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Hyaluronan: Metabolism and Function biomolecules Review Hyaluronan: Metabolism and Function Takashi Kobayashi 1 , Theerawut Chanmee 2 and Naoki Itano 3,* 1 Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan; [email protected] 2 Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Phutthamonthon, Nakhon Pathom 73170, Thailand; [email protected] 3 Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan * Correspondence: [email protected]; Tel.: +81-75-705-3064 Received: 2 October 2020; Accepted: 5 November 2020; Published: 7 November 2020 Abstract: As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis and degradation tightly control the turnover rate, concentration, and molecular size of hyaluronan in tissues. Despite the relatively simple chemical composition of this polysaccharide, its wide range of molecular weights mediate diverse functions that depend on molecular size and tissue concentration. Genetic engineering and pharmacological approaches have demonstrated close associations between hyaluronan metabolism and functions in many physiological and pathological events, including morphogenesis, wound healing, and inflammation. Moreover, emerging evidence has suggested that the accumulation of hyaluronan extracellular matrix and fragments due to the altered expression of hyaluronan synthases and hyaluronidases potentiates cancer development and progression by remodeling the tumor microenvironment. In addition to the well-known functions exerted by extracellular hyaluronan, recent metabolomic approaches have also revealed that its synthesis can regulate cellular functions via the reprogramming of cellular metabolism. This review highlights the current advances in knowledge on the biosynthesis and catabolism of hyaluronan and describes the diverse functions associated with hyaluronan metabolism. Keywords: hyaluronan; metabolism; biosynthesis; degradation; extracellular matrix; cancer 1. Introduction Hyaluronan (HA) comprises a major component of the extracellular matrix (ECM) in vertebrate connective tissues and is abundant in the cartilage, skin, brain, vitreous body, umbilical cord, and synovial fluid. Since HA was first discovered in bovine vitreous as a novel glycosaminoglycan [1], its structure, physical properties, physiological activity, and metabolism have been studied for almost a century. The HA polysaccharide is a non-sulfated linear glycosaminoglycan composed of repeating disaccharide units of [3)-β-d-N-acetylglucosamine (GlcNAc)-β(1,4)-d-glucuronic acid (GlcA)-β(1] (Figure1a) [ 2]. The concentration and size distribution of HA vary with tissue type, age, and disease severity [3,4]. With a broad molecular weight range, HA has multiple physical and physiological properties that depend on its molecular weight and concentration, both of which are regulated by the balance between HA biosynthesis and degradation [5]. In vertebrates, the dynamic metabolism of HA is tightly controlled by three synthases and several hyaluronidases [5]. The three isoforms of HA synthases (HAS1, HAS2, and HAS3), each with different characteristics and regulatory systems, control HA biosynthesis at multiple stages [6]. Among the HYAL family members of hyaluronidases, HYAL1 and HYAL2 are widely expressed in mammalian tissues and are thought Biomolecules 2020, 10, 1525; doi:10.3390/biom10111525 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 1525 2 of 20 Biomolecules 2020, 10, x 2 of 20 tocontributors be major contributorsto HA catabolism to HA [7]. catabolismMore recently [7]., cell More migration recently, inducing cell migration protein (CEMIP)/KIAA1199 inducing protein (CEMIP)and transmembrane/KIAA1199 and protein transmembrane 2 (TMEM2) protein have 2 (TMEM2)been identified have been as novel identified molecules as novel involved molecules in involvedextracellular in extracellular HA degradation HA degradation [8,9]. [8,9]. a Hyaluronan (HA) - COO CH2OH O O HO O O HO OH NH O C n CH3 GlcA GlcNAc b Hydrogen bond O O CH3 OC C CH2OH HO O O OH NH HO O O O HO O OH NH O O HO C CH2OH O C O H CH3 H O c d HA Extracellular space Extracellular space HAS NH2 COOH Cytoplasm UDP UDP Cytoplasm -UDP -UDP GlcA GlcNAc Figure 1. (a) Molecular structure of a HA disaccharide unit. HA is a negatively charged polysaccharide composed of repeating disaccharide units of glucuronic acid (GlcA; blue) and N-acetylglucosamine Figure 1. (a) Molecular structure of a HA disaccharide unit. HA is a negatively charged (GlcNAc). (b) Secondary structure of a HA tetrasaccharide with water. Hydrogen bonds are represented polysaccharide composed of