Hyaluronidase
Encyclopedia
The hyaluronidases are a family of enzyme
s that degrade hyaluronic acid.
In humans, there are six associated genes, including HYAL1
, HYAL2
, HYAL3
, and PH-20/SPAM1
.
the hydrolysis
of hyaluronan
, a constituent of the interstitial
barrier, hyaluronidase lowers the viscosity
of hyaluronan, thereby increasing tissue
permeability. It is, therefore, used in medicine in conjunction with other drugs
to speed their dispersion and delivery. Common applications are ophthalmic
surgery
, in combination with local anesthetic
s. It also increases the absorption rate of parenteral
fluids given by hypodermoclysis
, and is an adjunct in subcutaneous urography for improving resorption of radiopaque
agents. Hyaluronidase is also used for extravasation of hyperosmolar solutions.
Brand names of animal-derived hyaluronidase include HydaseTM (developed and manufactured by PrimaPharm Inc., distributed by Akorn Inc.) which has been FDA approved as a "thimerosal-free" animal-derived hyaluronidase, Vitrase (ISTA Pharmaceuticals), Amphadase (Amphastar Pharmaceuticals) and Wydase. Wydase, however, is no longer manufactured.
On December 2, 2005, the FDA approved a synthetic (recombinant or rDNA) "human" hyaluronidase, Hylenex (Halozyme Therapeutics
).
(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 play a role in the process of angiogenesis
, although most hyaluronidase preparations are contaminated with large amounts of angiogeneic growth factors. As previously mentioned, there are six hyaluronidase genes in the human genome, three of which can express active hyaluronidases (HYAL1, HYAL2 and PH20).
, Streptococcus pyogenes
, and Clostridium perfringens
, 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
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.
of the sperm
cell after it has reached the oocyte
, by digesting hyaluronan in the corona radiata
, 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 cells intertwined in an ECM 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, and the acrosome reaction can occur.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that degrade hyaluronic acid.
In humans, there are six associated genes, including HYAL1
HYAL1
Hyaluronidase-1 is an enzyme that in humans is encoded by the HYAL1 gene.- Further reading :...
, HYAL2
HYAL2
Hyaluronidase-2 is an enzyme that in humans is encoded by the HYAL2 gene.-Further reading:...
, HYAL3
HYAL3
Hyaluronidase-3 is an enzyme that in humans is encoded by the HYAL3 gene.-Further reading:...
, and PH-20/SPAM1
SPAM1
Hyaluronidase PH-20 is an enzyme that in humans is encoded by the SPAM1 gene.-Further reading:...
.
Use as a drug
By catalyzingCatalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
the hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of hyaluronan
Hyaluronan
Hyaluronan is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues...
, a constituent of the interstitial
Interstitial
An interstitial space or interstice is an empty space or gap between spaces full of structure or matter.In particular, interstitial may refer to:-Physical sciences:...
barrier, hyaluronidase lowers the viscosity
Viscosity
Viscosity is a measure of the resistance of a fluid which is being deformed by either shear or tensile stress. In everyday terms , viscosity is "thickness" or "internal friction". Thus, water is "thin", having a lower viscosity, while honey is "thick", having a higher viscosity...
of hyaluronan, thereby increasing tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
permeability. It is, therefore, used in medicine in conjunction with other drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
to speed their dispersion and delivery. Common applications are ophthalmic
Ophthalmology
Ophthalmology is the branch of medicine that deals with the anatomy, physiology and diseases of the eye. An ophthalmologist is a specialist in medical and surgical eye problems...
surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
, in combination with local anesthetic
Local anesthetic
A local anesthetic is a drug that causes reversible local anesthesia, generally for the aim of having local analgesic effect, that is, inducing absence of pain sensation, although other local senses are often affected as well...
s. It also increases the absorption rate of parenteral
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...
fluids given by hypodermoclysis
Hypodermoclysis
Hypodermoclysis, which can also be called interstitial infusion or subcutaneous infusion, is the subcutaneous administration of fluids to the body. This would often be in the form of a saline or glucose solution....
, and is an adjunct in subcutaneous urography for improving resorption of radiopaque
Radiodensity
Radiodensity refers to the relative inability of electromagnetic radiation, particularly X-rays, to pass through a particular material. Radiolucency indicates greater transparency or "transradiancy" to X-ray photons...
agents. Hyaluronidase is also used for extravasation of hyperosmolar solutions.
Brand names of animal-derived hyaluronidase include HydaseTM (developed and manufactured by PrimaPharm Inc., distributed by Akorn Inc.) which has been FDA approved as a "thimerosal-free" animal-derived hyaluronidase, Vitrase (ISTA Pharmaceuticals), Amphadase (Amphastar Pharmaceuticals) and Wydase. Wydase, however, is no longer manufactured.
On December 2, 2005, the FDA approved a synthetic (recombinant or rDNA) "human" hyaluronidase, Hylenex (Halozyme Therapeutics
Halozyme Therapeutics
Halozyme Therapeutics, based in San Diego, California, is a biopharmaceutical company developing and commercializing products targeting the extracellular matrix for the endocrinology, oncology, dermatology and drug delivery markets.* http://www.halozyme.com...
).
Role in cancer
The role of Hyaluronidases in cancer is controversial. 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 extracellular matrixExtracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(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 play a role in the process of angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, although most hyaluronidase preparations are contaminated with large amounts of angiogeneic growth factors. As previously mentioned, there are six hyaluronidase genes in the human genome, three of which can express active hyaluronidases (HYAL1, HYAL2 and PH20).
Role in pathogenesis
Some bacteria, such as Staphylococcus aureusStaphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
, Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...
, and Clostridium perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...
, 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 factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...
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.
Role in fertilization
In most mammalian fertilization, hyaluronidase is released by the acrosomeAcrosome
The acrosome is an organelle that develops over the anterior half of the head in the spermatozoa of many animals. It is a cap-like structure derived from the Golgi apparatus. Acrosome formation is completed during testicular maturation. In Eutherian mammals the acrosome contains digestive enzymes...
of the sperm
Spermatozoon
A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote...
cell after it has reached the oocyte
Oocyte
An oocyte, ovocyte, or rarely ocyte, 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 the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic...
, by digesting hyaluronan in the corona radiata
Corona radiata
In neuroanatomy, the corona radiata is a white matter sheet that continues caudally as the internal capsule and rostrally as the centrum semiovale. This sheet of axons contains both descending and ascending axons that carry nearly all of the neural traffic from and to the cerebral cortex...
, 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 cells intertwined in an ECM 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, and the acrosome reaction can occur.