Carbohydrate chemistry volume 40

Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 Carbohydrate Chemistry Chemical and Biological Approaches Volume 40 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 View Online View Online Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 A Specialist Periodical Report Carbohydrate Chemistry Chemical and Biological Approaches Volume 40 Editors Amelia Pilar Rauter, Universidade de Lisboa, Portugal Thisbe K Lindhorst, Christiana Albertina University of Kiel, Germany Yves Queneau, Universite ´ de Lyon, France Authors Isabelle Andre ´, Universite ´ de Toulouse, France Jean-Marie Aubry, Universite ´ Lille Nord de France, France Jacques Auge , University of Cergy-Pontoise, France ´ Caroline Ballet, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Chantal Barberot, Universite ´ de Reims Champagne-Ardenne, France Jean-Marie Beau, Universite ´ Paris-Sud, Orsay, and CNRS, Gif-sur-Yvette, France Thierry Benvegnu, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Davide Bini, Universita degli Studi di Milano-Bicocca, Italy Yves Ble ´riot, Universite ´ de Poitiers, France Julie Bouckaert, Universite ´ Lille Nord de France, France Yann Bourdreux, Universite ´ Paris-Sud, Orsay, France Francois-Didier Boyer, CNRS, Gif-sur-Yvette, and INRA, Versailles, France Alexandre Cavezza, L’Ore ´al Research & Innovation, Aulnay-sous-Bois, France Yves Chapleur, Universite ´ de Lorraine, Nancy, France Laura Cipolla, Universita degli Studi di Milano-Bicocca, Italy Claire Coiffier, Universite ´ de Reims Champagne-Ardenne, France Florent Colomb, Universite ´ Lille Nord de France, France Xavier Coqueret, Universite ´ de Reims Champagne Ardenne, France Stephen Cowling, University of York, UK Maria Dalko-Csiba, L’Ore ´al Research & Innovation, Aulnay-sous-bois, France Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 View Online Richard Daniellou, Universite d’Orle ´ans, France Samuel J Danishefsky, Sloan-Kettering Institute for Cancer Research and Columbia University, New York, USA David Daude ´, Universite ´ de Toulouse, France Edward Davis, University of York, UK Philippe Delannoy, Universite ´ Lille Nord de France, France Gilles Doisneau, Universite ´ Paris-Sud, Orsay, France Sandrine Donadio-Andre ´ i, Siamed’Xpress, Gardanne, France Nassima El Maă, SiamedXpress, Gardanne, France Alberto Fernandez-Tejada, Sloan-Kettering Institute for Cancer Research, New York, USA Vincent Ferrie ` res, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Luca Gabrielli, Universita degli Studi di Milano-Bicocca, Italy Charles Gauthier, Universite ´ de Poitiers, France Markus Glafg, Johannes Gutenberg-Universitaăt Mainz, Germany Peter Goekjian, Universite ´ de Lyon, France John Goodby, University of York, UK Alexandra Gouasmat, Universite ´ Paris-Sud, Orsay, France Eric Grand, Universite de Picardie Jules Verne, Amiens, France ´ Jaros"aw M Granda, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland Sophie Groux-Degroote, Universite ´ Lille Nord de France, France Ce line Guillermain, Universite de Reims Champagne Ardenne, France ´ ´ Laure Guillotin, Universite d’Orle ans, CNRS, France ´ ´ Dominique Harakat, Universite de Reims Champagne Ardenne, France ´ Sebastian Hartmann, Johannes Gutenberg-Universitaăt Mainz, Germany Arnaud Haudrechy, Universite de Reims Champagne-Ardenne, France Eric He non, Universite de Reims Champagne-Ardenne, France ´ ´ S"awomir Jarosz, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland Janusz Jurczak, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland Jose ´ Kovensky, Universite ´ de Picardie Jules Verne, Amiens, France Micha" Kowalski, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland Horst Kunz, Johannes Gutenberg-Universitaăt Mainz, Germany Laure LHaridon, Ecole Normale Supe ´rieure, Paris, France Pierre Lafite, Universite d’Orle ans, CNRS, France ´ Laurent Legentil, Ecole Nationale Supe rieure de Chimie de Rennes, ´ France Aure ´ lie Leme ´ tais, Universite Paris-Sud, Orsay, France Loăc Lemie ` gre, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Nade ` ge Lubin-Germain, University of Cergy-Pontoise, France Jun Luo, Tongji School of Pharmacy, Huazhong University of Science and technology, Wuhan, P R China Carine Maalaki, Universite ´ de Namur, Belgium Jean-Maurice Mallet, Ecole Normale Supe ´rieure, Paris, France Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 View Online Alberto Marra, Ecole Nationale Supe ´rieure de Chimie de Montpellier, France Olivier Massinon, Universite ´ de Namur, Belgium Aure ´ lie Mathieu, CNRS, Gif-sur-Yvette, France Yong Miao, Universite ´ Lille Nord de France, France Jean-Claude Michalski, Universite ´ Lille Nord de France, France Vale ´ rie Molinier, Universite ´ Lille Nord de France, France Pierre Monsan, Universite ´ de Toulouse, France Andre Mortreux, Universite ´ ´ Lille Nord de