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Natural Product Reports

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Current developments in natural products chemistry


Volume 29 | Number 9 | September 2012 | Pages 9371024

ISSN 0265-0568

COVER ARTICLE Isabelle Andr et al. Sucrose analogs: an attractive (bio)source for glycodiversification

0265-0568(2012)29:9;1-X

NPR
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REVIEW

Sucrose analogs: an attractive (bio)source for glycodiversication


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David Daud e,abc Magali Remaud-Sim eonabc and Isabelle Andr e*abc
Received 27th April 2012 DOI: 10.1039/c2np20054f

Covering: up to April 2012 Sucrose is a widespread carbohydrate in nature and is involved in many biological processes. Its natural abundance makes it a very appealing renewable raw material for the synthetic production of high-valued molecules. To further diversify the structure and the inherent properties of these molecules, the access to sucrose analogs is of utmost interest and has historically been widely explored through chemical means. Nature also offers a large panel of sucrose-scaffold derivatives, including phosphorylated or highly substituted phenylpropanoid esters amenable to transformation. Additionally, the use of microorganisms or enzymes could provide an alternative ecologicallycompatible manner to diversify sucrose-scaffold derivatives to enable the synthesis of oligo- or polysaccharides, glycoconjugates or polymers that could exhibit original properties for biotechnological applications. This review covers the main biological routes to sucrose derivatives or analogs that are prevalent in nature, that can be obtained via enzymatic processes and the potential applications of such sucrose derivatives in sugar bioconversion, in particular through the engineering of substrates, enzymes or microorganisms. 1 2 2.1 2.2 2.3 2.3.1 2.3.2 2.3.3 3 3.1 3.2 3.3 3.4 3.5 4 4.1 4.2 4.3 4.4 4.5 Introduction Natural occurrence of sucrose derivatives Phosphate derivatives Phenylpropanoid derivatives Glycosyl derivatives Glucosyl derivatives Fructosyl derivatives Galactosyl derivatives In vitro synthesis of sucrose derivatives Keto derivatives Ester derivatives Glycosylation of sucrose Phosphate derivatives Sucrose analogs Sucrose isomers as alternative sucrose skeletons Leucrose Turanose Trehalulose Maltulose Isomaltulose 5 6 7 8 Potential applications of sucrose derivatives in sugar bioconversion Conclusions Acknowledgements References

Introduction

Sucrose (a-D-glucopyranosyl-1,2-b-D-fructofuranoside) is a widespread carbohydrate among plants. This non-reducing disaccharide is formed by an a-D-glucopyranosyl unit and a b-Dfructofuranosyl moiety covalently linked by their respective anomeric carbons through a highly energetic bond (Scheme 1). Sucrose is known to be the most available low molecular weight carbohydrate.1 The Food and Agriculture Organization (FAO) estimated its annual production at around 167.5 million tons for 20102011, mainly ensured by extraction from sugar cane and

a  de Toulouse, INSA, UPS, INP, LISBP, 135 Avenue de Universite Rangueil, F-31077 Toulouse, France b CNRS, UMR5504, F-31400 Toulouse, France c nierie des Syste mes Biologiques et des Proce de s, INRA, UMR792 Inge F-31400 Toulouse, France. E-mail: isabelle.andre@insa-toulouse.fr; Fax: +33 561 559 400; Tel: +33 561 559 969

Scheme 1 Chemical structure of sucrose (a-D-glucopyranosyl-1,2-b-Dfructofuranoside).

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sugar beet, which contain 20% and 15% of sucrose by weight and ensures 77% and 22% of sugar production, respectively. The extremely efcient purication process leads to a remarkably pure product for a moderate nal cost. Although sucrose has been mainly used so far for nutrition purposes, as a food additive or in the chemical industry, its natural abundance makes it a very interesting renewable raw material for synthesis reactions. In particular, with the anticipated oil shortage, sucrose could be

 received an engiDavid Daude neers degree in biochemistry from the National Institute of Applied Science of Toulouse (France). He received his diploma in 2009. He is currently nishing his PhD under the supervision of Prof. Magali on and Dr Isabelle Remaud-Sime  at the Laboratoire Andre nierie des Syste mes BioldInge de s in Touogiques et des Proce louse. His work is focused on the David Daud e generation of protein libraries using original semi-rational strategies and their screening in the quest of enzymes with novel specicities. His research interests include the structurefunction aspects and the molecular evolution of glycoside-hydrolases.

seen as an alternative sustainable feedstock for the chemical industry.2 In the search for carbohydrates displaying novel properties, the access to a large structural diversity is of utmost interest. Aside from the variety offered (and often hidden) by nature, articial glycodiversication can be generated via chemical and biochemical transformations. However, carbohydrates are chemically difcult to handle due to the presence of numerous reactive hydroxyl groups. Regio- and stereo-selective modications thus require appropriate protection and deprotection steps of functional groups. Independent of these problems, the use of microorganisms or enzymes may be an alternative to diversify the sucrose-scaffold and synthesize, in an eco-compatible manner, sucrose derivatives that could display original properties for biotechnological applications. In particular, sucrose is used for the production of biodegradable polymers,3 synthetic intermediates or novel carbohydrate derivatives as sweeteners and prebiotic oligosaccharides for the food industry.4 Indeed, sucrose proves to be an interesting and accessible starting material for a variety of biochemical reactions. Among enzymes utilizing sucrose as donor substrate, glucansucrases (EC 2.4.1.4, EC 2.4.1.5, and EC 2.4.1.140) from the Glycoside-Hydrolase (GH) families 70 and 13, fructansucrases (EC 2.4.1.9, EC 2.4.1.10 and 3.2.1.26) from the GH68 family and some fructosyltransferases (e.g. EC 2.4.1.10, EC 2.4.1.99 or EC 2.4.1.100) from the GH32 family have emerged as attractive synthetic tools.58 Given their broad acceptor substrate promiscuity, these enzymes have been widely used for the stereo- and regioselective synthesis of original gluco-conjugates, oligo- and polysaccharides.9

on Magali Remaud-Sime received her PhD from the University of Toulouse in 1988. Then, she was a Post-Doctoral Fellow in the Chemical Engineering department of the University of Pennsylvania and became an associate professor at The University of Toulouse in 1990. Since 2001, she has been a Full Professor at the National Institute of Applied Science of Toulouse. As the head of the Magali Remaud-Sim eon Catalysis and Enzyme Molecular Engineering group since 2002, she is involved in enzyme optimization by protein engineering to provide useful tools for white biotechnology and synthetic biology. With her collaborators, she has elucidated the mechanism of action of several glucansucrases synthesizing dextran, alternan or amylose from sucrose substrate. Her work is currently focused on the search for enzymes acting on unnatural substrates.

