Hyaluronidase-1 is an enzyme that in humans is encoded by the HYAL1 gene. [5] [6] [7]
Hyaluronidase-1 is an enzyme that in humans is encoded by the HYAL1 gene. [5] [6] [7]
This gene encodes a lysosomal hyaluronidase. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. This enzyme is active at an acidic pH and is the major hyaluronidase in plasma. Mutations in this gene are associated with mucopolysaccharidosis type IX, or hyaluronidase deficiency. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. Multiple transcript variants encoding different isoforms have been found for this gene. [7]
HYAL1 was first purified from human plasma and urine. [5] [6] The enzyme is 435 amino acids long with a molecular weight of 55-60 kDa. [6] [8]
The crystal structure of HYAL1 was determined by Chao, Muthukumar, and Herzberg. [9] The enzyme is composed of two closely associated domains: a N-terminal catalytic domain (Phe22-Thr352) and a smaller C-terminal domain (Ser353-Trp435). [9] The catalytic domain adopts a distorted (β/α)8 barrel fold similar to that of bee venom hyaluronidase. [9] Within the catalytic domain, residues such as Tyr247, Asp129, Glu131, Asn350, and Tyr202 play important roles in the cleavage of the β1→4 linkage between N-acetylglucosamine and glucuronic acid units in hyaluronan. [10]
HYAL1 is responsible for the hydrolysis of intracellular hyaluronan of all sizes into fragments as small as tetrasaccharides. [9]
In the optimal pH state of 4.0, Asp129 and Glu131 share a proton. [10] Intermolecular resonance in the amide bond in the N-acetylglucosamine unit of the bound hyaluronan polymer leads to a transition state with a positive charge on the nitrogen and an oxyanion nucleophile, which is stabilized by hydrogen bond interactions with Tyr247, that can perform an intramolecular attack on the electrophilic carbon. [10] This attack forms a 5-membered ring that is stabilized by the negative charge of Asp129 that forms as the leaving hydroxyl group of the glucuronic acid unit takes the proton from Glu131. [10] The now negatively charged Glu131 is primed to activate a water molecule for the hydrolysis of the intermolecular ring intermediate to restore N-acetylglucosamine. [10]
Tyr202 and Asn350, while not directly involved in the β1→4 linkage cleavage, were identified to be important to HYAL1 function. [10] HYAL1 uses Tyr202 as a substrate binding determinant and also requires proper glycosylation of Asn350 for full enzymatic function. [10]
The optimal pH range for HYAL1 function is 4.0 to 4.3, though HYAL1 is still 50-80% active at pH 4.5. [11] [12]
HYAL1 is implicated in several types of cancers, likely due to the angiogenic effects of HYAL1-cleaved hyaluronan fragments. [13] [14] In bladder, prostate, and head and neck carcinomas, elevated hyaluronan and HYAL1 levels are found in tumor cells, tissues, and related body fluids (e.g. urine for bladder cancer and saliva for head and neck cancer). [15] [16] [17] [18] Urinary hyaluronan and hyaluronidase levels, measured by the HA-HAase test, have ~88% accuracy in detecting bladder cancer, regardless of the tumor grade and stage. [19]
In breast cancer, HYAL1 is also overexpressed in cell lines MDA-MB-231 and MCF-7 and invasive duct cancer tissues and metastatic lymph nodes. [20] Higher HYAL1 expression has also been detected in primary tumor tissue from patients with subsequent brain metastases versus those without. [21]
In biology, the extracellular matrix (ECM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.
Hyaluronidases are a family of enzymes that catalyse the degradation of hyaluronic acid. Karl Meyer classified these enzymes in 1971, into three distinct groups, a scheme based on the enzyme reaction products. The three main types of hyaluronidases are two classes of eukaryotic endoglycosidase hydrolases and a prokaryotic lyase-type of glycosidase.
Hyaluronic acid, also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial HA averages about 7 million Da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million Da.
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11. CD44 has been referred to as HCAM, Pgp-1, Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.
Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.
Chemokine-binding protein 2 is a protein that in humans is encoded by the CCBP2 gene.
Hyaluronidase-2 is a multifunctional protein, previously thought to only possess acid-active hyaluronan-degrading enzymatic function. In humans it is encoded by the HYAL2 gene.
Hyaluronan-mediated motility receptor (HMMR), also known as RHAMM (Receptor for Hyaluronan Mediated Motility) is a protein which in humans is encoded by the HMMR gene. RHAMM recently has been also designated CD168 (cluster of differentiation 168).
Hyaluronan synthase 2 is an enzyme that in humans is encoded by the HAS2 gene.
Hyaluronan synthase 1 is an enzyme that in humans is encoded by the HAS1 gene.
Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), also known as extracellular link domain containing 1 (XLKD1) is a Link domain-containing hyaladherin, a protein capable of binding to hyaluronic acid (HA), homologous to CD44, the main HA receptor. In humans it is encoded by the LYVE1 gene.
Sodium-coupled neutral amino acid transporter 3 is a protein that in humans is encoded by the SLC38A3 gene.
Hyaluronan synthase 3 is an enzyme that in humans is encoded by the HAS3 gene.
Hyaluronidase PH-20 is an enzyme that in humans is encoded by the SPAM1 gene.
Tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein or TSG-6 is a protein that in humans is encoded by the TNFAIP6 gene.
Aminoacylase-1 is an enzyme that in humans is encoded by the ACY1 gene.
Hyaluronidase-3 is an enzyme that in humans is encoded by the HYAL3 gene.
N-acetyltransferase 80 is a protein that in humans is encoded by the NAA80 gene. It acetylates the N-terminus of mature actin.
Hyaladherins, also known as hyaluronan-binding proteins, are proteins capable of binding to hyaluronic acid. Most hyaladherins belong to the Link module superfamily, including its main receptor CD44, hyalectans and TSG-6. In addition there is a diverse group of hyaladherins lacking a Link module; these include the receptor RHAMM, C1QBP (HABP1) and HABP2. The primary roles of hyaladherins are cell adhesion, structural support of the extracellular matrix (ECM) and cell signalling.
{{cite journal}}: CS1 maint: DOI inactive as of August 2023 (link)