Hyaluronidase-1 is an enzyme that in humans is encoded by the HYAL1gene.[5][6][7]
Function
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]
Structure
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]
Disease Relevance
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 neckcarcinomas, 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]
^Slevin M, Krupinski J, Kumar S, Gaffney J (August 1998). "Angiogenic oligosaccharides of hyaluronan induce protein tyrosine kinase activity in endothelial cells and activate a cytoplasmic signal transduction pathway resulting in proliferation". Laboratory Investigation; A Journal of Technical Methods and Pathology. 78 (8): 987–1003. PMID9714186.
^Rooney P, Kumar S, Ponting J, Wang M (March 1995). "The role of hyaluronan in tumour neovascularization (review)". International Journal of Cancer. 60 (5): 632–6. doi:10.1002/ijc.2910600511. PMID7532158. S2CID19133429.
^Aboughalia AH (January 2006). "Elevation of hyaluronidase-1 and soluble intercellular adhesion molecule-1 helps select bladder cancer patients at risk of invasion". Archives of Medical Research. 37 (1): 109–16. doi:10.1016/j.arcmed.2005.04.019. PMID16314195.
^Hautmann Stefan H.; Lokeshwar Vinata B.; Schroeder Grethchen L.; Civantos Francisco; Duncan Robert C.; Gnann Ralf; Friedrich Martin G.; Soloway Mark S. (2001-06-01). "ELEVATED TISSUE EXPRESSION OF HYALURONIC ACID AND HYALURONIDASE VALIDATES THE HA-HAase URINE TEST FOR BLADDER CANCER". Journal of Urology. 165 (6 Part 1): 2068–2074. doi:10.1016/S0022-5347(05)66296-9. PMID11371930.
^Schroeder GL, Lorenzo-Gomez MF, Hautmann SH, Friedrich MG, Ekici S, Huland H, Lokeshwar V (September 2004). "A side by side comparison of cytology and biomarkers for bladder cancer detection". The Journal of Urology. 172 (3): 1123–6. doi:10.1097/01.ju.0000134347.14643.ab. PMID15311054.
^Lokeshwar VB, Obek C, Pham HT, Wei D, Young MJ, Duncan RC, Soloway MS, Block NL (January 2000). "Urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade". The Journal of Urology. 163 (1): 348–56. doi:10.1016/s0022-5347(05)68050-0. PMID10604388.
^Witzel I, Marx AK, Müller V, Wikman H, Matschke J, Schumacher U, Stürken C, Prehm P, Laakmann E, Schmalfeldt B, Milde-Langosch K, Oliveira-Ferrer L (April 2017). "Role of HYAL1 expression in primary breast cancer in the formation of brain metastases". Breast Cancer Research and Treatment. 162 (3): 427–438. doi:10.1007/s10549-017-4135-6. PMID28168629. S2CID20477034.
Further reading
Wei MH, Latif F, Bader S, Kashuba V, Chen JY, Duh FM, Sekido Y, Lee CC, Geil L, Kuzmin I, Zabarovsky E, Klein G, Zbar B, Minna JD, Lerman MI (April 1996). "Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG". Cancer Research. 56 (7): 1487–92. PMID8603390.
Junker N, Latini S, Petersen LN, Kristjansen PE (2003). "Expression and regulation patterns of hyaluronidases in small cell lung cancer and glioma lines". Oncology Reports. 10 (3): 609–16. doi:10.3892/or.10.3.609 (inactive 1 November 2024). PMID12684632.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
Christopoulos TA, Papageorgakopoulou N, Theocharis DA, Mastronikolis NS, Papadas TA, Vynios DH (July 2006). "Hyaluronidase and CD44 hyaluronan receptor expression in squamous cell laryngeal carcinoma". Biochimica et Biophysica Acta (BBA) - General Subjects. 1760 (7): 1039–45. doi:10.1016/j.bbagen.2006.03.019. PMID16713680.
Hofinger ES, Spickenreither M, Oschmann J, Bernhardt G, Rudolph R, Buschauer A (April 2007). "Recombinant human hyaluronidase Hyal-1: insect cells versus Escherichia coli as expression system and identification of low molecular weight inhibitors". Glycobiology. 17 (4): 444–53. CiteSeerX10.1.1.533.3476. doi:10.1093/glycob/cwm003. PMID17227790.
