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Modulation of the Activity and Regioselectivity of a Glycosidase: Development of a Convenient Tool for the Synthesis of Specific Disaccharides

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Modulation of the Activity and Regioselectivity of a Glycosidase: Development of a Convenient Tool for the Synthesis of Specific Disaccharides molecules Article Modulation of the Activity and Regioselectivity of a Glycosidase: Development of a Convenient Tool for the Synthesis of Specific Disaccharides Yari Cabezas-Pérusse 1, Franck Daligault 2, Vincent Ferrières 1 , Olivier Tasseau 1 and Sylvain Tranchimand 1,* 1 Ecole Nationale Supérieure de Chimie de Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Université de Rennes, F-35000 Rennes, France; [email protected] (Y.C.-P.); [email protected] (V.F.); [email protected] (O.T.) 2 CNRS, UFIP (Unité de Fonctionnalité et Ingénierie des Protéines)—UMR 6286, Université de Nantes, F-44000 Nantes, France; [email protected] * Correspondence: [email protected] Abstract: The synthesis of disaccharides, particularly those containing hexofuranoside rings, requires a large number of steps by classical chemical means. The use of glycosidases can be an alternative to limit the number of steps, as they catalyze the formation of controlled glycosidic bonds starting from simple and easy to access building blocks; the main drawbacks are the yields, due to the balance between the hydrolysis and transglycosylation of these enzymes, and the enzyme-dependent regiose- lectivity. To improve the yield of the synthesis of β-D-galactofuranosyl-(1!X)-D-mannopyranosides catalyzed by an arabinofuranosidase, in this study we developed a strategy to mutate, then screen the catalyst, followed by a tailored molecular modeling methodology to rationalize the effects of the Citation: Cabezas-Pérusse, Y.; identified mutations. Two mutants with a 2.3 to 3.8-fold increase in transglycosylation yield were Daligault, F.; Ferrières, V.; Tasseau, O.; obtained, and in addition their accumulated regioisomer kinetic profiles were very different from Tranchimand, S. Modulation of the the wild-type enzyme. Those differences were studied in silico by docking and molecular dynamics, Activity and Regioselectivity of a and the methodology revealed a good predictive quality in regards with the regioisomer profiles, Glycosidase: Development of a which is in good agreement with the experimental transglycosylation kinetics. So, by engineering Convenient Tool for the Synthesis of CtAraf 51, new biocatalysts were enabled to obtain the attractive central motif from the Leishmania Specific Disaccharides. Molecules 2021, lipophosphoglycan core with a higher yield and regioselectivity. 26, 5445. https://doi.org/10.3390/ molecules26185445 Keywords: galactofuranoside; transglycosylation; molecular dynamics; mutagenesis Academic Editor: Vito Ferro Received: 29 June 2021 Accepted: 2 September 2021 1. Introduction Published: 7 September 2021 Leishmaniases are neglected tropical diseases occurring in several intertropical areas in South America, Africa and Asia. More than 1 million people are infected by these Publisher’s Note: MDPI stays neutral parasites every year, with various consequences, as the clinical forms of the disease can with regard to jurisdictional claims in be either cutaneous or visceral [1]. In the first case, the disease can heal spontaneously published maps and institutional affil- and lead to disgraceful scars. The second case is much more preoccupying, because iations. symptoms are very difficult to distinguish and without treatment, overinfections are almost inevitably occurring, causing death in the medium term [1]. The actual treatments are very expensive and necessitate heavy instruments in medical facilities of countries that cannot always afford them. There is an urgent need to develop new strategies for the Copyright: © 2021 by the authors. treatment and the diagnosis of these diseases. An interesting field of investigation is Licensee MDPI, Basel, Switzerland. the lipophosphoglycans (LPGs) present at the surface of Leishmania cells [2]. LPGs are This article is an open access article virulence factors constituted by 4 distinct domains: a lipid anchor, a core heptasaccharide, distributed under the terms and a polymeric repetitive tail and a cap. The core heptasaccharide is of particular interest conditions of the Creative Commons for two reasons: it constitutes a retained feature among Leishmania species and it contains Attribution (CC BY) license (https:// a galactofuranose (Figure1), a rare carbohydrate unit that is xenobiotic to mammals [ 3], creativecommons.org/licenses/by/ conferring a keen relevance to this moiety for diagnosis and treatment development [4]. The 4.0/). Molecules 2021, 26, 5445. https://doi.org/10.3390/molecules26185445 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 19 Molecules 2021, 26, 5445 2 