France, France Magali Nicollo, Siamed’Xpress, Gardanne, France Francesco Nicotra, Universita degli Studi di Milano-Bicocca, Italy Ste ´ phanie Norsikian, CNRS, Gif-sur-Yvette, France Caroline Nugier-Chauvin, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Jean-Marc Nuzillard, Universite ´ de Reims Champagne-Ardenne, France Bjo rn Palitzsch, Johannes Gutenberg-Universita ă ăt Mainz, Germany Nadia Pellegrini-Moăse, Universite de Lorraine, Nancy, France Michel Philippe, LOre al Research & Innovation, Aulnay-sous-Bois, ´ France Patrick Pichaud, L’Ore al Research & Innovation, Aulnay-sous-Bois, France Loăc Pichavant, Universite de Reims Champagne Ardenne, France Daniel Plusquellec, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Mykhaylo A Potopnyk, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland Yvan Portier, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Gwladys Pourceau, Universite de Picardie Jules Verne, Amiens, France ´ Magali Remaud-Sime on, Universite de Toulouse, France ´ ´ Myle ne Richard, Universite de Lorraine, Nancy, France ` ´ Catherine Robbe-Masselot, Universite ´ Lille Nord de France, France Maria C Rodrı´guez, Center for Biomolecular Chemistry, Havana, Cuba Catherine Ronin, Siamed’Xpress, Gardanne, France Laura Russo, Universita degli Studi di Milano-Bicocca, Italy Ram Sagar, Universite ´ de Poitiers, France Mathieu Sauthier, Universite ´ Lille Nord de France, France Marie-Christine Scherrmann, Universite ´ Paris-Sud, Orsay, France Antonella Sgambato, Universita degli Studi di Milano-Bicocca, Italy Jean-Francois Soule ´ , CNRS, Gif-sur-Yvette, France Arnaud Stevenin, CNRS, Gif-sur-Yvette, France Isabelle Suisse, Universite ´ Lille Nord de France, France Sylvestre Toumieux, Universite ´ de Picardie Jules Verne, Amiens, France Sylvain Tranchimand, Ecole Nationale Supe ´rieure de Chimie de Rennes, France Simon Trouille, L’Ore ´al Research & Innovation, Aulnay-sous-Bois, France Dominique Urban, Universite ´ Paris-Sud, Orsay, France Yury Valde ´ s Balbin, Center for Biomolecular Chemistry, Havana, Cuba Boris Vauzeilles, Universite ´ Paris-Sud, Orsay, and CNRS, Gif-sur-Yvette, France Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 View Online Vicente Verez Bencomo, Center for Biomolecular Chemistry, Havana, Cuba Ste ´ phane P Vincent, Universite ´ de Namur, Belgium Anne Wadouachi, Universite ´ de Picardie Jules Verne, Amiens, France Qian Wan, Tongji School of Pharmacy, Huazhong University of Science and technology, Wuhan, P R China Amandine Xolin, CNRS, Gif-sur-Yvette, France Rui Xu, Universite ´ de Lyon, France Philippe Zinck, Universite ´ Lille Nord de France, France View Online If you buy this title on standing order, you will be given FREE access to the chapters online Please contact sales@rsc.org with proof of purchase to arrange access to be set up Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 Thank you ISBN: 978-1-84973-965-8 ISSN: 0306-0713 DOI: 10.1039/9781849739986 A catalogue record for this book is available from the British Library & The Royal Society of Chemistry 2014 All rights reserved Apart from fair dealing for the purposes of research or private study for noncommercial purposes, or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act, 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reproduction in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP001 View Online Preface Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP009 DOI: 10.1039/9781849739986-FP009 Volume 40 of the Specialist Periodical Reports entitled Carbohydrate Chemistry – Chemical and Biological Approaches is dedicated to the ´ Lubineau This chemist, well known amongst memory of Prof Andre organic, carbohydrate, and green chemists for his work, left behind him not only his innovative work applied in industry and recognized for its excellence and uniqueness, but also many, many friends among his colleagues and students His former Ph.D student, Dr Yves Queneau, had the initiative to dedicate this volume to his memory and is very welcome as guest editor The first book chapter describes the industrial development of Lubineau’s C-glycosylation reaction to access a product for skin anti´als, a leading company in cosmetics The ageing marketed by L’Ore principles of green chemistry concerning water-promoted reactions such as cycloaddition, N-glycosylation and C-glycosyl compound formation, ´ Lubineau, are well documented in Chapter implemented by Andre The use of carbohydrates in sustainable chemistry is highlighted in ´ Lubineau’s contributions in this field with Chapter 3, exemplifying Andre various applications, namely carbohydrates as surfactants In Chapter 4, synthesis and properties of sugar-based hydrotropes are revised These compounds exhibit amphiphilicity and can be regarded as weak surfactants, being considered promising alternatives to the currently used