Biology:HYAL1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Hyaluronidase-1 is an enzyme that in humans is encoded by the HYAL1 gene.[1][2][3]

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.[3]

Structure

HYAL1 was first purified from human plasma and urine.[1][2]  The enzyme is 435 amino acids long with a molecular weight of 55-60 kDa.[2][4]

The crystal structure of HYAL1 was determined by Chao, Muthukumar, and Herzberg.[5]  The enzyme is composed of two closely associated domains: a N-terminal catalytic domain (Phe22-Thr352) and a smaller C-terminal domain (Ser353-Trp435).[5]  The catalytic domain adopts a distorted (β/α)8 barrel fold similar to that of bee venom hyaluronidase.[5]  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.[6]

Mechanism

Mechanism of hyaluronan degradation.[6]

HYAL1 is responsible for the hydrolysis of intracellular hyaluronan of all sizes into fragments as small as tetrasaccharides.[5]

In the optimal pH state of 4.0, Asp129 and Glu131 share a proton.[6]  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.[6]  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.[6]  The now negatively charged Glu131 is primed to activate a water molecule for the hydrolysis of the intermolecular ring intermediate to restore N-acetylglucosamine.[6]

Tyr202 and Asn350, while not directly involved in the β1→4 linkage cleavage, were identified to be important to HYAL1 function.[6]  HYAL1 uses Tyr202 as a substrate binding determinant and also requires proper glycosylation of Asn350 for full enzymatic function.[6]

The optimal pH range for HYAL1 function is 4.0 to 4.3, though HYAL1 is still 50-80% active at pH 4.5.[7][8]

Disease Relevance

HYAL1 is implicated in several types of cancers, likely due to the angiogenic effects of HYAL1-cleaved hyaluronan fragments.[9][10] 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).[11][12][13][14]  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.[15]

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.[16]  Higher HYAL1 expression has also been detected in primary tumor tissue from patients with subsequent brain metastases versus those without.[17]

See also

References

  1. ↑ 1.0 1.1 "Purification, cloning, and expression of human plasma hyaluronidase". Biochemical and Biophysical Research Communications 236 (1): 10–5. July 1997. doi:10.1006/bbrc.1997.6773. PMID 9223416. 
  2. ↑ 2.0 2.1 2.2 "Purification and microsequencing of hyaluronidase isozymes from human urine". FEBS Letters 417 (3): 307–10. November 1997. doi:10.1016/S0014-5793(97)01309-4. PMID 9409739. Bibcode: 1997FEBSL.417..307C. 
  3. ↑ 3.0 3.1 "Entrez Gene: HYAL1 hyaluronoglucosaminidase 1". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3373. 
  4. ↑ "Upregulation of HYAL1 expression in breast cancer promoted tumor cell proliferation, migration, invasion and angiogenesis". PLOS ONE 6 (7). 2011. doi:10.1371/journal.pone.0022836. PMID 21829529. Bibcode: 2011PLoSO...622836T.  (Retracted, see doi:10.1371/journal.pone.0277500, PMID 36342948)
  5. ↑ 5.0 5.1 5.2 5.3 "Structure of human hyaluronidase-1, a hyaluronan hydrolyzing enzyme involved in tumor growth and angiogenesis". Biochemistry 46 (23): 6911–20. June 2007. doi:10.1021/bi700382g. PMID 17503783. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Hyaluronidase activity of human Hyal1 requires active site acidic and tyrosine residues". The Journal of Biological Chemistry 284 (14): 9433–42. April 2009. doi:10.1074/jbc.M900210200. PMID 19201751. 
  7. ↑ "Stromal and epithelial expression of tumor markers hyaluronic acid and HYAL1 hyaluronidase in prostate cancer". The Journal of Biological Chemistry 276 (15): 11922–32. April 2001. doi:10.1074/jbc.M008432200. PMID 11278412. 
  8. ↑ "Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX". Proceedings of the National Academy of Sciences of the United States of America 96 (11): 6296–300. May 1999. doi:10.1073/pnas.96.11.6296. PMID 10339581. Bibcode: 1999PNAS...96.6296T. 
  9. ↑ "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. August 1998. PMID 9714186. 
  10. ↑ "The role of hyaluronan in tumour neovascularization (review)". International Journal of Cancer 60 (5): 632–6. March 1995. doi:10.1002/ijc.2910600511. PMID 7532158. 
  11. ↑ "Detection of bladder carcinoma by combined testing of urine for hyaluronidase and cytokeratin 20 RNAs". Cancer 103 (7): 1356–62. April 2005. doi:10.1002/cncr.20902. PMID 15717321. 
  12. ↑ "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. January 2006. doi:10.1016/j.arcmed.2005.04.019. PMID 16314195. 
  13. ↑ 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. PMID 11371930. 
  14. ↑ "A side by side comparison of cytology and biomarkers for bladder cancer detection". The Journal of Urology 172 (3): 1123–6. September 2004. doi:10.1097/01.ju.0000134347.14643.ab. PMID 15311054. 
  15. ↑ "Urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade". The Journal of Urology 163 (1): 348–56. January 2000. doi:10.1016/s0022-5347(05)68050-0. PMID 10604388. 
  16. ↑ "HYAL1 overexpression is correlated with the malignant behavior of human breast cancer". International Journal of Cancer 128 (6): 1303–15. March 2011. doi:10.1002/ijc.25460. PMID 20473947. 
  17. ↑ "Role of HYAL1 expression in primary breast cancer in the formation of brain metastases". Breast Cancer Research and Treatment 162 (3): 427–438. April 2017. doi:10.1007/s10549-017-4135-6. PMID 28168629. 

Further reading



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