Hyaluronidases are a family of

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s that catalyse the degradation of

hyaluronic acid Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans ...

(HA). Karl Meyer classified these enzymes in 1971, into three distinct groups, a scheme based on the

reaction products. The three main types of hyaluronidases are two classes of eukaryotic endoglycosidase hydrolases and a prokaryotic lyase-type of

glycosidase Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalyze the hydrolysis of glycosidic bonds in complex sugars. They are extremely common enzymes with roles in nature including degradation of biomass such as cellulose (c ...

. In humans, there are five functional hyaluronidases:

HYAL1 Hyaluronidase-1 is an enzyme that in humans is encoded by the ''HYAL1'' gene. Function This gene encodes a lysosomal hyaluronidase. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matr ...

HYAL2 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. This gene encodes a protein which is similar in structure to hya ...

HYAL3 Hyaluronidase-3 is an enzyme that in humans is encoded by the ''HYAL3'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' ...

, HYAL4 and HYAL5 (also known as

SPAM1 Hyaluronidase PH-20 is an enzyme that in humans is encoded by the ''SPAM1'' gene. Hyaluronidase Hyaluronidases are a family of enzymes that catalyse the degradation of hyaluronic acid (HA). Karl Meyer classified these enzymes in 1971, into ...

or PH-20); plus a pseudogene, HYAL6 (also known as HYALP1). The genes for HYAL1-3 are clustered in

chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...

, while HYAL4-6 are clustered in

chromosome 7 Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total D ...

. HYAL1 and HYAL2 are the major hyaluronidases in most tissues. GPI-anchored HYAL2 is responsible for cleaving high-molecular weight HA, which is mostly bound to the

CD44 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 (homing cell adhes ...

receptor. The resulting HA fragments of variable size are then further hydrolized by HYAL1 after being internalized into endo-

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...

s; this generates HA

oligosaccharides An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...

. According to their enzymatic mechanism, hyaluronidases are hyaluronoglucosidases (), i.e. they cleave the (1->4)-linkages between N-acetylglucosamine and glucuronate. The term hyaluronidase may also refer to

hyaluronoglucuronidase Hyaluronoglucuronidase (, ''hyaluronidase'', ''glucuronoglucosaminoglycan hyaluronate lyase'', ''orgelase'') is an enzyme with systematic name ''hyaluronate 3-glycanohydrolase''. This enzyme catalyses the following chemical reaction : Random hydr ...

s (), which cleave (1->3)-linkages. In addition, bacterial hyaluronate lyases () may also be referred to as hyaluronidases, although this is uncommon.

Use as a drug

Medical uses

By catalyzing the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

hyaluronan Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans ...

, a constituent of the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

(ECM), hyaluronidase lowers the

viscosity The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water. Viscosity quantifies the inte ...

of hyaluronan, thereby increasing tissue permeability. It is, therefore, used in medicine in conjunction with other

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

to speed their dispersion and delivery. Common applications are ophthalmic

surgery Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...

, in combination with

local anesthetic A local anesthetic (LA) is a medication that causes absence of pain sensation. In the context of surgery, a local anesthetic creates an absence of pain in a specific location of the body without a loss of consciousness, as opposed to a general an ...

s. It also increases the absorption rate of

parenteral A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

fluids given by

hypodermoclysis Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, ...

, and is an adjunct in subcutaneous

urography Pyelogram (or pyelography or urography) is a form of imaging of the renal pelvis and ureter. Types include: * #Intravenous pyelogram, Intravenous pyelogram – In which a contrast solution is introduced through a vein into the circulatory system. ...

for improving resorption of

radiopaque Radiodensity (or radiopacity) is opacity to the radio wave and X-ray portion of the electromagnetic spectrum: that is, the relative inability of those kinds of electromagnetic radiation to pass through a particular material. Radiolucency or hypod ...

agents. Hyaluronidase is also used for extravasation of hyperosmolar solutions. Besides, hyaluronidase is a recommended

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...

for

vinca alkaloid ''Vinca'' alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant ''Catharanthus roseus'' (basionym ''Vinca rosea'') and other ''vinca'' plants. They block beta-tubulin polymerizatio ...

overdose or extravasation. 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. Patrick Treacy is recognised to be among the first doctors worldwide to use hyaluronidase during vascular occlusion caused by these type of dermal fillers and to establish protocols for its use.

Purified and recombinant hyaluronidases

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. The three naturally-sourced hyaluronidases are orthologs of human HYAL5 (PH20) obtained from testicular preparations. They are sold under the trade names Vitrase (ovine, FDA-approved in May 2004), Amphadase (bovine, October 2004) and Hydase (bovine, October 2005). Human recombinant hyaluronidase (Hylenex)—approved for use in the United States in December 2005—corresponds to the soluble fragment of human HYAL5 (PH20) produced in

culture Culture () is an umbrella term which encompasses the social behavior, institutions, and norms found in human societies, as well as the knowledge, beliefs, arts, laws, customs, capabilities, and habits of the individuals in these groups.Tyl ...

by genetically engineered Chinese hamster ovary (CHO) cells containing a DNA plasmid encoding the enzyme.