hydrotropes from petroleum origin Chapter shows how green catalysis can be used in carbohydrate etherification A diversity of synthetic strategies are described in Chapters 6–10, focusing particularly on anomeric functionalization, either using exoglycals or glycosylation catalysed with iron salts or by gold, supplemented by electrochemical or enzymatic (thio)glycosylation Recent protocols for the synthesis of anionic oligosaccharides, that exhibit interesting biological activities in cell proliferation, angiogenesis and cancer, host-pathogen interactions, Alzheimer’s disease and plant protection are presented in Chapter 11 Synthesis of macrocycles from sucrose with interesting complexing properties, of carbohydrate-based dendrimers, and of polymers via radical free polymerization starting from allyl or vinyl pentosides, or by organo-catalysed polymerization of polyester-functionalized carbohydrates, is covered by Chapters 12–15 This volume illustrates the importance of glycochemistry for the production of biomolecular entities that are innovative regarding structure and usefulness Covering from simple sugars to polymeric structures and to glyco-conjugated biomolecules, this volume also demonstrates the importance of glyco-structures and technology for innovation in molecular glycobiology and health Glycolipid liquid crystals are revised in Chapter 16 giving a particular attention to their self-assembling properties, while Chapter 17 shows how glycolipid-containing nanosystems can be applied for novel nanotherapeutic strategies based on Carbohydr Chem., 2014, 40, ix–x | ix  c The Royal Society of Chemistry 2014 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-FP009 View Online drug/gene delivery systems or on adjuvants for vaccine applications Also a new approach to describe furanose ring conformational dynamics is revealed, based on inherent ring motions rather than arbitrarily restrictive descriptors, which is better able to describe unsymmetrical conformations that are lost by pseudo-rotational analysis (Chapter 18) In Chapter 19, glycofuranosyl-containing conjugates are reviewed as molecular tools for understanding enzyme activity as well as related biochemical pathways Chapters 20 and 21 include conformationally restricted glycosides as inhibitors of sugar-processing enzymes and receptors, as well as anion receptors having their binding pocket modified with monosaccharides It was shown how incorporation of a sugar into the backbone of a host molecule affects structural and binding properties of anion receptors Therapeutic glycoprotein hormone gonadotropins and anti-cancer multivalent constructs are documented in Chapters 22 and 23, respectively, while the field of carbohydrate-based vaccines is covered in the next three chapters, focusing on anti-cancer vaccines (Chapters 24 and 25), and antibacterial and antifungal vaccines (Chapter 26) Chapters on the role of mucins and mucin glycosylation in bacterial adhesion (Chapter 27), and on bioengineering of glucansucrases (Chapter 28) complete the collection of topics assembled in this volume The described achievements in glycochemistry and glycobiology demonstrate the importance of the glycosciences for innovation in health and in the corresponding societal challenges facing us More than that, ´ Lubineau as a scientist, and as a they show the charisma of Andre colleague and a friend Those who had the privilege of working or collaborating with him confirmed, through their contributions in this volume, their devotion to his memory As editors of the Specialist Periodical Reports: Carbohydrate Chemistry – Chemical and Biological Approaches, we are very honored to ´ Lubineau dedicate this book to the memory of Andre ´lia P Rauter, Thisbe K Lindhorst Ame and Yves Queneau x | Carbohydr Chem., 2014, 40, ix–x View Online OH OH H 3C O HO HO OH O OH HO OH O HO OH HO NHAc N-Acetyl-D-glucosamine OH [41] [68] OH HO O O HO HO O HO OH OH Maltose [41] HO O HO L-Rhamnose OH 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 O HO O OH OH OH Arbutin Salicin [69] [70, 71] OH OH OH O HO HO O HO HO O O OH OH HO O O Piceid Aesculin OH [71] [72] H O O HO HO O OH HO Hydroquinone O Caffeic acid [72] HO OH OCH Vanillin OH [71] Zingerose [71] [71] OH O HO OH OH OH O HO O HO OH OH OH (+) Catechin D-Arabinose [73] OH OH OH OH OH O O HO HO HO OH OH OH [74] [74] O HO OH OH OH L-Arabinose [74] OH OH OH OH D-Allose OH O OH HO [74] [74] HO O HO OH D-Xylose [74] O OH OH D-Altrose OH OH O HO HO OH D-Mannose OH [74] OH OH O HO OH D-Galactose HO D-Fucose [74] OH OH L-Fucose [74] L-Galactose [74] Fig Representation of some exogenous acceptors recognized by glucansucrases from GH13 family to catalyze transglucosylation reactions.68–73 632 | Carbohydr Chem., 2014, 40, 624–645 View Online HO HO OH O OH OH OH OH HO L-Mannose OH L-Xylose L-Altrose L-Allose [74] [74] OH OH