus Mutans, have their teichoic acids substituted by L-rhamnose polysaccharide chains instead, arranged in different motifs characterized by the presence of different residues both in the main backbone and side-chain. [2]

Specifically, Streptococcus pyogenesis bacteria (Group A Streptococcus, GAS) carry a glycopolymer of an alternating (1->3)- and (1->2)- linked α-L-rhamnoses to which N-Acetyl-β-D-glucosamine side-chains are attached in position 3 of every other rhamnose residue (Group A Carbohydrates, GAC). GAC has proven to be a valuable vaccine antigen and take part in fundamental cellular processes. [3]

The GAC biosynthesis is composed by a 12-gene encoded pathway, the first seven of which are assigned to the rhamnose backbone assembly and its transport. Four others are necessary to graft the GlcNAc side-chain residues. In the GAC biosynthesis an additional gene is present, denominated gacH. This gene confers the bacterium resistance to Zinc toxicity, a mechanism employed by the immune system to suppress GAS, [4] while conferring sensitivity of bacteria to human group IIA secreted phospholipase A2 (hGIIA). The function of GacH from a genetic, biochemical and structural level was unveiled. The structure of the extracellular domain of GacH was determined by X-ray crystallography and identified as a novel family of glycerol phosphate transferases.

In the current presentation, we show the presence of GroP in GAC together with its overall structure obtained by multidimensional NMR spectroscopy and bioinformatic analysis. [5]

Weidenmaier, C. & Peschel, A. Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions. Nat. Rev. Microbiol. 6, 276-287 (2008).

Mistou, M.Y., Sutcliffe, I.C. & van Sorge, N.M. Bacterial glycobiology: rhamnose containing cell wall polysaccharides in Gram-positive bacteria. FEMS Microbiol. Rev. 40, 464-479 (2016).

St Michael, F. et al. Investigating the candidacy of the serotype specific rhamnan polysaccharide based glycoconjugates to prevent disease caused by the dentalnpathogen Streptococcus mutans. Glycoconj. J. 35, 53-64 (2018).

Ong, C.L., Gillen, C.M., Barnett, T.C., Walker, M.J. & McEwan, A.G. An antimicrobial role for zinc in innate immune defense against group A streptococcus. J. Infect. Dis. 209, 1500-1508 (2014).

Edgar , R., van Hensbergen, V., Ruda, A., Turner, A., Deng, P., Le Breton, Y, El Sayed, N., Belew, A., McIver, K., McEwan, A., Morris, A., Lambeau, G., Walker, M., Rush, J., Korotkov, K., Widmalm, G., van Sorge, N., Korotkova, N. Discovery of glycerol phosphate modification on streptococcal rhamnose polysaccharides. Nature Chemical Biology, 15, 463–471 (2019).

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