 received a PhD in Isabelle Andre Molecular Chemistry (1995) from the University Joseph Fourier of Grenoble (France). She held a post-doctoral position (19961997) in the crystallography department at the Instituto Rocasolano-CSIC in Madrid, Spain. From 1997 to 2003, she occupied several positions in the Computational Chemistry group of GLYCODesign Inc. (Toronto, Canada). Isabelle Andr e Upon her return to France, she joined the CNRS in 2005 as a Research Scientist and she was promoted to Research Director in 2011. She is working at the nierie des Syste mes Biologiques et des Proce de s Laboratoire dInge in Toulouse (France) where she manages the computational biology research activities of the Catalysis and Molecular Enzyme Engineering group. Her research interests include understanding and exploiting enzyme mechanisms and structuredynamics activity relationships, developing molecular modelling methodologies to investigate molecular motions and assist protein design, and rational engineering of novel enzymes for chemo-enzymatic synthetic pathways and synthetic biology.
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Nevertheless, the sole use of natural sucrose limits the variety of accessible products to glucosyl and fructosyl derivatives; therefore limiting the production of original molecules. Efcient modications of sucrose are thus important in order to envision their use as alternative substrates of sucrose-utilizing transglycosidases and enable the production of a larger panel of glycoderivatives, such as prebiotics, tailor-made glycoconjugates and oligosaccharides. Combined with the use of enzyme engineering techniques, one can expect major advances in the development of novel biosynthetic ways to access carbohydrates.10 Although extensive work has been done over the years to utilize sucrose as a raw material for chemical and/or biochemical conversion into high-value molecules (e.g. 5-(hydroxymethyl) furfural, polyhydric alcohols) not structurally related to sucrose, we have chosen not to discuss these aspects here as they have already been reviewed in detail elsewhere.1 The intention of this review was rather to describe the main biological routes to sucrose derivatives or analogs (up to trisaccharides) reported in the literature and that can either be found in nature or obtained via enzymatic processes. As they were out of the scope, total chemical derivatizations of sucrose have been voluntarily discarded from this survey or only mentioned to discuss advantages of biological routes. For further details, refer to articles by Khan11 and Queneau.3 An outlook on the potential applications of sucrose derivatives in carbohydrate bioconversion is also given.

Scheme 2 Sucrose-60 -phosphate is a key precursor for sucrose biosynthesis.

2 Natural occurrence of sucrose derivatives


Sucrose is synthesized by photosynthetic organisms, such as plants and cyanobacteria. Precursors and derivatives of the molecule are naturally found in these organisms as well as in sucrose-utilizing ones. 2.1 Phosphate derivatives Two types of sucrose phosphate derivatives are naturally produced i.e. sucrose-60 -phosphate (S60 P) and sucrose-6-phosphate (S6P). The biosynthesis of sucrose in plants, reviewed by Lunn and MacRae,12 involves two distinct enzymes and a phosphorylated precursor. A sucrose phosphate synthase (EC 2.4.1.14) catalyzes rst the conversion of UDP-glucose and fructose-6-phosphate into S60 P, which is then hydrolyzed by a sucrose phosphatase (EC 3.1.3.24) to form sucrose (Scheme 2). S60 P is a key intermediate of the sucrose biosynthetic pathway and is found, for example, in plant leaves such as spinach,13 tea or strawberry.14 The levels of S60 P in strawberry leaves (Fragaria vesca var. Royal Sovereign) and in tea leaves (Camellia sinensis var. assemica) have been estimated at 0.36 and 0.05 mmol per 100 g, respectively. A concentration of S60 P of about 0.03 mM has also been measured in the cytosol of spinach leaves. Chemical synthesis of S60 P has been described by Buchanan with an overall yield of 6%,15 and further optimized by Kim up to 15%.16 Another phosphate derivative of sucrose, S6P, is commonly found in sucrose-utilizing bacteria and results from phosphoenolpyruvate-dependent phosphotransferase (PTS) sucrose uptake.17 For instance, S6P is an intermediate of sucrose catabolism found in many Gram positive bacteria including B. subtilis, cariogenic Streptococcus mutans or saccharolytic clostridia.18,19 As shown in Scheme 3, sucrose catabolism involves two steps.
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The rst one, involving the PTS system, allows sucrose transportation into cells. The S6P formed is then hydrolyzed by the specic sucrose-6-phosphate hydrolase into fructose and glucose6-phosphate (Scheme 3).20,21

2.2 Phenylpropanoid derivatives The majority of naturally occurring sucrose phenylpropanoid derivatives have not yet been experimentally synthesized in vitro and only a few chemical syntheses have been reported.2224 Access to most of these original molecules has been mainly achieved from crude material to proceed to further use and characterization. Phytochemical investigations have led to the isolation of unusual phenolic glycosides. Among them, a variety of sucrose derivatives have been characterized. These compounds listed in Table 1 and captioned in Scheme 4 reveal a huge structural diversity in terms of the nature and position of the substitutions. Indeed, more than 70 phenolic sucrose esters have been identied over the past 30 years. They have been extracted from various plants, such as tobacco,25 bulbs of Lilium species,26,27 fruits of

Scheme 3 Conversion of sucrose to sucrose-6-phosphate for internalization into the cell.

