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Hyaluronidases in Human Diseases

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Hyaluronidases in Human Diseases International Journal of Molecular Sciences Review Hyaluronidases in Human Diseases Aditya Kaul 1,2 , Walker D. Short 1,2 , Xinyi Wang 1,2,* and Sundeep G. Keswani 1,2,* 1 Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Texas Children’s Hospital, Houston, TX 77030, USA; [email protected] (A.K.); [email protected] (W.D.S.) 2 Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA * Correspondence: [email protected] (X.W.); [email protected] (S.G.K.); Tel.: +832-824-0469 (X.W.); +832-822-3135 (S.G.K.); Fax: +832-825-3141 (X.W.); +832-825-3141 (S.G.K.) Abstract: With the burgeoning interest in hyaluronic acid (HA) in recent years, hyaluronidases (HYALs) have come to light for their role in regulating catabolism of HA and its molecular weight (MW) distribution in various tissues. Of the six hyaluronidase-like gene sequences in the human genome, HYALs 1 and 2 are of particular significance because they are the primary hyaluronidases active in human somatic tissue. Perhaps more importantly, for the sake of this review, they cleave anti-inflammatory and anti-fibrotic high-molecular-weight HA into pro-inflammatory and pro- fibrotic oligosaccharides. With this, HYALs regulate HA degradation and thus the development and progression of various diseases. Given the dearth of literature focusing specifically on HYALs in the past decade, this review seeks to expound their role in human diseases of the skin, heart, kidneys, and more. The review will delve into the molecular mechanisms and pathways of HYALs and discuss current and potential future therapeutic benefits of HYALs as a clinical treatment. Keywords: disease; hyaluronic acid; hyaluronidase; molecular weight Citation: Kaul, A.; Short, W.D.; Wang, X.; Keswani, S.G. 1. Introduction to Hyaluronidases Hyaluronidases in Human Diseases. Int. J. Mol. Sci. 2021, 22, 3204. The role and significance of hyaluronidases are perhaps best understood by starting https://doi.org/10.3390/ijms22063204 with their substrate, hyaluronic acid. Originally elucidated by German biochemist Karl Meyer in 1934 [1], hyaluronic acid (HA) is a non-sulfated glycosaminoglycan (GAG) found Academic Editor: Lukáš Kubala in most vertebrates, and it has been largely associated with the pathogenesis of fibrosis [2]. While high-molecular-weight HA (HMW-HA) exerts anti-inflammatory and anti-fibrotic Received: 24 February 2021 effects [3], low-molecular-weight HA (LMW-HA) promotes inflammation and fibrosis [4]. Accepted: 18 March 2021 With this knowledge, the importance of hyaluronidases emerges as these enzymes are Published: 22 March 2021 responsible for the cleavage of anti-fibrotic HMW-HA into pro-fibrotic LMW-HA. Hyaluronidases (HYALs) themselves are endoglycosidases and are found in eukary- Publisher’s Note: MDPI stays neutral otes and prokaryotes alike. They were first observed by Duran-Reynals in 1928, who noted with regard to jurisdictional claims in the rapid spread of bacteria, drugs, antiviral vaccines, and subcutaneously-injected India published maps and institutional affil- ink in an extract of mammalian testes. Appropriately, he coined the term “spreading factor” iations. for this molecule [5], a property attributed to the fact that HYALs break down the structural integrity of HA, lowering its viscosity and leading to increased tissue permeability and thus spreading [6]. In 1971, the same Karl Meyer who detailed the chemical structure of HA classified Copyright: © 2021 by the authors. the HYALs into three discrete classes of enzymes [7]. Meyers based his categorization of Licensee MDPI, Basel, Switzerland. HYALs on their mechanism of action, with two groups comprised of endo-β-N-acetyl- This article is an open access article hexosaminidases and one group of endo-β-glucuronidases. Of the former, one class of distributed under the terms and vertebrate enzymes leverages substrate hydrolysis [8], and the other makes use of bacterial conditions of the Creative Commons eliminases, which employ β-elimination of the glycosidic linkage by way of an unsaturated Attribution (CC BY) license (https:// bond [9]. The third group of HYALs, endo-β-glucuronidases, are primarily found in creativecommons.org/licenses/by/ leeches [10], and although not much is known about this class of enzymes, their mechanism 4.0/). Int. J. Mol. Sci. 2021, 22, 3204. https://doi.org/10.3390/ijms22063204 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 13 Int. J. Mol. Sci. 2021, 22, 3204 2 of 11 mechanism of action is thought to be more closely related to the vertebrate enzymes than theirof action bacterial is thought counterparts. to be more closely related to the vertebrate enzymes than their bacterial counterparts.Critically, a