Combination treatments

A human recombinant hyaluronidase kit, HyQvia, was approved for use in the European Union in May 2013, Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. and in the United States in September 2014. It is a dual vial unit with one vial of immune globulin infusion 10% (human) and one vial of recombinant human hyaluronidase. It is an immune globulin with a recombinant human hyaluronidase indicated in the United States for the treatment of

primary immunodeficiency Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a ''primary'' immunodeficiency (PID), the cause of the immune deficiency must not be secondary in nature ( ...

in adults. This includes, but is not limited to, common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 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. * Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have failed or are contra‑indicated. * Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients. * Hypogammaglobulinaemia in patients pre‑ and post‑allogeneic hematopoietic stem cell transplantation (HSCT). A form of

subcutaneous immunoglobulin Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin or NHIG) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory de ...

(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 in

IVIG Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin or NHIG) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory dem ...

patients. Also in epidural lysis of adhesions for pain management. Hyaluronidase is available in some

fixed-dose combination A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC pr ...

drug products in the United States: rituximab/hyaluronidase (Rituxan Hycela), trastuzumab/hyaluronidase-oysk (Herceptin Hylecta), daratumumab/hyaluronidase-fihj (Darzalex Faspro), and pertuzumab/trastuzumab/hyaluronidase–zzxf (Phesgo). In July 2021, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(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.

Role in cancer

The role of hyaluronidases in cancer has been historically controversial due to contradictory observations, namely that levels of hyaluronidase (HYAL1/2) are increased in some cancers (

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...

, bladder, prostate, breast and brain), whereas low expression of HYAL1 is correlated with a decrease in survival of pancreatic adenocarcinoma patients. The reason for this apparent contradiction is that both the accumulation of HA (due to increased HAS levels and decreased HYAL levels), and the degradation of HA into HA oligosaccharides by high HYAL levels result in increased tumor malignancy. Elevated tissue expression of hyaluronic acid and hyaluronidase validates the HA-HAase urine test for bladder cancer. 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 (apigenin, sulfated glycosaminoglycans) 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 ECM surrounding the tumor, hyaluronidases help cancer cells escape from primary tumor masses. However, studies show that removal of hyaluronan from tumors prevents tumor invasion. Hyaluronidases are also thought to play a role in the process of

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

, although most hyaluronidase preparations are contaminated with large amounts of angiogenic growth factors.

Role in pathogenesis

Some bacteria, such as ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

'', ''

Streptococcus pyogenes ''Streptococcus pyogenes'' is a species of Gram-positive, aerotolerant bacteria in the genus ''Streptococcus''. These bacteria are extracellular, and made up of non-motile and non-sporing cocci (round cells) that tend to link in chains. They are ...

'', and ''

Clostridium perfringens ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, rod-shaped, anaerobic, spore-forming pathogenic bacterium of the genus ''Clostridium''. ''C. perfringens'' is ever-present in nature an ...

'', produce hyaluronidase as a means of using hyaluronan as a carbon source. It is often speculated that ''Streptococcus'' and ''Staphylococcus'' pathogens use hyaluronidase as a

virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...

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. Hyaluronidases are found in the

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

of certain lizards and snakes, as well as honeybees, where they are referred to as "spreading factors", having a function akin to bacterial hyaluronidases.

Role in immune response

White blood cells produce hyaluronidase to move more easily through connective tissue to get to infected sites.

Role in fertilization

In mammalian

fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...

, hyaluronidase is released by the

acrosome The acrosome is an organelle that develops over the anterior (front) half of the head in the spermatozoa (sperm cells) of many animals including humans. It is a cap-like structure derived from the Golgi apparatus. In placental mammals the acrosome ...

of the

sperm cell Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...

after it has reached the

oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...

, by digesting hyaluronan in the

corona radiata In neuroanatomy, the corona radiata is a white matter sheet that continues inferiorly as the internal capsule and superiorly as the centrum semiovale. This sheet of both ascending and descending axons carries most of the neural traffic from and ...

, thus enabling conception. Gene-targeting studies show that hyaluronidases such as PH20 are not essential for fertilization, although exogenous hyaluronidases can disrupt the cumulus matrix. The majority of mammalian ova are covered in a layer of

granulosa cell A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals. Structure and function In the primordial ovarian follicle, and la ...

s intertwined in an extracellular matrix that contains a high concentration of hyaluronan. When a capacitated 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 the

zona pellucida The zona pellucida (plural zonae pellucidae, also egg coat or pellucid zone) is a specialized extracellular matrix that surrounds the plasma membrane of mammalian oocytes. It is a vital constitutive part of the oocyte. The zona pellucida first ...

References

External links

* * * * * * * * {{Portal bar, Biology, Medicine, border=no EC 3.2.1 Extracellular matrix remodeling enzymes