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Table 1 Naturally occurring phenylpropanoid esters of sucrose R1 (E)-Sin H H H H Ac H Ac (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer Ac (E)-Fer (E)-Fer p-hydrobenz p-hydrobenz (E)-Sin H (E)-Fer H H H p-(E)-cou Ac Ac Ac Ac Ac H Ac H H (E)-Sin (E)-Sin Ac Ac Ac dh-Fer H Benzoyl p-(E)-cou p-(E)-cou (E)-Sin (E)-Sin (E)-trimethocinna (E)-Sin (E)-trimethocinna p-hydrobenz H (E)-Fer (E)-Sin Ac Ac Ac Ac Ac (E)-Fer (E)-Fer H p-(E)-cou p-(E)-cou (E)-Caf H H H Ac R2 H H H H H 3-methylvaleryl H H H H H Ac H H H (S)-3-Methpenta H H H H H H Ac p-(E)-cou p-(E)-cou p-(E)-cou H Ac H H Ac H H H Ac Ac Ac H Ac H Ac H H H H H H H H H H H (E)-Sin H H Ac H Ac Ac H H H H H H H H H H H R3 H H H H H 3-methylvaleryl H H H H H H H Ac Ac (S)-3-Methpenta H H H H H H H H H Ac H H Ac H H H H H Ac H H Ac Ac H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H R4 H H H H H 3-methylvaleryl H H H H H H H H H (S)-3-Methpenta H H H H H H H H Ac H H Ac Ac Ac Ac Ac Ac Ac H H H H Ac Ac Ac H H H H H H H H H H H H H H Ac Ac Ac Ac Ac H H H H H H H H Ac H R5 H p-(E)-cou (E)-Sin (E)-Sin Ac H H H H H H H H H H H H H H H H H H H H H H Ac Ac Ac H Ac Ac H Ac Ac H H H Ac Ac H H H H H H H H H H H H H H (E)-Fer (E)-Fer H p-(E)-cou p-(E)-cou p-(E)-cou (E)-Fer H H H H H p-(E)-cou p-(E)-cou p-(E)-cou R6 (E)-Sin p-(E)-cou (E)-Fer (E)-Sin (E)-Fer H (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer H (E)-Fer (E)-Fer (E)-trimethocinna (E)-Sin (E)-trimethocinna (E)-Fer (E)-Fer p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou p-(Z)-cou p-(Z)-cou (E)-Sin (E)-Sin (E)-Fer (E)-Fer H H (E)-trimethocinna (E)-trimethocinna (E)-Sin (E)-trimethocinna (E)-Sin (E)-trimethocinna (E)-trimethocinna H H H (E)-Sin H H (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer p-(E)-cou p-(E)-cou H H (E)-Fer (E)-Fer p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou R7 H H H H H H H H H Ac H H Ac H Ac H H Ac H H H H Ac H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H R8 H p-(E)-cou H H H H (E)-Fer (E)-Fer H H Ac H Ac Ac Ac H H H H H H H H H H H H Ac Ac Ac Ac H Ac Ac Ac Ac H H (E)-Fer (E)-Fer (E)-Fer H H H H H H H H H H H H H H (E)-Fer (E)-Fer (E)-Fer (E)-Fer (E)-Fer p-(E)-cou p-(E)-cou p-(E)-cou p-(E)-cou H H (E)-Fer (E)-Fer (E)-Fer (E)-Fer References 102 103 30 104 105 106

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25 107 31 26 27

28

32 108 33 34 109

110

111

35 112 113 114 115

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Table 1 (Contd. ) R1 H H H H H Ac p-(E)-cou (E)-Caf R2 H H H Ac H H H H R3 H H H H H H H H R4 H Ac H p-(E)-cou H H H H R5 (E)-Fer p-(E)-cou (E)-Fer Ac H H H H R6 p-(E)-cou (E)-Fer (E)-Fer p-(E)-cou (Z)-Fer (Z)-Fer p-(E)-cou p-(E)-cou R7 H H H H H H p-(E)-cou p-(E)-cou R8 (E)-Fer (E)-Fer (E)-Fer p-(E)-cou (Z)-Fer (Z)-Fer H H References

116 29 117

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glycosyl unit linked to sucrose as well as in the specicity of the glycosidic linkage between this unit and the sucrose moiety (Fig. 1). 2.3.1 Glucosyl derivatives. Erlose (a-D-glucopyranosyl-(14)a-D-glucopyranosyl-(12)-b-D-fructofuranoside) is a trisaccharide occurring in honeys and royal jelly.4145 The erlose content of 469 samples of honey was analyzed by Devillers and coworkers, revealing an average proportion of 0.33% with values going up to 1.55% (e.g. for acacia honey). It crystallizes in two hydrated forms whose structures have been determined.46,47 Erlose is a sucrose-like tasty carbohydrate but it is non-cariogenic.48,49 Along with erlose, melezitose (a-D-glucopyranosyl-(13)-b-Dfructofuranosyl-(21)-a-D-glucopyranoside) is commonly found in honey as well as in honeydews and saps of many trees and plants (e.g. meleze). Melezitose is the main component of aphid honeydew (59%).50 A correlation between the amount of honeydew produced by aphids and the intensity of ant-attendance has been underlined. Thus, ants are attracted by melezitose-rich honeydew secreted by aphids and protect them against natural predators creating a cooperative mutualism.5153
Scheme 4 Naturally occurring phenylpropanoid esters of sucrose.

Prunus sp.28 or plenty of medicinal plants, including Bistorta manshuriensis,29 Polygala species,3032 Sparganium stoloniferum,33 or Vaccaria segetalis.34 These molecules are usually bioactive, acting as plant growth inhibitors, insecticides, bactericides or avour precursors in the plant. Some of them have also shown therapeutic properties. Two phenylpropanoid esters of sucrose, namely vanicoside B and lapathoside A from Polygonum lapathifolium, which exhibit anti-tumor-promoting effects and inhibit Epstein-Barr virus early antigen induction, have been identied as cancer chemo-preventive agents.35 Some phenylpropanoyl sucrose compounds from Polygala tenuifolia also revealed their efciency in the prevention of memory disorders.36,37 Considering the potential applications of these glycoside derivatives and their low natural abundance (less than 5% in plants),38 the identication of genes39 involved in their biosynthesis could enable the development of efcient microbial production processes via metabolic engineering.40 2.3 Glycosyl derivatives A variety of monoglycosylated derivatives of sucrose can be found in nature. These trisaccharides differ in the nature of the
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Fig. 1 Naturally occurring mono-glycosylated sucrose compounds.