repeating disaccharide units of glucuronic acid (GlcA; blue) and N- by red dashed lines. (c) Predicted structure of mammalian HAS. HAS enzymes contain multiple acetylglucosamine (GlcNAc). (b) Secondary structure of a HA tetrasaccharide with water. Hydrogen membrane-spanning regions at both the amino and carboxyl terminus and catalytic sites at the central bonds are represented by red dashed lines. (c) Predicted structure of mammalian HAS. HAS enzymes part of the molecule. (d) Schematic illustration of HA synthesis and secretion. HAS enzymes catalyze thecontain alternative multiple addition membrane-spanning of UDP-GlcA and regions UDP-GlcNAc at both tothe the amino nascent and HA carboxyl chain andterminus extrude and it throughcatalytic thesites plasma at the membrane.central part of the molecule. (d) Schematic illustration of HA synthesis and secretion. HAS enzymes catalyze the alternative addition of UDP-GlcA and UDP-GlcNAc to the nascent HA chain HAand isextrude a biopolymer it through with the plasma excellent membrane. water retention ability and can form a meshwork structure. As high molecular weight (HMW) HA is stabilized by intermolecular and intramolecular interactions with hydrogenHA is a biopolymer and hydrophobic with excellent bonds in water an aqueous retention solution, ability highlyand can concentrated form a meshwork solutions structure. exhibit considerableAs high molecular viscoelasticity weight (HMW) (Figure 1HAb) [ is10 stabilized]. Due to itsby lowintermolecular diffusivity, and HMW intramolecular HA forms a pericellularinteractions ECMwith aroundhydrogen its producingand hydrophobic cells. The bonds composition in an aqueou ands function solution, of highly the HA concentrated ECM are multiply solutions regulated exhibit byconsiderable association viscoelasticity states and combinations (Figure 1b) with [10]. specific Due tobinding its low diffusivity, molecules [ 11HMW–13]. HA HA forms not only a pericellular functions asECM a structural around framework,its producing but cells. also activatesThe composition intracellular and signal function transduction of the HA by interacting ECM are withmultiply cell surfaceregulated receptors by association for the regulationstates and ofcombinations such dynamic with cell specific behaviors binding as cell molecules proliferation, [11–13]. adhesion HA not andonly migration, functions allas ofa whichstructural are suggestedframework, to bebut involved also activates in morphogenesis intracellular and signal wound transduction healing [14 by]. Theinteracting HA receptor with CD44cell surface participates receptors in many for physiologicalthe regulation and of pathologicalsuch dynamic processes cell behaviors by interacting as cell withproliferation, HA and activating adhesion keyand signaling migration, cascades all of whic [15] (Figureh are suggested2). Such interactions to be involved initiate in themorphogenesis expression and wound healing [14]. The HA receptor CD44 participates in many physiological and pathological processes by interacting with HA and activating key signaling cascades [15] (Figure 2). Such Biomolecules 2020, 10, x 3 of 20 Biomolecules 2020, 10, 1525 3 of 20 interactions initiate the expression of genes related to cell growth and survival and induce cytoskeletal rearrangement and membrane ruffling, leading to active cell migration. On the other of genes related to cell growth and survival and induce cytoskeletal rearrangement and membrane hand, HA fragments degraded by the action of hyaluronidases diffuse throughout tissues and bind ruffling, leading to active cell migration. On the other hand, HA fragments degraded by the action to HA receptors on peripheral cells to act as intercellular signals [14]. Thus, HA has a variety of of hyaluronidases diffuse throughout tissues and bind to HA receptors on peripheral cells to act as functions that cannot be easily imagined from its simple structure. These functions are controlled by intercellular signals [14]. Thus, HA has a variety of functions that cannot be easily imagined from its modulating concentration, sugar chain length, turnover rate, and other features of HA as well as by simple structure. These functions are controlled by modulating concentration, sugar chain length, HA association states with binding molecules. turnover rate, and other features of HA as well as by HA association states with binding molecules. HA Extracellular space CD44 RTK P Gab1 HSP90/ PI3K/Akt Cdc37 Ezrin Cytoplasm Rho-GEF Grb2/Vav2 Ras Rac1 Actin cytoskeleton P Raf P MAPK Cell growth Migration Pro-survival
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