OH HO OH OH OH HO OH 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 OH OH OH [74] OH OH O HO OH OH OH [74] HO OH O O OH HO OH OH OH D-Sorbitol OH OH D-Arabitol D-Mannitol [74] [74] [74] OH O HO HO OH OH O OH HO OH OH HO HO OH HO OH OH HO OH OH D-Xylitol [74] OH OH D-Maltitol [74] Myo-inositol [74] Fig (Continued) from the glucan produced by the native strain in terms of solubility or susceptibility to endo-dextranase hydrolysis.76 Variants B-742CA and B-742CB synthesized dextran with a-1,4 branched linkages and a high percentage of a-1,3 bonds, respectively.77 Mutants Lm M281 and Lm M286 derived from L mesenteroides strain Lm 28 were shown to produce more active glucosyltransferases or resistant glucan, respectively.78 Synchrotron radiations in the 70–1000 eV region were also considered for further engineering the Leuconostoc mesenteroides B-12FMC variant.79 From this work, a hyperproducing mutant constitutive for dextransucrase, namely B-512FMCM, was shown to produce 13-fold increase in activity and 1000-fold increase in glucansucrase protein compared to the parental strain UV radiations were also used to engineer the dextransucrase producing strain Leuconostoc mesenteroides KIBGE IB-22 One mutant over the 42 generated showed a 6.75 fold increase in activity compared to the wild-type enzyme.80 Altogether, these results underline that genetic engineering of native strains may be useful for both increasing the production of glucans and modulating their properties 2.2 Random engineering of recombinant enzymes Because native strains may be sometimes difficult to handle, the use of recombinant enzymes produced into well-known organisms such as Escherichia coli has been investigated Genes coding for glucansucrases have been isolated, heterologously expressed and further considered for bioengineering experiments Ultrasoft X-ray irradiations have been applied to an Escherichia coli transformant to generate dextransucrase Carbohydr Chem., 2014, 40, 624–645 | 633 View Online A Amylosucrase from N polysaccharea (GH13) GTF180-ΔN from L reuteri (GH70) N N C 746 Domain V Domain N 1751 C 90 Domain B 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 184 793 1639 Domain IV 260 Domain B 927 1605 990 1591 Domain B’ 395 460 Domain A 550 Domain C Domain A 1238 636 1377 Domain C C B GH13 amylosucrase from N polysaccharea (PDB 1G5A) R446 GH70 glucansucrase GTF180-ΔN from L reuteri (PDB 3KLK) Subsite +1 D394 Subsite +1 D1136 R509 D393 Q1140 W1065 H1135 D507 N1411 H392 E328 F250 D144 R284 R1023 D1458 E1063 D1025 D286 Y1465 Y147 Subsite -1 H187 Subsite -1 D1504 Q1509 Fig Structural comparisons of glucansucrases from GH13 and GH70 families (A) Overall three-dimensional structure of amylosucrase from N polysaccharea (pdb:1G5A) and glucansucrase GTF180 from L reuteri (pdb:3KLK) (B) Representation of subsites À and ỵ constituting the bottom of active site pocket, docked with sucrose (extracted from pdb:1JGI and pdb:3HZ3, respectively) Subsites of glucansucrases from both GH13 and GH70 families share a similar spatial organization and involve comparable hydrogen bonding networks mainly due to subsite À Catalytic residues are highlighted in bold and water molecules are repredented as spheres variants of DSRB742 with increased constitutive activity for the synthesis of highly a-1,3 branched dextran.81 The same procedure was applied to generate the novel dextransucrase gene DSRN and was further combined with site-directed mutagenesis to construct four mutants (DSRN1 to DSRN4), one of them DSRN3 (K395T) showing the highest transglucosylation efficiency with diverse acceptors (maltose, salicin, gentiobiose).82 634 | Carbohydr Chem., 2014, 40, 624–645 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online Along with these reports, combinatorial engineering have been attempted to increase the specific activity of glucansucrases The performance of amylosucrase from Neisseria polysaccharea (NpAS) was enhanced by random mutagenesis, gene shuffling and selective screening Variants with up to a five fold increase in activity toward sucrose were isolated (R20C/F598S and V389L/N503I).83 Variants with increased polymerization efficiency (E227G), thermostability (P157A/D231Y, P234L/ G554S and N387D) or activity (N76D, E62K/D506N, N387D, Q613H) were further isolated.84 Random engineering strategies may thus be useful for enhancing the performances of recombinant enzymes what is of prime interest for biotechnological purposes Moreover, industrial processes often require high reaction temperatures and the enhancement of enzyme thermostability is still challenging Directed evolution of NpAS by error-prone PCR has been performed and led to the isolation of two double mutants (R20C/A451T and A170V/Q353L) and a single mutant (P351S) with 3.5 up to 10 fold increased half-lives at 50 1C as compared to the parental wild-type