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Melezitose has been crystallized in two monohydrated forms.5456 Gentianose (b-D-glucopyranosyl-(16)-a-D-glucopyranosyl(12)-b-D-fructofuranoside) is another glucosyl derivative of sucrose trisaccharide that was rst extracted from Gentiana lutea57 and is commonly found in gentian roots, hence its name. 2.3.2 Fructosyl derivatives. Three fructosyl derivatives are commonly found in nature, namely 1-kestose, 6-kestose and neokestose. 1-kestose was rst observed and isolated during the action of yeast invertase on concentrated sucrose solutions.58 It has been identied in honey, as well as in many plants.5962 In higher plants the synthesis of 1-kestose results from the enzymatic transfer of the fructosyl moiety of sucrose onto another molecule of sucrose and is catalyzed by a sucrose:sucrose fructosyltransferase (1-SST EC 2.4.1.99).6265 In fructooligosaccharide-producing plants, the fructan synthesis starts with the synthesis of 1-kestose. NMR studies have shown that both neokestose and 1-kestose were present in plant extracts, such as Asparagus, Festuca or Dactylis.66,67 Anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) also allowed the detection of neokestose and 1-kestose in table grapes.68 Neokestose and 1-kestose were also found in Agave vera cruz.69 The less abundant 6-kestose has been isolated from the seeds of the horse chestnut (Aesculus hippocastanum L.).70 2.3.3 Galactosyl derivatives. Rafnose (a-D-galactopyranosyl-(16)-a-D-glucopyranosyl-(12)-b-D-fructofuranoside) is another sucrose-scaffold based molecule that is encountered in many plants though in small amounts. This water-soluble trisaccharide can be found in cottonseed meal,71 jute plant,72 sugar beets,73,74 sunower, Gramineae species,75 lupins,76 soybean,77 and many edible leguminous crops.78 Although abundant in human nutrition, this oligosaccharide is nondigestible but is fermented by intestinal bidobacteria, thus acting as a prebiotic molecule by stimulating the benecial gut microbiota.79,80 Notably, rafnose is used as a functional food ingredient in Japan.81 Rafnose also shows cryo-preserving effects,82 and ameliorates atopic dermatitis in human subjects.83 Two enzymes are involved in the biosynthesis of rafnose in plants, namely galactinol synthase, which catalyzes the bioconversion of UDP-galactose into galactinol and rafnose synthase, which catalyzes the synthesis of rafnose from galactinol and sucrose.84 For Arabidopsis and the common bugle Ajuga reptans L., these enzymes are located in the cytosol where rafnose appears to be rst synthesized before being translocated across the envelope of the chloroplast by a specic transporter.85 The presence of rafnose has also been detected in algal cells of Chlorella vulgaris where a chilling shock stops the cell growth and leads to rafnose accumulation.86 On the industrial scale, rafnose is extracted from molasses,87 in particular sugar beet molasses. Rafnose usually represents 0.52% of beet molasses. Upon desugaration, the blackstrap molasses contain up to 15% rafnose,88 from which the molecule can be efciently extracted and crystallized.89,90 The a-galactosyl derivative loliose (a-D-galactopyranosyl-(1 3)-a-D-glucopyranosyl-(12)-b-D-fructofuranoside) has been detected in Lolium sp. as well as in Festuca species.9193 Its biosynthesis is ensured by a UDP-Gal:sucrose 3-galactosyltransferase.94
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Another trisaccharide, namely planteose, was rst extracted from the seeds of Plantago sp.95 where it acts as a reserve carbohydrate.96 It was rst prepared from Plantaginaceae,97 tobacco or mint seeds,98 and has been identied as the major carbohydrate in seeds of Fraxinus excelsior.99 Its structure was determined ten years later as being the a-D-galactopyranosyl-(16)-b-D-fructofuranosyl-(21)-a-D-glucopyranoside. It has recently been reported in honey samples.60,100 Chemical synthesis of planteose involving a low yield multistep mechanism has been proposed.101

In vitro synthesis of sucrose derivatives

Due to a limited variety of sucrose derivatives available in nature and their low level of natural abundance, the extraction of natural compounds remains a tedious task. In vitro synthesis using either microorganisms or enzymes appears thus to be a solution of choice to access sucrose-like carbohydrates in mild conditions with selective introduction of a variety of functional groups at distinct reactive positions of sucrose-scaffold. An overview of these modications is proposed in Scheme 5. 3.1 Keto derivatives Chemical synthesis of carbonyl-sucrose derivatives was rst demonstrated by Andersson using bromine oxidation of sucrose in aqueous solution, a mixture of four keto-derivatives was obtained.118 However, the process presented several drawbacks as 10% of starting material and acidic compounds remained in the nal mixture. Furthermore, the keto-sugars showed a low stability that required their subsequent conversion into more stable O-methyloximes to proceed to their biochemical and structural characterization. The specic etherication of sucrose into 2-O-benzyl-sucrose has also been performed to produce a precursor for the synthesis of 2-ketosucrose,119 albeit this synthesis involved a low-yield multi-step process. To avoid such problems, efcient enzymatic syntheses of carbonyl-derivatives of sucrose have been proposed. Different categories of enzymes have been used for either C-2 oxidation or C-3 dehydrogenation of the sucrose glucosyl moiety (Scheme 6). The D-glucoside 3dehydrogenase (G3DH EC 1.1.99.13) from Agrobacterium tumefaciens has been widely studied during the past decades for its capacity to regioselectively produce the 3-ketosucrose (b-Dfructofuranosyl a-D-ribo-hexopyranosid-3-ulose).120122 The activity of this enzyme has been shown to be dependent on the manganese concentration in the reaction medium, which can be optimized to increase conversion yield.123 The enzyme activity is also FAD-dependent, thus using whole cells of Agrobacterium tumefaciens offers the possibility of in vivo cofactor regeneration but raises the problem of separating 3-ketosucrose from other compounds present in culture medium. During 3-ketosucrose purication, Hough et al. also obtained a claried concentrate containing a signicant amount of 2-ketosucrose (b-D-fructofuranosyl-a-D-arabino-hexopyranosid-2-ulose) probably resulting from enolisation of 3-ketosucrose.124 An alternative synthetic route to 3-ketosucrose consists of using a pyranose dehydrogenase (PDH) from Agaricus sp.125,126 Notably, PDH from Agaricus meleagris efciently catalyzes dehydrogenation of a wide range of carbohydrates (yields $ 90%), including sucrose.127,128
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Scheme 5 The in vitro synthesis of sucrose derivatives.