of 19 a keen relevance to this moiety for diagnosis and treatment development [4]. The core coreheptasaccharide heptasaccharide was was already already been been obtained obtained by by chemical chemical synthesis, synthesis, but but this this was aa veryvery longlong and and difficult difficult multistep multistep process, process, with with a a large large number number of of protection protection and and deprotection deprotection stepssteps inherentinherent to oligosaccharide oligosaccharide synthesis. synthesis. The The presence presence of a of galactofuranose a galactofuranose moiety moiety was wasan additional an additional difficulty difficulty in this in thissynthesis, synthesis, as it asis not it is the not thermodynamically the thermodynamically favored favored form formof galactose of galactose and so and implies so implies particular particular conditions conditions to be to maintained be maintained [5,6]. [ 5Due,6]. Dueto the to com the‐ complexityplexity of its of itssynthesis, synthesis, this this core core heptasaccharide heptasaccharide has has not not yet yet been evaluated forfor medical medical applications.applications. InIn orderorder toto accessaccess moremore easily easily such such kind kind of of galactofuranoconjugates, galactofuranoconjugates, with with a a limitedlimited number number of of steps steps and and in in a a way way that that follows follows the the concepts concepts of of green green chemistry, chemistry, our our team team developeddeveloped tools tools to to obtain obtain galactofuranoconjugates galactofuranoconjugates through through a a biocatalytic biocatalytic process process involving involving thethe useuse of an arabinofuranosidase from from ClostridiumClostridium thermocellum thermocellum (Ct(AraCtAraf51)f 51) [7–9]. [7– In9]. the In pre the‐ presentsent study study we we engineered engineered this this enzyme enzyme to to obtain obtain the disaccharide β‐β-DD-galactofuranosyl-‐galactofuranosyl‐ (1(1!→3)-3)‐DD-mannopyranose,‐mannopyranose, the the central central part part of of this this core core heptasaccharide, heptasaccharide, with with a higher a higher re‐ regioselectivitygioselectivity and and a a higher higher yield. yield. With With the the aim aim of following the greengreen chemistrychemistry rules,rules, basedbased on on our our previous previous results, results, we we replaced replaced the the generally generally used usedp-nitrophenyl p‐nitrophenyl derivatives derivatives as donoras donor substrates substrates by aby fully a fully biosourced biosourced donor, donor,n-octyl n‐octylβ-D β‐-galactofuranosideD‐galactofuranoside [7]. [7]. FigureFigure 1.1. LPGLPG general general structure structure with with a special a special emphasis emphasis on the on core the core heptasaccharide heptasaccharide and the and target the targetdisaccharide. disaccharide. 2.2. ResultsResults andand DiscussionDiscussion 2.1.2.1. TransglycosylationTransglycosylation Profiles Profiles with with p-Nitrophenyl p‐Nitrophenyla α‐-DD-Mannopyranoside‐Mannopyranoside (Manp-pNP) (Manp‐pNP) as as Acceptor Using the Wild-Type (WT) CtAraf51 Enzyme Acceptor Using the Wild‐Type (WT) CtAraf51 Enzyme CtAraf 51 is a thermostable arabinofuranosidase from the GH51 family that was shown CtAraf51 is a thermostable arabinofuranosidase from the GH51 family that was to be an interesting tool for the synthesis of galactofuranosides [7–9], with various effi- shown to be an interesting tool for the synthesis of galactofuranosides [7–9], with various ciencies depending on the acceptor substrates. The enzyme follows the typical retaining efficiencies depending on the acceptor substrates. The enzyme follows the typical retain‐ glycosidase mechanism, i.e., a double-displacement mechanism. First, the nucleophilic ing glycosidase mechanism, i.e., a double‐displacement mechanism. First, the nucleo‐ residue (E292) attacks the anomeric carbon of a donor substrate leading, with the concomi- philic residue (E292) attacks the anomeric carbon of a donor substrate leading, with the tant help of an acid/base residue (E173), to the formation of a covalent glycosyl-enzyme concomitant help of an acid/base residue (E173), to the formation of a covalent glycosyl‐ intermediate and the release of the aglycone part of the donor. Then, a nucleophilic ac- enzyme intermediate and the release of the aglycone part of the donor. Then, a nucleo‐ ceptor (water, alcohol) is activated by the later acid/base residue and attacks back the philic acceptor (water, alcohol) is activated by the later acid/base residue and attacks back glycosyl-enzyme intermediate to release either hydrolysis or transglycosylation products. the glycosyl‐enzyme intermediate to release either hydrolysis or transglycosylation prod‐ In transglycosylation reactions, the main limitation is the competition between the different reactionsucts. In transglycosylation catalyzed
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