enzyme The increased stability was suspected to be due to the introduction of additional hydrogen-bonding interactions and salt-bridge rearrangements that are assumed to strengthen the overall structure.85 Structure-based engineering of glucansucrases 3.1 Scaffold diversification Glucansucrases are usually large proteins (W120kDa except amylosucrase (70kDa)) which can hinder their efficient production To circumvent this limitation, the construction of truncated variants was considered to generate more stable and more soluble proteins A truncated variant of alternansucrase from Leuconostoc mesenteroides NRRL B-1355, with modified repeating units of the C-terminal domain was constructed and showed the same specificity as the native enzyme while being highly active.86,87 Mutants rationally shortened of their signal peptide have also been constructed and resulted in efficient, active and stable recombinant glucansucrases.88–90 Truncated forms of DSRE563, a dextransucrase obtained from the constitutive mutant CB4-BF563 derived from L mesenteroides B-1299, were constructed These trimmed enzymes DSRE563-1 and DSRE563-2 were shown to synthesize a less-soluble dextran.91 Glucansucrases such as DSR-E produced by L mesenteroides NRRL B-1299 are known to display original structures harbouring two active sites In this case, Catalytic Domain (CD1) synthesizes a-1,6 linkages, while Catalytic Domain (CD2) is responsible for the rare and unusual a-1,2 specificity Truncated forms of this protein have been constructed CD2 domain was deleted to produce the engineered DSR-E-D(CD2) enzyme responsible for the synthesis of dextran containing mainly a-1,6 linkages, as well as a-1,3 and a-1,4 linkages but no a-1,2 bond Conversely, the truncated form of the first catalytic domain GBD-CD2 (DSR-E-D(VZ-CD1)) after construction, turned out to be unable to catalyze polymerization reactions and only hydrolytic reactions were observed Nevertheless, using sucrose as donor and isomalto-oligosaccharides as Carbohydr Chem., 2014, 40, 624–645 | 635 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online acceptors, the GBD-CD2 enzyme was able to catalyze transglucosylation reactions and interestingly, it synthesized solely a-1,2 linkages.92 The mode of branching of this enzyme was investigated through the analysis of a 1.5 kDa grafted dextran and revealed a stochastic branching process.93 In order to provide better insights on the sequence-structure-function relationships of glucansucrases, attempts have been made to diversify their three-dimensional organization by varying enzyme scaffolds In vitro constructions of chimeric glucansucrases have been attempted Selected sites of glucansucrases DSRS and DSRT5 from Leuconostoc mesenteroides NRRL 512-F have been exchanged and six chimeric variants were constructed Upon analysis, their products were found to differ from the glucans synthesized by their parental enzyme in terms of solubility and linkage specificity.94 Fusion proteins DXSR harbouring dextransucrase and dextranase activities were generated and successfully expressed in E coli and used for the production of linear isomalto-oligosaccharides (IMO) further increased by the introduction of metal ions to reach a 30-fold increase in the production of IMO as compared to a mixture of the two enzymes.95 Another fusion protein namely DSXR has also been constructed and the expression level was optimized using response surface methodology to overcome the low productivity of DXSR but conserving similar properties.96 Fusion protein involving glucansucrases were also considered for transgenic investigations Dextransucrase DSR-S from Leuconostoc mesenteroides fused to the chloroplastic ferredoxin signal peptide was used to transform two potato genotypes (cv Kardal and the amylose-free mutant (amf)) Dextrans were detected in potatoes tuber juices from transformants of both species but with a two fold increased concentration for Kardal No dextran could be detected inside the starch granule, however the morphology of this latter was altered probably due to an accumulation of dextran in the tuber juices.97 A truncated mutansucrase GtfICAT without starch-binding domain derived from GtfI was expressed in Kardal The production of mutan adhering to starch granules was detected but not incorporated in the starch granules.98 A fusion protein comprising GtfICAT and a starch-binding domain (SBD) at either N- or C- terminal end was introduced in two genetically different potato backgrounds The fusion protein was detected in starch granules Starches from the plant expressing GtfICAT contained less mutan than GtfI expressing plant However, the granule morphology was altered in both genetic backgrounds These results underline the fact that expression of engineered glucansucrases can be used to interfere with starch biosynthetic pathway in plants.99 