Nevertheless, the reaction necessitates an electron acceptor, such as 1,4-benzoquinone, that has to be removed after reaction.127 The in vitro bioconversion of sucrose in 2-ketosucrose has recently been described.129 A commercial pyranose-2-oxidase (POase EC 1.1.3.10) has been used for the reaction catalysis in water with oxygen aeration. This oxidation and the associated reduction of O2 into H2O2were coupled to the action of a catalase (EC 1.11.1.6.) used to degrade the neo-formed hydrogen peroxide and prevent enzyme inhibition. A full conversion of sucrose was observed within 24 h. The enzymes were removed by ultraltration and the ltrate was dried into vacuum to obtain a pure fraction of 2-ketosucrose. Of interest, sucrose keto-derivatives can also be used as a starting material for other chemical transformations including amination, silylation,130 cyanohydrination,131 or epimerisation.123 3.2 Ester derivatives Fatty acid monoesters of sucrose (reviewed by Polat and Linhardt, 2001)132 have drawn considerable attention for their
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pharmaceutical interest or potential applications as surfactants or emulsiers. The regioselective esterication of sucrose can be achieved through chemical means. Industrial routes using basic catalysts have been developed. They involve solvent or solventfree reactions yielding sucrose ester mixtures containing predominantly monoesters (up to 70%). Among the eight potential reactive hydroxyl groups, the primary hydroxyls at carbons 6 and 60 exhibit the highest reactivity. Nonetheless, the synthesis of selectively acylated sucrose in its pure form remains difcult. The synthesis of acylated sucrose at position 60 with a yield of isolated product up to 43% has been described in DMF in the presence of 1,4-diazobicyclo[2.2.2]octane (DABCO). Prerequisite modications of sucrose using dibutyltin oxide have also been reported for the synthesis 6-O-acylsucroses and 6,30 -diO-acylsucroses in DMF with good yields.133,134 The synthesis of 2-O-acylsucroses in anhydrous pyridine has also been achieved in 4564% yield.135,136 Numerous studies have shown that enzymatic catalysts can be used as powerful tools for the selective acylation of sucrose. Indeed, a wide variety of enzymes are able to convert sucrose into
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Scheme 6 The biosynthesis of carbonyl-derivatives of sucrose.

mono or di-esters mainly, depending on the acyl donor, the reaction conditions and the catalyst used (Table 2). Among them, lipases are commonly used to produce a large panel of sucrose esters using a variety of acyl donors of different chain length in distinct solvents. In particular, lipases from Candida antarctica,137 Thermomyces lanuginosus,138 Mucor miehei,139 Byssochlamys fulva,140 Pseudomonas sp.,141 Penicillium chrysogenum,142 Aspergillus oryzae,143 Aspergillus terreus,144 or Rhizopus sp.143 have been shown to be highly efcient to acylate sucrose at positions 6 and 60 . Proteases from Bacillus subtilis and the metalloprotease thermolysin from Bacillus thermoproteolyticus also lead to the production of sucrose esters modied at positions 10 and 2, respectively.145,146 A protease from Bacillus licheniformis can also be used to generate sucrose acrylate esters,147 sucrosecontaining aromatic polymers,148 and sucrose amino acid esters.149 Original chemo-enzymatic processes for sucrose acylation have also been proposed by either coupling the use of lipases and chemically-produced sucrose acetals,150 or by glucosylating a glucose-6-acetate with a fructosyltransferase from Bacillus subtilis.151 The preparation of the sweetener sucralose also involves an ester derivative of sucrose, namely sucrose-6-acetate, which is chlorinated and deacetylated to give the nal product.152 Another way of retrieving a partially acetylated sucrose consists of de-acetylating the easily chemically synthesized sucrose octaacetate using proteases and lipases in organic solvent.153,154 In any case, one major difculty in obtaining acylated molecules in a pure form is related to the low solubility of sucrose in most organic environments, thus requiring the use of non-environmental friendly solvents in which the disaccharide is more soluble (e.g. pyridine, dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexane).
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3.3 Glycosylation of sucrose Sucrose can be used as a glycosyl donor or acceptor for the enzymatic synthesis of short oligosaccharides, such as functional galacto-derivatives or short chain fructooligosaccharides (FOS) acting and classied as prebiotics.155157 We will limit our review to both naturally-occurring and tailor-made trisaccharides synthesized in vitro using transglycosidases. We did not consider oligosaccharide production resulting from additional elongation. Galactosyl transfer onto disaccharides has been proposed using both activated and non-activated carbohydrates. Besides its extraction from plants, rafnose can also be efciently obtained by in vitro synthesis using the galactinol-sucrose galactosyltransferase from Vicia faba and sucrose and galactinol (aD-galactopyranosyl-(13)-1D-myo-inositol) or p-nitrophenyl- a84 D-galactopyranoside as substrates. Reverse hydrolysis activity of the a-galactosidase from Absidia corymbifera, which acts on sucrose and galactose was also investigated to produce rafnose with an overall conversion ratio improved up to 10% (w/v) (Scheme 7).158 b-galactosidase from Bacillus circulans has been used for the synthesis of lactosucrose (b-D-galactopyranosyl-(1 4)-a-D-glucopyranosyl-(12)-b-D-fructofuranoside) as well as its b(13) isomer.159 Biosynthesis of planteose has also been proposed with the cell-free extract of sesame seeds (Sesasum indicum) involving either UDP-galactose or galactinol as donors and sucrose as the acceptor.160 Synthesis of planteose has also been described with an a-galactosidase from Plantago ovato using galactose.161 The biosynthesis of umbelliferose has also been demonstrated in an enzyme preparation from leaves of Aegopodium podagraria L. using sucrose as the acceptor and UDP-galactose as the donor.162 An original trisaccharide derived from sucrose has been
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Table 2 Esters derivatives of sucrose and their synthesis conditions Yield (%) 1 35 98 70 80 <25 8 36,6 <30 39 48 42 28 70 70 67 71 39 46 67 80 42 60 76 43 6 up to 93 90

