Hyaluronidases are a family ofenzymes that catalyse the degradation ofhyaluronic acid.Karl Meyer classified these enzymes in 1971, into three distinct groups, a scheme based on theenzyme reaction products.[1] The three main types of hyaluronidases are two classes of eukaryotic endoglycosidase hydrolases and a prokaryotic lyase-type ofglycosidase.[2]
In humans, there are five functional hyaluronidases:HYAL1,HYAL2,HYAL3, HYAL4 and HYAL5 (also known asSPAM1 or PH-20); plus apseudogene, HYAL6 (also known as HYALP1).[3][4] The genes for HYAL1-3 are clustered inchromosome 3, while HYAL4-6 are clustered inchromosome 7.[3] HYAL1 and HYAL2 are the major hyaluronidases in most tissues.GPI-anchored HYAL2 is responsible for cleaving high-molecular weight hyaluronic acid, which is mostly bound to theCD44 receptor. The resulting hyaluronic acid fragments of variable size are then further hydrolyzed by HYAL1 after being internalized intoendo-lysosomes; this generates hyaluronic acidoligosaccharides.[5]
Hyaluronidases arehyaluronoglucosidases (EC3.2.1.35), i.e. they cleave the (1→4)-linkages between N-acetylglucosamine and glucuronate. The term hyaluronidase may also refer tohyaluronoglucuronidases (EC3.2.1.36), which cleave (1→3)-linkages. In addition, bacterial hyaluronate lyases (EC4.2.2.1) may also be referred to as hyaluronidases, although this is uncommon.[6]
Bycatalyzing thehydrolysis ofhyaluronan, a constituent of theextracellular matrix, hyaluronidase lowers theviscosity of hyaluronan, thereby increasingtissue permeability. It is, therefore, used in medicine in conjunction with otherdrugs to speed their dispersion and delivery. Common applications areophthalmicsurgery, in combination withlocal anesthetics. It also increases the absorption rate ofparenteral fluids given byhypodermoclysis, and is an adjunct in subcutaneousurography for improving resorption ofradiopaque agents. Hyaluronidase is also used for extravasation of hyperosmolar solutions.[medical citation needed] Besides, hyaluronidase is a recommendedantidote forvinca alkaloid overdose or extravasation.[15] Hyaluronidase can be injected to dissolve hyaluronic acid type dermal fillers and is the best treatment option for those looking at dissolving lip filler or dealing with related complications.[16]
Four different purified hyaluronidases have been approved for use in the United States, three of animal origin and one recombinant. They are indicated as adjuvants in subcutaneous fluid administration for achieving hydration, for increasing the dispersion and absorption of other injected drugs, or for improving resorption of radiopaque agents, in subcutaneous urography.[17][13][18]
The three naturally-sourced hyaluronidases are orthologs of human HYAL5 (PH20) obtained from testicular preparations. They are sold under the brand names Vitrase (ovine, FDA-approved in May 2004),[19] Amphadase (bovine, October 2004)[20] and Hydase (bovine, October 2005).[21]
Human recombinant hyaluronidase (Hylenex Recombinant)—approved for use in the United States in December 2005[22][23]—corresponds to the soluble fragment of human HYAL5 (PH20) produced inculture by genetically engineeredChinese hamster ovary cells containing a DNA plasmid encoding the enzyme.[14]
A human recombinant hyaluronidase kit, Hyqvia, was approved for use in the European Union in May 2013,[24] and in the United States in September 2014.[25][26] It is a dual vial unit with one vial of immune globulin infusion 10% (human) and one vial of recombinant human hyaluronidase.[12] It is an immune globulin with a recombinant human hyaluronidase indicated in the United States for the treatment ofprimary immunodeficiency in adults. This includes, but is not limited to, common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.[12] In the European Union it is indicated as replacement therapy in adults, children and adolescents (0–18 years) in:
Primary immunodeficiency syndromes with impaired antibody production.[24]
Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed or are contra‑indicated.[24]
Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients.[24]
Hypogammaglobulinaemia in patients pre‑ and post‑allogeneic hematopoietic stem cell transplantation.[24]
A form ofsubcutaneous immunoglobulin (SCIG) that uses Hylenex to allow for a far greater volume of SCIG to be administered than would normally be possible to administer subcutaneously, providing a form of SCIG that can be dosed on a monthly basis, a longer period of time than other forms of SCIG allow. HyQvia had a rate of systemic adverse effects higher than traditional subcutaneous forms of immunoglobulin injection, but lower than those typical inIVIG patients.[27]
In July 2021, the USFood and Drug Administration (FDA) approved daratumumab and hyaluronidase-fihj in combination with pomalidomide and dexamethasone for adults with multiple myeloma who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor.[35]