3.2 Semi-rational and rational engineering Glucansucrases are mainly involved in the synthesis of a wide variety of gluco-oligosaccharides and high molecular weight glucopolymers Determination of the three-dimensional structures of glucansucrases have enabled to investigate the role of the different subsites and glucan binding domains of the enzymes Intensive work has shown that properties of the glucan synthesized such as specificity of the osidic linkages 636 | Carbohydr Chem., 2014, 40, 624–645 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online or chain length are enzyme-dependent and may be modulated through protein engineering Mutagenesis experiments of Q937 and D569 positions of glucansucrase GTF-I from Streptococcus downei showed that single amino acid substitutions can impact the glucan linkage.100,101 Another enzyme, dextransucrase DSRS from Leuconostoc mesenteroides NRRL B-512F, has been submitted to site-directed mutagenesis Lysine residues were introduced at the N-terminal end Two single mutants, T350K and S455K, and the corresponding double-mutant T350K/S455K were constructed Their products showed an enhanced amount of 1,6-linked Glcp going from 70 to 85% for the single mutants and the unusual presence of 2,6-linked Glcp for the double-mutant.102 Recent semi-combinatorial engineering of this enzyme has also underscored the impact of amino acid mutations on glucan structures and properties Eight residues from the catalytic domain were targeted from sequence analysis and engineered using Incorporating Synthetic Oligos via Gene Reassembling (ISOR) method.103 Products obtained using the variants of a truncated DSRS (DSRS vardel D4N) harbouring from one to four amino acid substitutions (F353T, S512C, F353W, H463R/T464D/S512C, H463R/T464V/S512C, D460A/ H463S/T464L, D460M/H463Y/T464M/S512C) were analyzed and revealed polymers differing in their a-1,3 linkage contents and their gel-like properties in solution This work provided a useful toolbox of glucansucrases producing increasing amounts of a-1,3 linkages.104 Reuteransucrase from Lactobacillus reuteri 121 GTF-A was also successfully engineered The role of N1134 located right next to the catalytic residue D1133 was investigated and it was shown to be involved in both product specificity and hydrolysis/transglucosylation ratio Single mutants at this position affected the total specific activity going from 45–75% loss for N1134Q, N1134G or N1134H up to two fold increase for N1134A, N1134D and N1134S.105 Another study on this enzyme converted its reuteransucrase activity into a dextransucrase activity by increasing the amount of a-1,6 linkage from B35% up to B85% and decreasing the amount of a-1,4 linkages from B45% down to B5% for the quintuple mutant P1026V/I1029V/N1134S/N1135E/S1136V These results underline the role of amino acid changes in enzyme mechanism and product nature.106 Bioengineering of glucansucrase GTF-180, an a-1,3/a-1,6 linkage synthesizing enzyme, from Lactobacillus reuteri strain 180 was undertaken leading to the creation of a triple mutant V1027P/S1137N/A1139S able to synthesize a-1,4 linkages Twelve other variants were also identified as producing modified exopolysaccharides, some of them generating a-1,4 linkages The products synthesized by these variants were analyzed and showed discrepancies in their structural and physical properties such as solubility, molecular weight or structure.107,108 Specificity of glucansucrase GTF-R from Streptococcus oralis was also modulated through random mutagenesis of a conserved motif surrounding the transition state stabilizer.109 A triple mutant R624G/V630I/ D717A was identified as producing a mutan type polymer harbouring mainly a-1,3 linkages by opposition to the wild-type produced dextran Carbohydr Chem., 2014, 40, 624–645 | 637 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online type polymer which is mainly composed of a-1,6 linkages Mutagenesis at position S268 was also applied what led to variants with modified transglucosylation properties Variants mainly synthesizing short-chain oligosaccharides, among which mutants S268D and S268R, lost their capacity to synthesize polymers probably by facilitating the release of acceptor reaction products as well as the attack of GTFR-Glc intermediate by water and acceptor substrates.109 Amino acid residues located near the active site of DSRBCB4 dextransucrase from Leuconostoc mesenteroides B-1299CB4 were targeted by site-directed mutagenesis The triple mutant V532P/E643N/V644S was constructed and showed to add a-1,3 and a-1,4 linkages onto the a-1,6 linked glucan mainly synthesized by the wild-type enzyme The V535I/ S642N mutations were subsequently introduced by directed mutagenesis The resulting variant was shown to synthesize an increased amount of a-1,4 linkages (up to 11%) compared to the triple-mutant.110 