Enzymes Lipase

Species Candida antarctica

Acylating agents Ethyl butanoate Ethyl laurate Vinyl laurate

Solvents tert-butanol tert-butanol tert-butanol:DMSO (80 : 20) tert-butanol:DMSO (80 : 20) tert-butanol:DMSO (80 : 20) tert-butanol:DMSO (80 : 20) solvent free CH2Cl2:DMF (90 : 10) tert-butanol Pyridine tert-butanol:DMSO (80 : 20) DMF DMSO tert-butanol:DMSO (80 : 20) DMF Isoamyl alcohol Hexane Hexane Hexane Hexane Hexane Hexane DMSO DMF DMF DMF DMF DMF Anhydrous pyridine Anhydrous pyridine Anhydrous pyridine DMSO DMSO

Main Products 6 and 60 -Obutanoylsucrose 6,60 -di-O-lauroylsucrose 6,60 -di-O-lauroylsucrose 6-O-lauroylsucrose 6-O-lauroylsucrose 6-O-palmitoylsucrose 6-O-capryloylsucrose 6-O-L-alanyl-sucrose Linoleylsucrose 6O-butyrylsucrose 6-O-lauroylsucrose Benzoylsucrose Benzoylsucrose 6-O-lauroylsucrose 6-O-acetylsucrose 6-O-acetylsucrose Butyrylsucrose Caprylsucrose Capryloylsucrose Myristoylsucrose Palimtoylsucrose Stearoylsucrose Lauroylsucrose 10 -O-butyrylsucrose 10 -O-butyrylsucrose 10 -O-isobutyrylsucrose 10 -O-transcrotonylsucrose 10 -O-methacryloylsucrose 10 ; 6,10 ; 10 ,60 -Oacryloylsucrose sucrose-terephatalate sucrose amino acid esters sucrose-40 -acetate 2-O-lauroylsucrose

References 137 170 170 138 138 139 171 140 141 142 143 143 142 143 143 144 144 144 144 144 144 143 145 146 146 146 146 147

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Thermomyces lanuginosus

Vinyl laurate Vinyl laurate Vinyl palmitate

Mucor miehei Byssochlamys fulva Pseudomonas sp.

Capric acid L-alanine Linoleic acid Vinyl butyrate Vinyl laurate

Benzoic anhydride p-Nitrobenzoic acid Penicillium chrysogenum Vinyl laurate Aspergillus oryzae Aspergillus terreus Acetic acid Acetic acid Butyric acid Caproic acid Capric acid Myristic acid Palmitic acid Stearic acid Lauric acid Trichloroethyl butyrate Triuoroethyl butyrate Triuoroethyl isobutyrate Triuoroethyl transcrotonate Triuoroethyl methacrylate Vinyl acrylate bis(2,2,2-triuoroethyl)terephtalate Amino acid esters Serratia sp. SYBC H Metalloprotease Bacillus thermoproteolyticus Vinyl acetate Vinyl laurate

Protease

Rhizopus sp. Bacillus subtilis

Bacillus licheniformis

up to 98 148 up to 56.3 >90 90 149 172 173

synthesized by transglycosylation using a recombinant b-glycosidase from Sulfolobus shibatae. This reaction involved lactose as the donor and sucrose as the acceptor to form a new product whose structure was determined to be the b-D-galactopyranosyl

(16)-a-D-glucopyranosyl-(12)-b-D-fructofuranoside. The yield was calculated as 20% from the acceptor sucrose. The biosyntheses of melezitose and erlose have also been performed by incubating, in an articial phloem sap, isolated

Scheme 7 The biosynthesis of rafnose by the a-galactosidase of A. corymbifera.

This journal is The Royal Society of Chemistry 2012

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guts of Metropeurum fuscoviride and Macrosiphoniella tanacetaria, respectively.163 The in vitro fructosylation of various disaccharides involving a fructosyltransferase or a fructofuranosidase has been described.164 The enzymatic synthesis of lactosucrose has been performed using levansucrases as catalysts, and sucrose and lactose as the fructofuranosyl donor and acceptor, respectively. With the levansucrase from Aerobacter levanicum, a yield of 32.9% (w/w) was obtained.165 The fructofuranosyl moiety of sucrose is cleaved and transferred onto the glucopyranosyl moiety of lactose via the reformation of the sucrose characteristic a(12)b linkage. Lactosucrose bioconversion from lactose and sucrose using whole cells of Paenibacillus polymyxa has also been reported.166 More recently, the efciency of lactosucrose conversion has been raised to 43.2% using a mixed-enzyme system containing a levansucrase from Zymomonas mobilis and a glucose oxidase for increasing conversion by removing glucose.167 The levansucrase of Pseudomonas aurantiaca has also been used for this purpose.168 The use of b-fructofuranosidase from Arthrobacter sp. K-1 also enabled the synthesis of lactosucrose from sucrose and lactose with an overall yield close to 27% (Scheme 8).169 The conversion has been improved up to 50% in a batch process with an equimolar ratio of substrates. Kang and coworkers have reported the synthesis of erlose from sucrose as a donor and maltose as an acceptor using levansucrase from Leuconostoc mesenteroides B-512 FMC (25% reaction product).174 A similar synthesis involving the levansucrase from Bacillus subtilis has also been described with an optimized yield of 45% (calculated from the donor sucrose).175 The production of 1-kestose using the intact mycelium of Aspergillus phoenicis containing a sucrose fructosyltransferase has been described from a 750 g L1 sucrose solution with a yield of 300 g L1 of 1-kestose in 8 h.176 A continuous production involving an immobilized b-fructofuranosidase from Aureobasidium has also been proposed with a 1-kestose concentration of 90 g L1 for up to 168 h, allowing a synthesis of 287 g during this time.177 1-kestose production has also been performed using a fructosyltransferase from Aspergillus foetidus expressed in an invertase-decient mutant of Saccharomyces cerevisiae.178 Levansucrase from Lactobacillus sanfranciscencis also mainly

