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Label-Free Electrochemical Lectin-Based Biosensors

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Label-Free Electrochemical Lectin-Based Biosensors Open Chem., 2015; 13: 636–655 Review Article Open Access Dominika Pihíková, Peter Kasák, Jan Tkac* Glycoprofiling of cancer biomarkers: Label-free electrochemical lectin-based biosensors Abstract: Glycosylation of biomolecules is one of the 1 Introduction most prevalent post- and co-translational modification in a human body, with more than half of all human proteins Carbohydrates are an essential part of every living organism being glycosylated. Malignant transformation of cells and are considered to be the most abundant organic influences glycosylation machinery resulting in subtle molecules found in nature [1-3]. It is widely known that changes of the glycosylation pattern within the cell glycans modulate or mediate cell-cell or cell-biomolecule populations as a result of cancer. Thus, an altered terminal interactions, cell signalling, host-pathogen interactions, glycan motif on glycoproteins could provide a warning disease progression or metastasis [4-7]. Changes in the signal about disease development and progression glycosylation, mediated by multiple enzymes, play critical and could be applied as a reliable biomarker in cancer roles in regulation of numerous biological processes. diagnostics. Among all highly effective glycoprofiling Oligosaccharides may covalently link to a protein tools, label-free electrochemical impedance spectroscopy backbone in order to stabilize, functionalize it and create (EIS)-based biosensors have emerged as especially highly specific sites for biorecognition. There are two suitable tool for point-of-care early-stage cancer main types of glycan attachments to glycoproteins: (i) detection. Herein, we highlight the current challenges N-linked glycosylation e.g. glycans are covalently bound in glycoprofiling of various cancer biomarkers by to asparagine residues in a consensus sequence Asn- ultrasensitive impedimetric-based biosensors with low X-Ser/Thr (X can be any amino acid except for proline) sample consumption, low cost fabrication and simple via N-acetylglucosamine (N-GlcNAc); and (ii) O-linked miniaturization. Additionally, this review provides a short glycosylation e.g. attachment of glycans to the hydroxyl introduction to the field of glycomics and lectinomics and groups of serine or threonine [8]. Glycosylation is quite a gives a brief overview of glycan alterations in different complex process catalysed by glycosyltransferases in the types of cancer. endoplasmic reticulum (ER)-Golgi apparatus [9,10]. The structural variety of glycans derives from Keywords: glycosylation, lectins, electrochemical the various ways in which monosaccharides can be impedance spectroscopy, cancer biomarkers, biosensors linked together and from many available isomers of monosaccharides [9]. Covalent glycosidic bond can be DOI: 10.1515/chem-2015-0082 designed in two possible positions at an anomeric carbon; received May 23, 2014; accepted September 26, 2014. i.e. via either an α- or a β- glycosidic linkage. A vast complexity of glycans can be illustrated by a theoretical number of all possible saccharides formed from 4 building blocks, when 4 different amino acids can form 24 different tetrapeptides, but four different hexoses may potentially generate 35,560 unique tetrasaccharides [1,11]. In addition, glycans can be enzymatically modified, which *Corresponding author: Jan Tkac: Department of Glycobiotechnology, further increases the number of possible saccharidic units Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 38 Bratislava, Slovakia, E-mail: [email protected] potentially present in biological systems [12]. Dominika Pihíková: Department of Glycobiotechnology, Institute of In order to understand the function of glycans on Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 a molecular level, advanced mass spectrometry (MS), 38 Bratislava, Slovakia; liquid chromatography (LC), capillary electrophoresis Peter Kasák: Center for Advanced Materials, Qatar University, (CE), microarray techniques, and biosensors have been P.O.Box 2713 Doha, Qatar © 2015 Dominika Pihíková et al., licensee De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. Glycoprofiling of cancer biomarkers: Label-free electrochemical lectin-based biosensors 637 employed [13,14]. Glycan arrays and arrays of glycan- Lectins can also be classified, based on their binding biomolecules have become “a must have” carbohydrate binding specificity, into five main component for highly robust and parallel glycoprofiling groups with a specificity to: L-fucose, galactose/N- in glycomics and for glycoprofiling of various diseases acetylgalactose, sialic acids, mannose and/or glucose, [3,15-20] and N-acetylglucosamine [22]. 