large turnover of HA is common in vertebrate tissue [11]. In fact, levels of HACritically, rise rapidly a large under turnover pathological of HA isconditions, common inincluding vertebrate burns, tissue shock, [11]. Inand fact, after levels major of surgeriesHA rise rapidly [12]. Understanding under pathological how conditions,HYALs promote including HA burns,degradation shock, helps and afterdetermine major theirsurgeries influence [12]. Understandingin various disease how states. HYALs As promote such, the HA next degradation section of helpsthis review determine will theirspe- cificallyinfluence focus in various on HYALs disease in states.humans As by such, detailing the next the section HYALs of and this their review mechanism will specifically of ac- tion.focus on HYALs in humans by detailing the HYALs and their mechanism of action. 2. Background and Mechanism of Action in Humans Six hyaluronidase hyaluronidase-like-like genes have been elucidated in the human genome, allall of which are highly homologous, both within the paralog and acrossacross otherother vertebrates,vertebrates, includingincluding mice. In terms of location, HYALs 1, 2, and 3 are found tightlytightly clustered on chromosomechromosome loci 3p21.3,3p21.3, andandHYALs HYALs 4 ,45, ,5 and, and6 are6 are found found in ain similar a similar fashion fashion on chromosomeon chromosome 7q31.3 7q31.3 [13]. HYALs[13]. HYALs 5 and 56 andare 6 also are knownalso known as sperm as sperm adhesion adhesion molecule molecule 1 (SPAM1/PH20 1 (SPAM1/PH20) and) HYALP1and HY-, ALP1respectively., respectively.HYAL6 HYAL6is known is known as HYALP1 as HYALP1as it isas a it pseudogene is a pseudogene that isthat transcribed is transcribed but butnot not translated translated in humansin humans [14 [14].]. The The arrangement arrangement of of the the genes genes suggests suggests that that oneone originaloriginal gene sequence underwent two duplication events and a subsequent en masse duplication event to generate the chromosomal distribution found in humans and mice; notably, this means that that properties properties of of HYALs HYALs uncovered uncovered in in murine murine studies studies can can largely largely be be translated translated to humans.to humans. We We indicate indicate the the chromosomal chromosomal locations locations of of these these six six HYALsHYALs andand their primary function, degradation of HA in the extracellular space, inin Figure1 1.. Figure 1. Schematic illustration depicting thethe chromosomalchromosomal locationslocations ofof hyaluronidases hyaluronidases ( HYALs(HYALs) 1–6) 1and–6 and a secreted a secreted HYAL HYAL enzyme enzyme cleaving cleaving hyaluronic hyaluronic acid (HA).acid (HAHYALs). HYALs 1–3 are 1– located3 are located on chromosome on chro- mosome loci 3p21.3, and HYALs 4–6 on 7q31.3. Hyaluronidases are involved in the constant turno- loci 3p21.3, and HYALs 4–6 on 7q31.3. Hyaluronidases are involved in the constant turnover of the ver of the extracellular proteoglycan hyaluronan, generating fragments of various molecular extracellular proteoglycan hyaluronan, generating fragments of various molecular weights depending weights depending on the type of hyaluronidase. Pictured here is an extracellular hyaluronidase degradingon the type HA, of hyaluronidase. although it is Picturedimportant here to isnote an extracellularthat HYAL may hyaluronidase reside inside degrading endosomes HA, or although be boundit is important to the membrane to note that surfa HYALce. mayThis residefigure insideis a broad endosomes illustration or be and bound is not to drawn the membrane to scale. surface. Cre- atedThis figurewith BioRender.com. is a broad illustration and is not drawn to scale. Created with BioRender.com. Among the sixsix HYALs,HYALs, HYALs HYALs 1 1 and and 2 are2 are the the primary primary hyaluronidases hyaluronidases responsible responsible for forthe the catabolism catabolism of HA of HA in somatic in somatic tissue. tissue. Because BecauseHYALs HYALs 3, 4 ,3 and, 4, and5 have 5 have weak weak expression expres- sionpatterns patterns and HYAL6and HYAL6is a pseudogene, is a pseudogene, by process by process of elimination, of elimination these, fourthese HYALs four HYALs likely do not participate in cleavage of HA [14]. (Refer to Table1 for a summary of the human Int. J. Mol. Sci. 2021, 22, 3204 3 of 11 HYALs). However, this theory was properly corroborated by Csoka et al. when the group discovered that the mechanism for catabolism of HA involves HYAL2 working in lockstep with HA-receptor CD44 to break down HMW-HA into 20 kDa fragments. HYAL2, secured at the cell surface by glycosylphosphatidylinositol (GPI), produces the fragments, which are then packaged into acidic endosomes and transported intracellularly. Once
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