The molecular basis of glucan production of amylosucrase from Neisseria polysaccharea was also investigated through the engineering of subsites ỵ 1, ỵ 2, ỵ residues An outstanding variant R446A was isolated which synthesizes twice as much insoluble glucan as the parental enzyme while generating lower amounts of by-products.38 The use of glucansucrases might be impaired by uncontrolled levels of sucrose hydrolysis which is a minor reaction occurring naturally The transglucosylation/hydrolysis ratio has thus to be considered when optimizing performances of GS in order to limit their side reactions Hybrid reuteransucrases have been constructed in this way Some variants exhibiting strongly increased transglucosylation activities were obtained by targeting specific regions of the catalytic domains The conversion of sucrose into oligosaccharide and polysaccharide products was increased Two variants namely GTFO-A-dN and GTFO-dN-RS, derived from the reuteransucrase GTFO from Lactobacillus reuteri ATCC55730, displayed reduced hydrolysis activities as compared to their parental enzyme but maintained the a-1,4 linkage specificity.111 The transglucosylation/hydrolysis ratio appears thus to be controllable through rational protein engineering Though mainly used for glucan synthesis, glucansucrases can also be exploited for synthesizing glucoconjugates or short oligosaccharides, polymerization being then undesired for this purpose The polymerization capacity of GS may be modulated to favour the production of short glucosylated products The gene encoding the amylosucrase from Neisseria polysaccharea was submitted to high-rate segmental random mutagenesis A segment coding for amino acids involved in substrates recognition was targeted Two residues, D394 and G396 were identified as playing a major role in the control of generated chain length Indeed, by substituting these residues with bulky amino acids, the synthesis of short oligosaccharides (up to three units) was shown to be favoured Steric hindrance introduced at these sites was thought to interfere with the elongation of amylose chains The variants selected were specific of the synthesis of mono and di-glucosylated products and could be considered for the limited glucosylation of acceptors.112 638 | Carbohydr Chem., 2014, 40, 624–645 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online As described earlier in this manuscript, GS are known to glucosylate more or less efficiently a wide range of hydroxylated molecules The efficiency of this non-natural reaction will strongly depend on how well the exogenous acceptor is able to compete with the natural products resulting from sucrose utilization and present in the reaction media The development of biocatalysts with enhanced or even new glucosylation capabilities is thus challenging and has only scarcely been considered Mutagenesis experiments applied to the amylosucrase from Neisseria polysaccharea have been recently used to improve the acceptor glucosylation rate using sucrose as donor In this report, seven residues were targeted for saturation mutagenesis and 133 mono-variants were constructed The efficiency of the glucosylation of 2-acetamido-2-deoxy-aD-glucopyranoside was remarkably enhanced by some single mutants to reach conversion degrees over 90% which were accompanied by up to 130-fold enhanced catalytic efficiency This library was also assayed toward another molecule, the methyl-a-L-rhamnopyranoside, non-recognized by the wild-type enzyme Fifteen mutants harbouring mutations at either positions 228 or 290 displayed a remarkable novel specificity toward the exogenous acceptor and they were able to glucosylate it with remarkable conversion degrees going up to 44% after protein purification.113,114 The pairwise recombination of these mutations was further applied and led to the isolation of several double mutants displaying a spectacular 400-fold improvement of their catalytic efficiency toward 2-acetamido-2-deoxy-a-D-glucopyranoside.115 A structure-based engineering of this amylosucrase using stability change predictions was recently reported.22 The reshaping of subsite À was investigated leading to the evaluation of 57 single mutants Some variants were found more stable than the wild-type enzyme or able to synthesize a series of oligosaccharides with original distribution profile Protein engineering appears to be noteworthy for developing novel glucansucrases with unprecedented properties that need to be further investigated in this purpose Screening methods applied to detect novel or improved glucansucrases Enzyme engineering strategies often require generating an important number of variants and positive selection pressure usually have to be applied for isolating original mutants from large libraries Highthroughput screening methods have been developed to assay glucansucrase