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synthesizes 1-kestose.179 Recently, a combination of both genetic and substrate engineering has been used for the preparative synthesis of fructooligosaccharides, notably 1-kestose.180 The conversion of sucrose into FOS using whole Penicillium citrinum led to the conversion of sucrose into both 1-kestose and neokestose. Kritzinger and coworkers have optimized the production parameters of the trisaccharide neokestose by Xanthophyllomyces dendrorhous (Phafa rhodozyma) to reach a production yield of 0.85 g of neokestose per g of sucrose and a proportion of 95% neokestose of the total oligosaccharides.181,182 The production of the other fructooligosaccharide 6-kestose has also been demonstrated using, for example, the b-fructofuranosidase from Thermoascus aurantiacus or Schwanniomyces occidentalis.183,184 The b-fructofuranosidases from Saccharomyces cerevisae and Rhodotorula dairenensis are also known for producing mainly 6-kestose.185,186 3.4 Phosphate derivatives Sucrose-6-phosphate (S6P) was obtained using permeabilized cells of different strains. Martin et al. have rst identied a phosphoenolpyruvate-dependent phosphotransferase system in Streptococcus mutans.187 Two enzymes are involved in the catabolism of sucrose by S. mutans, a sucrose phosphotransferase (PTS) and a sucrose-6-phosphate hydrolase. Permeabilized cells of a mutant strain constitutive for the PTS system and missing hydrolytic activity have been isolated and used for the biosynthesis of sucrose-6-phosphate.188 More recently, Thompson et al. showed that phosphorylation of sucrose as well as that of its ve linkage isomers was possible using permeabilized cells of Klebsellia pneumoniae at low pH (Scheme 9).189 Previous work by Kunst et al. showed that sucrose-6-phosphate can be synthesized from glucose-6-phosphate (G6P) and sucrose using a levansucrase, which under the operating conditions led to the conversion of 45% of the G6P into S6P.190 3.5 Sucrose analogs The sucrose derivatives described previously conserve the sucrose-scaffold, which constitutes a fructofuranosyl unit linked

Scheme 8 The biosynthesis of lactosucrose using the b-fructofuranosidase from Arthrobacter sp.

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Scheme 9 The synthesis of sucrose-6-phosphate using permeabilized cells from S. mutans or K. pneumoniae.

to a glucopyranosyl unit via an a(12)b glycosidic bond. However, another way to modify sucrose is to replace the glucosyl unit by alternative glycosyl moieties. Following this idea, sucrose-like disaccharides which conserve the characteristic a(1 2)b glycosidic bond have been produced by fructosylation of various monosaccharides using fructosyltransferases (e.g. levansucrase) (Scheme 10). The synthesis of four sucrose analogs by fructosylation of D-glycopyranosides, such as D-galactose, Dmannose, D-xylose and D-fucose, was rst described using a levansucrase from Bacillus subtilis with yields of 54, 4, 62 and 21%, respectively.191 Further biocatalytic investigations enabled, fructosylation from sucrose as a fructosyl donor to other carbohydrates, including monosaccharides (e.g. 2-deoxy-Dglucose, D-allose, 3-ketoglucose) and disaccharides (e.g. isomaltose, maltose, melibiose, cellobiose or lactose) with yields going from 0.01% for D-allose to 53% for isomaltose. Using rafnose as fructosyl donor, the fructosylation of L-sugars (e.g. Lglucose, L-rhamnose, L-galactose, L-fucose and L-xylose) was also successfully achieved with yields going from 0.1% for L-rhamnose up to 27% for L-xylose.175 Interestingly, some of these

sucrose analogs a-D-xylopyranosyl-b-D-fructofuranoside (XylFru), a-D-mannopyranosyl-b-D-fructofuranoside (Man-Fru) and a-D-galactopyranosyl-b-D-fructofuranoside (Gal-Fru) were further tested as acceptor substrates by the highly active recombinant b-fructofuranosidase from Aspergillus niger, leading to fructosylated products, such as 1-kestose and 1-nystose analogs. Of note, two analogs were previously described by Avigad et al. using a levansucrase from Aerobacter levanicum.192,193 In this report, Xyl-Fru and Gal-Fru were synthesized from 10 g of rafnose as the fructosyl donor and xylose or galactose, respectively, as the fructosyl acceptors to produce pure Xyl-Fru (400 mg) and Gal-Fru (70 mg).

Sucrose isomers as alternative sucrose skeletons

Some properties of sucrose isomers, such as sweetness, solubility, or cariogenic effect, differ signicantly from those of sucrose, thus offering novel opportunities for the development of prebiotics or edulcorants. Five sucrose isomers are naturally accessible and can be produced either in vitro using carbohydrate-active enzymes (CAZy)194 or in vivo using selected microorganisms. Of note, the fructosyl moiety in sucrose isomers has been found in many different forms (e.g. acyclic, cyclic, furanose, pyranose). Hereafter are described the biochemical syntheses of leucrose, turanose, trehalulose, maltulose and isomaltulose (palatinose). 4.1 Leucrose a-D-glucopyranosyl-1,5-b-D-fructose, commonly named leucrose, is a reducing disaccharide derived from sucrose. Although half as sweet as sucrose, leucrose is fully digestible and noncariogenic. It was rstly isolated from dextran-producing cultures of Leuconostoc mesenteroides and Streptococcus bovis.195,196 Different experimental conditions have been tested, allowing high product yield and the proposition of a kinetic model.197 Production of leucrose from sucrose using immobilized dextransucrase entrapped in calcium alginate beads has been carried out, showing its best results in a tubular reactor.198,199 More recently, immobilization of the dextransucrase from Leuconostoc mesenteroides NRRL B-512F using a convenient afnity interaction with resin showed promising results by increasing conversion rate up to 74% after one day.200 4.2 Turanose a-D-glucopyranosyl-1,3-b-D-fructose or turanose was rst discovered by Alekhine in 1889. It resulted from the hydrolysis of melezitose, a trisaccharide extracted from Turkestan Manna, giving an equimolar mixture of glucose and turanose.201 Like leucrose, it is non-cariogenic and half as sweet as sucrose. Turanose has also been identied as a by-product of the polymerization reaction catalyzed by amylosucrases.202204 The synthesis of turanose from sucrose using Neisseria polysaccharea amylosucrase has been improved by increasing the substrate concentration up to 2.5 M. The production of turanose was thus favoured and allowed a maximal production yield of 56.2% after a 120 h at 35  C. Turanose was further puried using preparative HPLC.205 The amylosucrase from Deinococcus geothermalis has been described to synthesize equimolar amounts of turanose and trehalulose.204,206
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Scheme 10 A schematic representation of sucrose analogs synthesized using a levansucrase from B. subtilis.

