α-Galactosidase ( EC 3.2.1.22, α-GAL, α-GAL A; systematic name α-
D-galactoside galactohydrolase) is a
glycoside hydrolase
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 (ce ...
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 ...
that catalyses the following reaction:
: Hydrolysis of terminal, non-reducing α-
D-galactose residues in α-
D-galactosides, including galactose oligosaccharides, galactomannans and galactolipids
It catalyzes many catabolic processes, including cleavage of glycoproteins, glycolipids, and polysaccharides.
The enzyme is encoded by the ''GLA'' gene.
Two
recombinant forms of human α-galactosidase are called agalsidase α (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
) and agalsidase β (INN). A mold-derived form is the primary ingredient in gas relief supplements.
Function
This enzyme is a homodimeric glycoprotein that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins. It predominantly hydrolyzes
ceramide
Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetylsphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up ...
trihexoside, and it can catalyze the hydrolysis of
melibiose
Melibiose is a reducing disaccharide formed by an α-1,6 linkage between galactose and glucose (D-Gal-α(1→6)-D-Glc). It differs from lactose in the chirality of the carbon where the galactose ring is closed and that the galactose is linked to a ...
into galactose and glucose.
Reaction mechanism
Disease relevance
Fabry disease
Signs and Symptoms
Defects in human α-GAL result in
Fabry disease
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...
, a rare
lysosomal storage disorder
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
and
sphingolipidosis
Sphingolipidoses are a class of lipid storage disorders or degenerative storage disorders caused by deficiency of an enzyme that is required for the catabolism of lipids that contain ceramide,Lynn, D. Joanne, Newton, Herbert B. and Rae-Grant, Ale ...
that results from a failure to catabolize α-
D-galactosyl glycolipid moieties. Characteristic features include episodes of pain in hands and feet (
acroparesthesia
Paresthesia is an abnormal sensation of the skin (tingling, pricking, chilling, burning, numbness) with no apparent physical cause. Paresthesia may be transient or chronic, and may have any of dozens of possible underlying causes. Paresthesias ar ...
), dark red spots on skin (
angiokeratoma
Angiokeratoma is a benign cutaneous lesion of capillaries, resulting in small marks of red to blue color and characterized by hyperkeratosis. ''Angiokeratoma corporis diffusum'' refers to Fabry's disease, but this is usually considered a distinct c ...
), decreased sweating (
hypohidrosis
Hypohidrosis is a disorder in which a person exhibits diminished sweating in response to appropriate stimuli. In contrast with hyp''er''hidrosis, which is a socially troubling yet often benign condition, the consequences of untreated hypohidrosi ...
), decreased vision (corneal opacity), gastrointestinal problems, hearing loss,
tinnitus
Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...
, etc.. Complications for this disease can be life-threatening and may include progressive kidney damage, heart attack, and stroke. This disease may have late onset and only affect the heart or kidneys.
Fabry disease
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...
is an
X-linked disease
Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). In humans, these are termed X-linked recessive, ...
, affecting 1 in 40,000 males. However, unlike other X-linked diseases, this condition also creates significant medical problems for females carrying only 1 copy of the defective GLA gene. These women may experience many classic symptoms of the disorder including cardiac and kidney problems. However, a small number of females carrying only one copy of the mutated GLA gene never shows any symptoms of
Fabry disease
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...
.
Cause
Mutations to the GLA gene encoding α-GAL may result in complete loss of function of the enzyme. α-GAL is a lysosomal protein responsible for breaking down
globotriaosylceramide
Globotriaosylceramide is a globoside. It is also known as CD77, Gb3, GL3, and ceramide trihexoside. It is one of the few clusters of differentiation that is not a protein.
It is formed by the alpha linkage of galactose to lactosylceramide catalyze ...
, a fatty substance stored various types of cardiac and renal cells. When
globotriaosylceramide
Globotriaosylceramide is a globoside. It is also known as CD77, Gb3, GL3, and ceramide trihexoside. It is one of the few clusters of differentiation that is not a protein.
It is formed by the alpha linkage of galactose to lactosylceramide catalyze ...
is not properly catabolized, it is accumulated in cells lining blood vessels in the skin, cells in the kidney, heart and nervous system. As a result, signs and symptoms of
Fabry disease
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...
begin to manifest.
Treatment
There are three treatment options for Fabry disease:
recombinant enzyme replacement therapy, pharmacological chaperone therapy, and organ specific treatment.
= Recombinant enzyme replacement therapy (RERT)
=
RERT was approved as a treatment for Fabry disease in the United States in 2003.
Two
recombinant enzyme replacement therapies are available to functionally compensate for α-galactosidase deficiency. Agalsidase α and β are both
recombinant forms of the human α-galactosidase A enzyme and both have the same amino acid sequence as the native enzyme. Agalsidase α and β differ in the structures of their
oligosaccharide
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 ...
side chains.
In Fabry disease patients, 88% percent of patients develop
IgG
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
towards the injected recombinant enzyme, as it is foreign to their immune system. One suggested approach to solving this problem involves converting the
paralogous
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
enzyme
α-NAGAL (NAGA) into one that has with α-GAL activity. Because patients still have a functional NAGA gene, their immune system will not produce NAGA antibodies.
Agalsidase α
The pharmaceutical company
Shire
Shire is a traditional term for an administrative division of land in Great Britain and some other English-speaking countries such as Australia and New Zealand. It is generally synonymous with county. It was first used in Wessex from the beginn ...
manufactures agalsidase alfa (INN) under the
trade name
A trade name, trading name, or business name, is a pseudonym used by companies that do not operate under their registered company name. The term for this type of alternative name is a "fictitious" business name. Registering the fictitious name w ...