2 Lectins 2.1 Lectin-carbohydrate interactions Lectins are ubiquitous natural proteins specifically Details about lectin-saccharide interactions and about recognizing and binding carbohydrate complexes. structural basics of the carbohydrate specificity of lectins Structural studies indicated that the carbohydrate- have been provided by several studies based on X-ray binding activity of lectins was generated by a limited crystallography and other instrumental techniques polypeptide segment designated as the carbohydrate [17,21,24,26]. Lectin-glycoconjugate biorecognition is recognition domain (CRD) [1,21]. Most lectins interact specific, like in the case of antibody-antigen or enzyme- with terminal non-reducing carbohydrate residues of substrate binding [10,27]. These interactions are mediated a glycoprotein and glycolipid component of the cell by hydrogen bonds, van der Waals interactions, and membrane. Variety of lectins are localized in different hydrophobic binding [28]. For instance, polar parts of parts of the organism, depending on their functional galactose are recognized by a lectin through hydrogen- role (e.g. intracellular lectins are involved in protein bond interactions, while less polar side of galactose trafficking, membrane-bound lectins mediate host- interacts with a lectin via hydrophobic interactions pathogen interactions, etc.) [22]. The term lectin is (i.e. tryptophan residues in lectin) [10]. Many lectins evolved from the Latin word legere meaning to choose, contain two or more carbohydrate-binding sites. The pick or select [23]. Furthermore, these carbohydrate- binding-sites for monosaccharides are stabilized via binding molecules are able to agglutinate cells (e.g. numerous hydrogen bonds, most often by Asp, Asn, and Gly erythrocytes). It is believed that the earliest description of residues [28]. Moreover, based on thermodynamic studies ability to agglutinate erythrocytes was by Peter Hermann it was concluded that the dominant forces stabilizing the Stillmark in 1888 [21]. He described the agglutination complex would appear to be intermolecular hydrogen activity of toxin Ricinus communis in his doctoral thesis. bonds and van der Waals interactions [29]. Electrostatic However, the modern age of lectinomics began almost interactions are limited to specific monosaccharides one hundred years later [1]. such as various forms of sialic acid [28]. In general, -3 -4 -1 Lectins have been isolated from various sources, such lectins exhibit low affinity (KD = 10 –10 mol L ) while as plants, bacteria, viruses, and animals [18,24]. Plant binding with carbohydrates [30]. On the other hand, lectins are the biggest family of lectins; one of the best antigen-antibody interactions typically exhibit KD in the characterized types of plant lectin are the ones isolated subnanomolar range [30]. from Legeminosae sp. The Leguminosae lectins are Ca2+- and Lectins as biorecognition elements and valuable Mn2+-dependent metalloproteins, such as concanavalin glycan affinity reagents have been broadly utilized in A (ConA), lentil lectin (LCA), soybean agglutinin (SBA), numerous applications, such cancer diagnostics [18,25,31], and others [24]. Some of the plant lectins (Ricinus communis drug delivery [32], immunohistological studies [28], agglutinin, and lectin from Abrus precatorius) exhibit analysis of pathogenic bacteria [33], HIV research [34], etc. toxic effect to animal cells [25]. Animal lectins belong Plenty of analytical techniques have been employed to study to endogenous lectins and are further classified into lectin-carbohydrate binding profiles and subtle changes a C-type (Ca2+-dependent) and S-type (sulphhydryl- in the glycosylation pattern. The most high-throughput dependent galectins usually occurring in a soluble methods in glycomics are advanced mass spectrometry form) [9,25]. Viral lectins are known as hemagglutinins (MS) ones combined with liquid chromatography and and the influenza virus hemagglutinin was the first electrophoresis [14]; and lectin/carbohydrate microarrays. glycosyaminoglycan-binding protein isolated from Additionally, numerous laboratory techniques have lower organisms in 1950 [9]. The overview of lectins with been adapted to integrate lectins (lectin affinity carbohydrate specificity, source, and molecular weight is chromatography, enzyme-linked lectin assay (ELLA), given in Table 1. lectin blotting, agglutination methods, histo- and 638 Dominika Pihíková et al. Table 1: List of lectins with their common abbreviations, source, preferred carbohydrate specificity and molecular weight [17,31,36,38]. Lectin from Abbr. S Carbohydrate specificity Mw Aleuria aurantia AAL A α-L-Fuc 72 Anguilla anguilla AAA F α-L-Fuc 50 Aspergillus oryzae AOL MO α-1,6Fuc n/a Concanavalin A Con A P α-D-Man, α-D-Glc; branched
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