This journal is The Royal Society of Chemistry 2012

4.3 Trehalulose In 1973, Lund and Wyatt identied the a-D-glucopyranosyl-1,1b-D-fructose in cultures of Erwinia carotovora var. atroseptica grown on medium containing 24% sucrose.207 This compound, also known as trehalulose, is a highly soluble reducing disaccharide nearly 70% as sweet as sucrose.208 It has been found in honeydew from Bemisia tabaci (Gennadius), thus relating its production to Insecta.209 The presence of trehalulose has been investigated for various plantinsect couples going from 0.3% up to 70% of the total carbohydrates.210 The biochemical synthesis of trehalulose was previously described in 1959 using a-glucosidases from yeast strains.211 Novel methods have since been developed for the in vitro production of trehalulose. Among others, sucrose isomerase from Erwinia rhapontici NCPPB 1578 or immobilized cells of Pseudomonas mesoacidophila MX-45 have been used for the conversion of sucrose into trehalulose with yields of 60% and 83%, respectively.212,213

5 Potential applications of sucrose derivatives in sugar bioconversion


If recognized by the enzyme, sucrose-like molecules could offer new opportunities as potential substrates of sucrose-utilizing a-transglycosidases. Among them, glucansucrases, classied in families 13 and 70 of glycoside-hydrolases are naturally able to either polymerize glucose from solely sucrose or glucosylate a wide variety of hydroxylated acceptors.5,236,237 These enzymes are highly specic for the glucosyl moiety from sucrose and only a few examples can be found in the literature where a sucrose derivative has been used as an alternative glycosyl donor. A sucrose epimer, namely a-D-galactopyranosyl-1,2-b-D-fructofuranoside, has been earlier described as a substrate for a preparation of amylosucrase from cells of Neisseria perava producing a mixture of galactose, fructose, and an aldosidoketoside, likely being a trisaccharide.193 Another example concerns the utilization by a dextransucrase (E.C.2.4.1.5) of the 2-ketosucrose for the synthesis of novel carbonyl-group-containing dextrans.129 The last example, to our knowledge, uses allosucrose (a-D-allopyranosyl-1,2-b-D-fructofuranoside) and an amylosucrase functioning as an allosyltransferase to glycosylate low mass acceptor molecules.238 The three sucrose analogs reported to date as an alternative donor substrate for native glucansucrases only bear subtle chemical modications compared to parental sucrose. Nonetheless, such successful examples of novel catalytic reactions are full of promise and one could envision extending the concept to sucrose-active enzymes in general in order to enlarge accessible glycodiversication.

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4.4 Maltulose a-D-glucopyranosyl-1,4-b-D-fructose, or maltulose, is a natural sucrose isomer. It was isolated in low yield from a-amylase hydrolysates of waxy corn starch214 and rabbit liver-glycogen.215 Its presence was also detected during saccharication of starch.216 It was identied in honey in 1959 thanks to its previously reported infrared analysis.217,218 The in vitro synthesis of maltulose from sucrose using intestinal a-glucosidases has also been described.219

6
4.5 Isomaltulose Isomaltulose (a-D-glucopyranosyl-1,6-b-D-fructose or palatinose) was discovered in 1957 in Protaminobacter rubrum isolated from sugar beet raw juice.220 It is about half as sweet as sucrose but less soluble, less hygroscopic and much more stable to acidity.221223 The US Food and Drink Association approved the non-cariogenic health claim for isomaltulose in 2007. Moreover, the slow hydrolysis of the glycosidic linkage limits the diffusion of glucose into the blood, avoiding glycaemia and insulin peaks,224 and making it suitable as a sweetener for industrial applications.225 Isomaltulose naturally occurs in honey and sugar cane.226,227 Its biochemical synthesis has been widely studied and various methods of production have been proposed.228 Glucosyltransferaseproducing microorganism Klebsiella sp. can be used for the conversion of sucrose into isomaltulose with yields up to 86%. Strains of Erwinia sp. are also likely to perform this bioconversion and various processes have been proposed, such as immobilized cells,229 free cells,230 fermentation,231 potato tubers as bioreactors and high isomaltulose yields were obtained.232 Bioconversions involving microorganisms such as Pantoea dispersa UQ68J,233 Enterobacter sp. FMB-1234 and Serratia plymuthica,229,235 have also been investigated leading to a remarkable increase of conversion rates up to 98 100%.
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Conclusions

The main purpose of this article was to review the main biological routes reported to date to produce sucrose derivatives or analogs either by direct isolation from natural sources or in vitro enzymatic synthesis. These structures may differ in the type of regio- and/or chemo-modications of sucrose, the type of glycosidic linkage, or the nature of the glycosyl moiety linked to the fructofuranosyl moiety. Libraries of sucrose-related classes of molecules are thus accessible. Within this pool, sucrosederivatives are all attractive intermediates for further glycodiversication through carbohydrate chemistry and/or biochemistry. Such future developments may represent promising sources for novel oligosaccharides, polysaccharides, sugarderived synthons, rare sugars, alternative sweeteners, or biologically active molecules. However, all these molecules may not be accessible yet at yields compatible with industrial applications or further derivatization. In addition, regarding biological transformation, the diversity often remains limited by the substrate specicity of the enzymes. These drawbacks could be circumvented through the engineering of enzymes to generate more efcient catalysts with adequate substrate specicity for non-natural donor or acceptor substrates,239 although this has not been explored yet for sucrose-utilizing enzymes. Another major evolution that could be considered is coming from the rising eld of synthetic biology. Indeed, optimization of native metabolic pathway as well as redesigning of synthetic metabolic pathways can now be
This journal is The Royal Society of Chemistry 2012

investigated for the development of novel synthetic processes to access carbohydrates displaying original properties and the multiple products derived from them.

7 Acknowledgements
D. Daud e was supported by a grant from the French Ministry of Research.
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