Replagal as a treatment for Fabry disease,
and was granted marketing approval in the EU in 2001.
FDA approval was applied for the United States.
However, in 2012, Shire withdrew their application for approval in the United States citing that the agency will require additional clinical trials before approval.
Agalsidase β
The pharmaceutical company
Genzyme
Genzyme was an American biotechnology company based in Cambridge, Massachusetts. Since its acquisition in 2011, Genzyme (also known as Genzyme Transgenics Corp or GTC Biotherapeutics) has been a fully owned subsidiary of Sanofi. In 2010, Genzyme ...
produces synthetic agalsidase β (INN) under the trade name Fabrazyme for treatment of Fabry disease. In 2009, contamination at Genzyme's
Allston, Massachusetts
Allston is an officially recognized neighborhood within the City of Boston, Massachusetts, United States. It was named after the American painter and poet Washington Allston. It comprises the land covered by the zip code 02134. For the most part ...
plant caused a worldwide shortage of Fabrazyme, and supplies were rationed to patients at one-third the recommended dose. Some patients have petitioned to break the company's patent on the drug under the "march-in" provisions of the
Bayh–Dole Act
The Bayh–Dole Act or Patent and Trademark Law Amendments Act ( Pub. L. 96-517, December 12, 1980) is United States legislation permitting ownership by contractors of inventions arising from federal government-funded research. Sponsored by senat ...
.
= Pharmacological chaperone therapy
=
![Chaperones](https://upload.wikimedia.org/wikipedia/commons/c/c1/Chaperones.png)
Fabry patients who display neurological symptoms cannot receive RERT because recombinant enzymes cannot normally pass the blood-brain barrier. Thus, a more suitable alternative treatment is used: pharmacological
chaperone therapy.
It has been shown that more potent
competitive inhibitors of an enzyme can act as a more powerful chemical chaperone for the corresponding mutant enzyme that fails to maintain proper folding and conformation, despite its intact
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
. These chemical chaperones bind to the
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
of the mutant enzyme, which can help promote proper folding and stabilize the mutant enzyme. Thus, this results in functional mutant enzymes that will not be degraded via the
ubiquitin-proteasome pathway.
1-Deoxygalactonojirimycin (DGJ) has been shown to be both a potent competitive inhibitor of α-GAL and an effective chaperone to for
Fabry disease
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...
, increasing intracellular α-GAL's activity by 14-fold.
Modifying blood type group B to group O
α-GAL, known as B-zyme in this context, has also demonstrated its ability to convert
human blood group B to
human blood group O, which can be transfused to patients of all blood types in the ABO blood group categorization. The current B-zyme used comes from ''
Bacteroides fragilis
''Bacteroides fragilis'' is an anaerobic, Gram-negative, pleomorphic to rod-shaped bacterium. It is part of the normal microbiota of the human colon and is generally commensal, but can cause infection if displaced into the bloodstream or surrou ...
''.
The idea of maintaining a blood supply at healthcare facilities with all non-O units converted to O units is achieved using enzyme-converted to group O technology, first developed in 1982.
Advantages
A blood bank with ECO blood demonstrates the following advantages:
* Compatible with and transfusable to patients of all blood groups
* Reduce the demand for specific ABO blood groups A, B, AB
* Reduce cost of maintaining a blood bank inventory in hospitals
* Reduce blood transfusion reactions due to human error and ABO incompatibility
* Reduce wastage of less needed blood types
Mechanism of Action
Red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
(RBC) surfaces are decorated with the
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s and
glycolipid
Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connec ...
s that have the same basic sequence with terminal sugar α1‐2‐linked
fucose
Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on ''N''-linked glycans on the mammalian, insect and plant cell surface. Fucose is the fundamental sub-unit of the seaweed polysaccharide fucoidan. The α(1→3) li ...
linked to the penultimate
galactose
Galactose (, '' galacto-'' + '' -ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molec ...
. This galactose molecule is called the
H antigen
H antigen can refer to one of various types of antigens having diverse biological functions. H antigen is located on the 19th chromosome in humans, and has a variety of functions and definitions as follows:
* Also known as substance H, H antigen ...
.
Blood type A, B, AB, and O differ only in the sugar (red molecule in the illustration) linked with the penultimate galactose. For blood type B, this linked sugar is an α-1‐3‐linked galactose. Using α-GAL, this terminal galactose molecule can be removed, converting RBC to type O.
Supplements
α-GAL derived from the mold ''
Aspergillus niger
''Aspergillus niger'' is a mold classified within the ''Nigri'' section of the ''Aspergillus'' genus. The ''Aspergillus'' genus consists of common molds found throughout the environment within soil and water, on vegetation, in fecal matter, on de ...
'' is an active ingredient in products marketed to reduce stomach gas production after eating foods known to cause gas. It is optimally active at 55°C, after which its half-life is 120 minutes.
Commercial products with α-galactosidase include:
*
Beano
* CVS BeanAid
* Enzymedica's BeanAssist
* Gasfix
* Bloateez (in India as Cogentrix)
See also
*
β-galactosidase
β-Galactosidase (EC 3.2.1.23, lactase, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase), is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides.
β ...
*
Migalastat
Migalastat, sold under the brand name Galafold, is a medication for the treatment of Fabry disease, a rare genetic disorder. It was developed by Amicus Therapeutics. The US Food and Drug Administration (FDA) granted it orphan drug status in 2004 ...
, a drug targeting α-galactosidase
*
Classification of α-galactosidases (according to CAZy)
References
Further reading
* Republished as:
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External links
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EC 3.2.1
Enzymes
Galactosides
Sanofi
Enzymes of known structure