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Glycosaminoglycans and Proteoglycans pharmaceuticals Editorial Glycosaminoglycans and Proteoglycans Vitor H. Pomin 1 and Barbara Mulloy 2,* 1 Program of Glycobiology, Institute of Medical Biochemistry Leopoldo de Meis and University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil; [email protected] 2 Glycosciences Laboratory, Department of Medicine, Imperial College London, Burlington Danes Building, Du Cane Road, London W12 0NN, UK * Correspondence: [email protected] Received: 19 February 2018; Accepted: 26 February 2018; Published: 27 February 2018 Abstract: In this editorial to MDPI Pharmaceuticals special issue “Glycosaminoglycans and Proteoglycans” we describe in outline the common structural features of glycosaminoglycans and the characteristics of proteoglycans, including the intracellular proteoglycan, serglycin, cell-surface proteoglycans, like syndecans and glypicans, and the extracellular matrix proteoglycans, like aggrecan, perlecan, and small leucine-rich proteoglycans. The context in which the pharmaceutical uses of glycosaminoglycans and proteoglycans are presented in this special issue is given at the very end. Keywords: chondroitin sulfate; decorin; dermatan sulfate; glycosaminoglycans; glypican; heparan sulfate; heparin; hyaluronan; keratan sulfate; perlecan; proteoglycans; serglycin; syndecan 1. Introduction This short article is intended to provide a brief introduction to the structures of glycosaminoglycans (GAGs) and proteoglycans (PGs) to set the articles in this special issue of Pharmaceuticals on “Proteoglycans and Glycosaminoglycans” into context. The class of glycosylated proteins known as PGs is represented in the pharmaceutical world chiefly by its carbohydrate constituents. These are polysaccharides known as GAGs, such as heparin (Hp) [1] and chondroitin sulfate (CS) [2]. When attached to their native protein cores these polysaccharides form the glycoconjugates known as PGs. Whole PGs are less often proposed as therapeutic agents, though recently, particularly in the context of regenerative medicine, the concept of PG mimetics, ‘neoproteoglycans’, is becoming more familiar [3]. The development of PG- and GAG-based medicines is beginning to take into account the way the GAGs are organized and presented by attachment to their PG cores, as well as the sequences and covalent structures of the compounds themselves. In this special issue, contributed articles will cover the current pharmaceutical uses of GAGs and their mimetics, with others describing the involvement of GAGs in processes, such as cell growth and differentiation, morphogenesis, inflammation, and healing; all of which are likely to give rise to future therapeutic uses of GAGs and PGs. 2. Glycosaminoglycans 2.1. Structural Features GAGs are linear and heterogeneous sulfated glycans. Although they are structurally complex, the backbones of these polysaccharides are simply made up of repeating disaccharide building blocks composed of alternating uronic acid (UA) and hexosamine units. The UA units can be either β-D-glucuronic acid (GlcA) or its C5 epimerized version, α-L-iduronic acid (IdoA). The amino sugars can be either glucose (Glc)-based (α-D- or β-D-glucosamine, GlcN) or galactose (Gal)-based, as N-acetyl-β-D-galactosamine (GalNAc). The permutation of these monosaccharide units within the Pharmaceuticals 2018, 11, 27; doi:10.3390/ph11010027 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2018, 11, x FOR PEER REVIEW 2 of 9 Pharmaceuticals 2018, 11, 27 2 of 9 can be either glucose (Glc)-based (α-D- or β-D-glucosamine, GlcN) or galactose (Gal)-based, as N-acetyl-β-D-galactosamine (GalNAc). The permutation of these monosaccharide units within the GAGGAG backbonesbackbones givesgives riserise toto differentdifferent GAGGAG families,families, suchsuch asas thethe GlcN-containingGlcN-containing heparanheparan sulfatesulfate (HS)(HS) andand Hp Hp [4 [4,5],,5], and and the the GalNAc-containing GalNAc-containing CS CS and and dermatan dermatan sulfate sulfate (DS) (DS) [6]. Keratan[6]. Keratan sulfate sulfate (KS) alternates(KS) alternatesN-acetyl-glucosamine N-acetyl-glucosamine (GlcNAc) (GlcNAc) with with Gal, Gal, and and does does not containnot contain UA UA [7,8 ];[7,8]; hyaluronan hyaluronan or hyaluronicor hyaluronic acid acid (HA) (HA) alternates alternates GlcNAc GlcNAc with with GlcA, GlcA, and and does does not not have have a protein a protein core core [9]. [9]. TheThe disaccharidesdisaccharides ofof HSHS andand HpHp areare bothboth composedcomposed ofof alternatingalternating 4-linked4-linked UAUA andand 4-linked4-linked αα-GlcN-GlcN unitsunits [[4,5].4,5]. Structurally, Structurally, HS HS and and Hp Hp diff differer only in thethe relativerelative proportionsproportions ofof theirtheir monosaccharidemonosaccharide andand disaccharidedisaccharide substructures.substructures. HS hashas bβ--D-GlcA as itsits majormajor UAUA typetype whilewhile HpHp hashas αα--LL-IdoA.