libraries Automated protocols have been proposed for the isolation of amylosucrase variants with improved biochemical properties such as thermostability or organic solvent tolerance or activity These methods enabled already the identification of mutants generated by random mutagenesis approach using a human mutagenic DNA polymerase displaying up to 25-fold increased activity at 50 1C as compared to the parental NpAS.116,117 Variants with increased activity (up to 5-fold) were identified using automated reducing sugar assay.83 Methods for the isolation of effective transformants displaying desired properties have also been developed A pH sensitive high-throughput screening has been Carbohydr Chem., 2014, 40, 624–645 | 639 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online used for the selection of sucrose-utilizing transglycosylases E coli competent cells unable to use sucrose, transformed by a plasmid containing an engineered gene coding for an amylosucrase activity, were grown on solid medium containing sucrose and bromothymol blue (BTB) as pH colour indicator Cells expressing an active amylosucrase variant were able to use sucrose and synthesize an amylose-like polymer The fructose released during the polymerization reaction was metabolized by E coli cells through glycolysis pathway to synthesize acidic products, the local acidification being detected by BTB color change from blue to yellow.118 Another method has been developed for isolating E coli cells displaying intracellular dextransucrase activities that can be identified through a polymer-forming based strategy E coli transformants are grown on solid medium supplemented by 2% of sucrose Clones displaying dextransucrase activity synthesize an extracellular glucan and can thus be detected.119 Recently, a powerful medium-throughput screening of glucansucrase specificity has been developed Product specificities of more than 4,000 glucansucrase variants generated by combinatorial engineering were screened through a quantitive and highly sensitive NMR based-approach with a rate of 480 variants per day Altogether, 303 variants were successfully identified for their altered specificity underlining the potential of this method in glycomics for screening natural glucan biodiversity.103 Surface Plasmon Resonance spectroscopy has also been used for the detection of transglycosylase-catalyzed polymer synthesis and the determination of enzymatic activity using the alternansucrase from Leuconostoc mesenteroides NRRL B-1355 Such a methodology might be used for glucan-synthesizing enzyme screening.120 Prospects As illustrated above, the molecular evolution of glucansucrases has shown to be powerful for modulating activities or creating new transglucosylation reactions (Fig 5) Exploring further the fitness landscape of Fitness Variant Variant Sequence Variant WT Sequence Fig Exploring protein fitness landscape by directed evolution to modify specificity or create new functions and modulating biophysical properties such as thermostability, tolerance to solvents, flexibility 640 | Carbohydr Chem., 2014, 40, 624–645 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online these enzymes may offer new opportunities for optimizing non-natural functions and extend the range of synthesized products.121,122 Recent successes in the molecular evolution of glycoside-hydrolases have paved the way to future investigations towards tailor-made oligosaccharides and glycoconjugates syntheses Tools have been developed for enhancing stability, activity, expression, promiscuity and specificity of glucansucrases Though efficient for transglucosylation reactions catalysis, the use of alternative donor substrates remains a major challenge for glucansucrase applications In this context, sucrose derivatives and analogs appear relevant if utilized as substrates to further diversify the glyco-structures generated by GS.27 Moreover, investigation of structureactivity 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Bornscheuer, G W Huisman, R J Kazlauskas, S Lutz, J C Moore and K Robins, Nature, 2012, 485, 185–194 Carbohydr Chem., 2014, 40, 624–645 | 645 12/04/2014 12:03:29 Published on 20 March 2014 on http://pubs.rsc.org | doi:10.1039/9781849739986-00624 View Online ... 10.1039/9781849739986-FP011 The aim of this volume 40 of Carbohydrate Chemistry, Chemical and Biological Approaches is to illustrate how wide is the scope of carbohydrate chemistry, from synthetic methodology... Conclusion References xx | Carbohydr Chem., 2014, 40, xv–xxiii 341 341 344 359 367 372 373 374 378 378 380 382 385 388 394 395 397 398 401 401 402 405 411 413 413 Published on 20 March 2014 on... doi:10.1039/9781849739986-FP001 A Specialist Periodical Report Carbohydrate Chemistry Chemical and Biological Approaches Volume 40 Editors Amelia Pilar Rauter, Universidade de Lisboa, Portugal