The role of hyaluronidases in cancer has been historically controversial due to contradictory observations,[46] namely that levels of hyaluronidase (HYAL1/2) are increased in some cancers (colorectal,[47] bladder, prostate, breast and brain), whereas low expression of HYAL1 is correlated with a decrease in survival ofpancreatic adenocarcinoma patients.[48] The reason for this apparent contradiction is that both the accumulation of hyaluronic acid (due to increasedhyaluronan synthase levels and decreased HYAL levels) and the degradation of hyaluronic acid into hyaluronic acid oligosaccharides by high HYAL levels result in increased tumor malignancy.[5]
Elevated tissue expression of hyaluronic acid and hyaluronidase validates the hyaluronic acid-hyaluronidases urine test for bladder cancer.[49] Limited data support a role of lysosomal hyaluronidases in metastasis, while other data support a role in tumor suppression. Other studies suggest no contribution or effects independent of enzyme activity. Non-specific inhibitors (e.g., apigenin and sulfatedglycosaminoglycans) or crude enzyme extracts have been used to test most hypotheses, making data difficult to interpret. It has been hypothesized that by helping degrade the extracellular matrix surrounding the tumor, hyaluronidases help cancer cells escape from primary tumor masses. However, studies show that removal of hyaluronan from tumors prevents tumor invasion.[citation needed] Hyaluronidases are also thought to play a role in the process ofangiogenesis, although most hyaluronidase preparations are contaminated with large amounts of angiogenic growth factors.[50]
Some bacteria, such asStaphylococcus aureus,Streptococcus pyogenes,[51] andClostridium perfringens,[52] produce hyaluronidase as a means of using hyaluronan as a carbon source. It is often speculated thatStreptococcus andStaphylococcus pathogens use hyaluronidase as avirulence factor to destroy the polysaccharide that holds animal cells together, making it easier for the pathogen to spread through the tissues of the host organism, but no valid experimental data are available to support this hypothesis.[citation needed]
Hyaluronidases are found in thevenom of certain lizards and snakes, as well as honeybees, where they are referred to as "spreading factors", having a function akin to bacterial hyaluronidases.[53]
Plasmahyaluronic acid is elevated insepsis andseptic shock and correlate with disease severity, but the effect on mortality shows conflicting results.[55][56] Hyaluronidase, when injected into the circulation, results in the loss ofglycocalyx[57] and is therefore considered as a potential endogenous sheddase.[58] However, plasma hyaluronidase activity is decreased in experimental as well as in clinical septic shock.[59] Concomitant, the endogenous hyaluronidase inhibition in plasma was increased and may explain to certain extent the decreased plasma hyaluronidase activity.[citation needed]
In mammalianfertilization, hyaluronidase is released by theacrosome of thesperm cell after it has reached theoocyte, by digesting hyaluronan in thecorona radiata, thus enablingconception. Gene-targeting studies show that hyaluronidases such as PH20 are not essential for fertilization.[60]
Mammalian ova are covered in a layer ofgranulosa cells intertwined in an extracellular matrix that contains a high concentration of hyaluronan. When acapacitated sperm reaches the ovum, it is able to penetrate this layer with the assistance of hyaluronidase enzymes present on the surface of the sperm. Once this occurs, the sperm is capable of binding with thezona pellucida.[61]
^abCsóka AB, Scherer SW, Stern R (September 1999). "Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31".Genomics.60 (3):356–61.doi:10.1006/geno.1999.5876.PMID10493834.
^Csoka AB, Frost GI, Stern R (December 2001). "The six hyaluronidase-like genes in the human and mouse genomes".Matrix Biology.20 (8):499–508.doi:10.1016/S0945-053X(01)00172-X.PMID11731267.
^abcde"HyQvia EPAR".European Medicines Agency (EMA). 3 June 2013. Retrieved1 May 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^Sanford M (August 2014). "Human immunoglobulin 10 % with recombinant human hyaluronidase: replacement therapy in patients with primary immunodeficiency disorders".BioDrugs.28 (4):411–20.doi:10.1007/s40259-014-0104-3.PMID24925799.S2CID8091134.
^Anand D, Ray S, Srivastava LM, Bhargava S (July 2016). "Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients".Clinical Biochemistry.49 (10–11):768–776.doi:10.1016/j.clinbiochem.2016.02.014.PMID26953518.
^Yagmur E, Koch A, Haumann M, Kramann R, Trautwein C, Tacke F (January 2012). "Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity".Clinical Biochemistry.45 (1–2):82–87.doi:10.1016/j.clinbiochem.2011.10.016.PMID22085533.
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