-IdoA. GlcAGlcA inin HSHS usuallyusually alternatesalternates withwith GlcNAcGlcNAc units,units, butbut lowerlower amountsamounts ofofN N-sulfated-sulfated glucosamineglucosamine (GlcNS)(GlcNS) andand rarerare amountsamounts ofof unsubstitutedunsubstituted GlcNGlcN cancan alsoalso occur.occur. HpHp isis converselyconversely predominantlypredominantly composedcomposed ofof 2-sulfated2-sulfated IdoAIdoA unitsunits (IdoA2S)(IdoA2S) togethertogether withwith NN,6-di-sulfated,6-di-sulfated GlcNGlcN unitsunits (GlcNS6S).(GlcNS6S). TheseThese disaccharidesdisaccharides areare reflectedreflected inin thethe three-dimensionalthree-dimensional structuresstructures ofof HS/Hp HS/Hp tetrasaccharidestetrasaccharides shownshown inin FigureFigure1 1A,B.A,B. They They are are experimental experimental structures structures from from the the Protein Protein Databank Databank (PDB),(PDB), andand clearlyclearly adoptadopt fairlyfairly linearlinear shapes,shapes, thoughthough inin solutionsolution theythey maymay twisttwist andand foldfold toto varyingvarying extentsextents dependingdepending onon thethe exactexact monosaccharidemonosaccharide sequencesequence [10[10].]. FigureFigure 1. Three-dimensionalThree-dimensional tetrasaccharide tetrasaccharide represen representations,tations, taken takenfrom files from in filesthe PDB in the as PDBindicated, as indicated, of: (A) Heparin of: ([IdoA2S(A) Heparinα1→4)GlcNS6S( [IdoA2S(αα11!→4)GlcNS6S(4)IdoA2S(αα11→!4)GlcNS6S]4)IdoA2S(α from1!4)GlcNS6S] 1HPN; (B) fromheparan 1HPN; sulfate (B) heparan[GlcA(β1→ sulfate4)GlcNAc( [GlcA(α1β→14)GlcA(!4)GlcNAc(β1→4)GlcNAc]α1!4)GlcA( fromβ1! 4)GlcNAc]3E7J; (C) chondroitin from 3E7J; (4-sulfateC) chondroitin [GlcA(β1 4-sulfate→3)GalNAc4S( [GlcA(ββ1→1!4)GlcA(3)GalNAc4S(β1→3)GalNAc4S]β1!4)GlcA( fromβ1! 1OFM;3)GalNAc4S] (D) dermatan from 1OFM;sulfate ([IdoA(D) dermatanα1→3)GalNAc4S( sulfate [IdoA(β1→α14)IdoA(!3)GalNAc4S(α1→3)GalNAc4S]β1!4)IdoA( αfrom1!3)GalNAc4S] 1OFL; ( fromE) 1OFL;keratan (E ) keratansulfate sulfate[Gal6S( [Gal6S(β1→4)GlcNAc6S(β1!4)GlcNAc6S(β1→3)Gal6S(β1!3)Gal6S(β1→4)GlcNAc6S]β1!4)GlcNAc6S] from from1KES; 1KES; and and (F (F) ) hyaluronanhyaluronan [GlcA([GlcA(ββ11!→3)GlcNAc(β1→!4)GlcA(4)GlcA(ββ11→!3)GlcNAc]3)GlcNAc] from from 2BVK. 2BVK. The atoms inin thethe ball-stickball-stick representationsrepresentations areare carboncarbon (grey),(grey), nitrogennitrogen (blue),(blue), hydrogenhydrogen (light(light grey);grey); oxygenoxygen (red)(red) andand sulfursulfur (yellow).(yellow). AA andand FF areare NMRNMR solutionsolution structures,structures, andand non-exchangeablenon-exchangeable protonsprotons areare shown;shown; thethe othersothers areare crystalcrystal structuresstructures so so are are shown shown without without protons. protons. Rarely,Rarely, 3- 3-OO-sulfation-sulfation at at the the GlcNS6S GlcNS6S units units can can also also occur occur (GlcNS3S6S) (GlcNS3S6S) inin bothboth HSHS andand HpHp butbut isis moremore commoncommon inin thethe HpHp chains;chains; aa pentasaccharidepentasaccharide containingcontaining thisthis unusualunusual monosaccharidemonosaccharide residueresidue confersconfers highhigh affinityaffinity forfor antithrombinantithrombin and, and, thereby, thereby, high high anticoagulant anticoagulant activity, activity, on on Hp Hp [1 [1].]. SinceSince thethe lengthlength ofof GAGGAG chainschains cancan varyvary widely,widely, bothboth amongamong differentdifferent GAGGAG typestypes andand amongamong chainschains ofof thethe samesame GAGGAG type,type, thethe rangerange ofof MWsMWs inin GAGsGAGs isis veryvery broad,broad, rangingranging fromfrom aa fewfew kDakDa toto overover aa hundred hundred kDa. kDa. It isIt alsois also true true that manufacturingthat manufacturing processes processes can alter can the alter molecular the molecular weight (MW) weight of GAGs;(MW) forof GAGs; example, for unfractionated example, unfractionated heparin (UFH) heparin and low-molecular (UFH) and low-molecular weight heparin weight (LMWH) heparin have chains(LMWH) whose have average chains whose MWs areaverage respectively MWs are ~15 respectively kDa (~25 ~15 disaccharide kDa (~25 disaccharide units) and less units) than and 8 kDa less (~12than disaccharide 8 kDa (~12 units disaccharide or fewer). Theunits measurement or fewer). The of MWs measurement for LMWH of is notMWs straightforward, for LMWH asis Hpnot consistsstraightforward, of a mixture as Hp of sequenceconsists of types a mixture as described of sequence above, types each as occurring described in domainsabove, each with occurring particular in Pharmaceuticals 2018, 11, 27 3
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