Alglucosidase alfa, Recombinant Human enzyme acid alpha-glucosidase (GAA)
The product consists of the human enzyme acid alpha-glucosidase (GAA) which is essential for the degradation of glygogen to glucose in lysosomes. It is encoded by the most predominant of nine observed haplotypes of this gene. The product is produced by recombinant DNA technology in a Chinese hamster ovary cell line. The product degrades glycogen by catalyzing the hydrolysis of a-1,4- and a-1,6- glycosidic linkages of lysosomal glycogen. Structurally, the product is a glycoprotein with a calculated mass of 98,008 daltons for the 883 residue mature polypeptide chain, and a total mass of approximately 109,000 daltons, including carbohydrates.
Lyophilized protein should be stored at < -20°C, though stable at room temperature for 3 weeks. Reconstituted protein solution can be stored at 2-8 °C for 1 week. Aliquots of reconstituted samples are stable at < -20°C for 3 months.
For the treatment of Pompe disease (GAA deficiency) in infants and pediatric patients.
Examples of Clinical Use:
Pompe disease (GAA deficiency)
Pompe disease (glycogen storage disease type II, GSD II, glycogenosis type II, acid maltase deficiency) is an inherited disorder of glycogen metabolism caused by the absence or marked deficiency of the lysosomal enzyme GAA. In the infantile-onset form, Pompe disease results in intralysosomal accumulation of glycogen in various tissues, particularly cardiac and skeletal muscles, and hepatic tissues, leading to the development of cardiomyopathy, progressive muscle weakness, and impairment of respiratory function. In the juvenile- and adult-onset forms, intralysosomal accumulation of glycogen is limited primarily to skeletal muscle, resulting in progressive muscle weakness. Death in all forms is usually related to respiratory failure. The product provides an exogenous source of GAA. Binding to mannose-6-phosphate receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in cleaving glycogen.
Mechanism of action:
Alglucosidase alfa is designed to act as an exogenous source of GAA, acting to correct GAA deficiency that is the hallmark of Pompe disease. Alglucosidase alfa binds to mannose-6-phosphate receptors on the cell surface via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in cleaving glycogen. Specifically, it hydrolyses alpha-1,4-glucose bonds.
Acid alpha-glucosidase (GAA) is an enzyme that has gained importance in scientific studies due to its role in various biological pathways and its association with several medical conditions.
Acid alpha-glucosidase is a lysosomal enzyme involved in the degradation of glycogen, discovered in the mid-20th century as research into glycogen storage diseases expanded. It was speculated that a special enzyme could break down glycogen within the cells' lysosomes. Subsequent research led to the discovery of acid alpha-glucosidase, confirming these early hypotheses.
Gene Locus and Protein Structure
The gene locus for GAA is present on chromosome 17, specifically in the q25.2-q25.3 region. The acid alpha-glucosidase protein is composed of 952 amino acids, with five glycosylation sites. The enzyme has two forms distinguished by cleavage at the aminoterminal end; a 76 KDa precursor and a 70 KDA mature form. This cleavage event is essential for the enzyme's transfer to the lysosomes.
Function of GAA
GAA plays a critical role in energy metabolism by breaking down glycogen, a polymeric form of glucose, into glucose monomers within lysosomes. This process, referred to as lysosomal glycogen degradation, is crucial for normal cellular function.
GAA Associated Signaling Pathways
GAA is associated with critical metabolic pathways. For instance, in the lysosomal degradation pathway, GAA is a key player in the breakdown of glycogen. This process is significantly more relevant in cells, such as muscle cells, that rely heavily on glycogen as an energy source. The enzyme's dysfunction could disrupt these pathways, leading to pathological conditions at the cellular and whole organism level.
GAA Related Diseases
The most notable disease linked to GAA is Pompe's disease (also known as Glycogen storage disease type II). It is an autosomal recessive disorder that occurs due to a deficiency in GAA, resulting in the accumulation of lysosomal glycogen in various tissues, predominantly within muscles. Symptoms range from muscle weakness, respiratory problems to heart disease. The severity and onset of symptoms are variable, with forms ranging from severe early onset to a relatively milder late onset.
Application of GAA in Medicine
The critical role of GAA in metabolic pathways and related diseases has driven significant interest in its potential therapeutic uses. Enzyme replacement therapy (ERT) is one such application, where a biologically engineered form of GAA, alglucosidase alfa, is used to treat Pompe's disease. Despite certain limitations, such as immune responses to the therapy, ERT has shown significant improvements in motor function and survival rate in patients.
Drug Candidates related with GAA
While alglucosidase alfa remains the primary drug, several other drug candidates for GAA-related diseases are under investigation, including chaperone therapy and gene therapy. Small molecule chaperones, such as ambroxol, assist in the correct folding of misfolded GAA protein, improving its stability and activity.
Moreover, next-generation therapies such as gene therapy aim to deliver a functional copy of the GAA gene into cells, providing a long-term cure for the disease. These innovative therapeutic strategies highlight the potential of GAA as a therapeutic target for addressing metabolic disorders.
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without prior written approval from Creative BioMart.
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